SURF1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0033617 mitochondrial respiratory chain complex IV assembly	IBA GO_REF:0000033	ACCEPT	Summary: SURF1 is a well-established assembly factor for mitochondrial Complex IV (cytochrome c oxidase). Phylogenetic inference (IBA) based on conserved function from yeast Shy1 through human SURF1 is strongly supported. The founding paper (PMID:9843204) demonstrated that SURF1 mutations cause COX deficiency and concluded "a role for SURF1 in the biogenesis of the COX complex." Subsequent work confirmed SURF1 as a component of the MITRAC complex that regulates COX assembly (PMID:26321642, PMID:23260140). The deep research review (Guaragnella et al., 2024; Luo et al., 2024) further confirms this as the core conserved function across species. Reason: Mitochondrial respiratory chain complex IV assembly is the core biological process of SURF1. This IBA annotation is well-supported by extensive experimental evidence from multiple organisms and is at the correct level of specificity. SURF1/Shy1 has been consistently identified as a CIV assembly factor across yeast, fission yeast, and human studies. Supporting Evidence: PMID:9843204 These data suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease. PMID:26321642 The MITRAC complex represents the central assembly intermediate during this process as it receives imported subunits and regulates mitochondrial translation of COX1 mRNA. file:human/SURF1/SURF1-deep-research-falcon.md Functions as a Complex IV (cytochrome c oxidase) assembly factor required for COX1 maturation and COX assembly; implicated in cofactor (heme/Cu) handling during assembly
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: SURF1 is unambiguously a mitochondrial protein. UniProt annotates it to the mitochondrion inner membrane (by sequence similarity to mouse ortholog P09925). The IBA annotation is conservative (mitochondrion rather than mitochondrial inner membrane), which is acceptable. Proteomics data (PMID:34800366) and structural studies from the yeast homolog (Luo et al., 2024) both confirm mitochondrial localization. Reason: Mitochondrial localization is universally agreed upon. While GO:0005743 (mitochondrial inner membrane) is more specific and also present in the annotation set, having the broader mitochondrion annotation from IBA is acceptable as it is phylogenetically well supported. Supporting Evidence: PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase file:human/SURF1/SURF1-deep-research-falcon.md Localizes to the inner mitochondrial membrane with two transmembrane domains and an intermembrane-space (IMS)-facing region
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	REMOVE	Summary: This IEA annotation was inferred via logical inference from GO:0004129 (cytochrome-c oxidase activity), since cytochrome c oxidase catalyzes proton translocation across the inner mitochondrial membrane. However, SURF1 is NOT a structural subunit of Complex IV and does not itself catalyze proton transport. It is an assembly factor that facilitates the biogenesis of the complex. Proton transmembrane transport is an activity of the assembled Complex IV, not of the assembly factor. Reason: SURF1 does not directly participate in proton transmembrane transport. This annotation derives from the erroneous upstream annotation of cytochrome-c oxidase activity (GO:0004129) to SURF1 via Ensembl Compara. Since SURF1 is an assembly factor and not a catalytic subunit of Complex IV, attributing the catalytic process of proton pumping to SURF1 is incorrect. The assembled complex performs proton translocation; the assembly factor does not.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: SURF1 localizes to the mitochondrial inner membrane as a multi-pass membrane protein with two predicted transmembrane helices (residues 61-79 and 274-290 per UniProt). UniProt annotates this based on sequence similarity to the mouse ortholog P09925. Experimental work in fission yeast Shy1 confirmed IMM localization by mitochondrial fractionation and protease protection assays (Luo et al., 2024). Reactome also places SURF1 at the inner membrane as part of the MITRAC complex (R-HSA-9865350). Reason: Mitochondrial inner membrane localization is the correct and specific CC annotation for SURF1. This is well-supported by UniProt topology predictions (two TM helices), conservation with yeast Shy1 where inner membrane localization was experimentally confirmed, and Reactome pathway curation. Supporting Evidence: file:human/SURF1/SURF1-deep-research-falcon.md Localizes to the inner mitochondrial membrane with two transmembrane domains and an intermembrane-space (IMS)-facing region (experimental in S. pombe; inferred for human) Reactome:R-HSA-9865350 Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62), COA1 (C7orf44, MITRAC15), COA3 (MITRAC12)...SMIM20 (C4orf52, MITRAC7), and SURF1
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: SURF1 is indeed a membrane protein with two predicted transmembrane helices, placed in the mitochondrial inner membrane. The generic GO:0016020 (membrane) annotation from InterPro domain mapping is not wrong but is very unspecific compared to the more precise GO:0005743 (mitochondrial inner membrane) annotations already present. Reason: While very general, this IEA annotation from InterPro is technically correct. SURF1 contains transmembrane domains and is an integral membrane protein. More specific mitochondrial inner membrane annotations are present from other evidence codes. It is acceptable for an IEA to be broader than what is established by more detailed evidence.
GO:0005515 protein binding	IPI PMID:23260140 MITRAC links mitochondrial protein translocation to respirat...	REMOVE	Summary: This IPI annotation is based on physical interaction between SURF1 and COA3 (Q9Y2R0, also known as MITRAC12), identified in the MITRAC complex dissection study by Mick et al. (2012). The study identified SURF1 as part of the MITRAC complex containing COA3, COX14, and other factors required for early cytochrome c oxidase assembly intermediates. While the interaction is biologically meaningful, 'protein binding' is uninformative. Reason: The term 'protein binding' (GO:0005515) is uninformative per GO curation guidelines. The interaction between SURF1 and COA3 within the MITRAC complex is biologically meaningful and supports SURF1's role in CIV assembly, but this is already captured by the process annotations (GO:0033617). A more informative CC annotation to the MITRAC complex (GO:0062011) would better represent this information. Supporting Evidence: PMID:23260140 we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation
GO:0004129 cytochrome-c oxidase activity	IEA GO_REF:0000107	REMOVE	Summary: This IEA annotation was transferred from the mouse ortholog (P09925) via Ensembl Compara. However, SURF1 is NOT a structural or catalytic subunit of cytochrome c oxidase. It is an assembly factor that facilitates the biogenesis of the complex. SURF1 does not itself possess cytochrome-c oxidase enzymatic activity (the catalysis of ferrocytochrome c oxidation coupled to proton pumping). The original paper (PMID:9843204) explicitly states SURF1 encodes "a factor involved in the biogenesis of cytochrome c oxidase," not a subunit with catalytic activity. Reason: This is an incorrect annotation. Cytochrome-c oxidase activity (GO:0004129) describes the catalytic reaction performed by the assembled Complex IV holoenzyme. SURF1 is an assembly factor, not a catalytic subunit. It does not catalyze the reduction of oxygen or pump protons. The Ensembl Compara transfer is erroneous here, likely propagating an annotation from the mouse ortholog that was itself over-annotated. UniProt explicitly describes SURF1 as a "Component of the MITRAC complex that regulates cytochrome c oxidase assembly" (PMID:24027061, PMID:9843204, PMID:26321642), not as having COX catalytic activity. Supporting Evidence: PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. PMID:26321642 The MITRAC complex represents the central assembly intermediate during this process as it receives imported subunits and regulates mitochondrial translation of COX1 mRNA.
GO:0033617 mitochondrial respiratory chain complex IV assembly	IEA GO_REF:0000107	ACCEPT	Summary: This IEA annotation via Ensembl Compara transfers the CIV assembly annotation from the mouse ortholog. Unlike the erroneous cytochrome-c oxidase activity transfer, this annotation is correct: SURF1 does participate in mitochondrial Complex IV assembly. This is consistent with the IBA and IMP annotations for the same term already present. Reason: The Ensembl Compara transfer of Complex IV assembly is correct. This is the core function of SURF1 and is supported by multiple independent evidence lines (IBA, IMP, TAS). The IEA annotation is redundant with these but not incorrect. Supporting Evidence: PMID:9843204 These data suggest a role for SURF1 in the biogenesis of the COX complex
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: SURF1 was identified as part of the high-confidence human mitochondrial proteome by Morgenstern et al. (2021), a comprehensive quantitative proteomics study of the mitochondrial proteome. This HTP evidence confirms mitochondrial localization via mass spectrometry-based identification. Reason: The HTP annotation is based on large-scale quantitative proteomics and is consistent with all other evidence for SURF1 mitochondrial localization. While less specific than the inner membrane annotation, it provides independent experimental support. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865350	ACCEPT	Summary: Reactome places SURF1 at the mitochondrial inner membrane as part of the MITRAC complex in the step where nascent MT-CO1 binds to MITRAC. SURF1 is listed as a subunit of MITRAC alongside CMC1, COX14, COA1, COA3, and SMIM20 (MITRAC7). Reason: The Reactome annotation correctly places SURF1 at the mitochondrial inner membrane, consistent with its topology (two TM helices) and its role as a component of the membrane-bound MITRAC complex. This is well-supported by the Reactome pathway curation. Supporting Evidence: Reactome:R-HSA-9865350 SMIM20 (C4orf52, MITRAC7), and SURF1 (Zhu et al., 1998; Dennerlein et al., 2015).
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865412	ACCEPT	Summary: This Reactome annotation places SURF1 at the inner membrane during the step where TIMM21 carries COX4, COX5A, and COX6C subunits to the MT-CO1:MITRAC complex. SURF1 is part of the MITRAC complex that receives these imported subunits. Reason: Consistent with SURF1 being a component of the inner membrane-bound MITRAC complex that receives imported COX subunits. Duplicate CC annotation from a different Reactome reaction step is acceptable. Supporting Evidence: Reactome:R-HSA-9865412 COX5A and COX6C across the inner membrane, where they bind to the MT-CO1:MITRAC complex
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865449	ACCEPT	Summary: This Reactome annotation places SURF1 at the inner membrane during the copper insertion step into MT-CO1. The Reactome entry for this step describes a metallochaperone complex that inserts Cu2+ into MT-CO1, and SURF1 is present in the broader assembly context at this stage. Reason: Consistent with SURF1 inner membrane localization during the COX assembly pathway. The copper insertion step occurs at the inner membrane where the assembly intermediates reside. Supporting Evidence: Reactome:R-HSA-9865449 A metallochaperone complex... carries a copper cation from the outer side of the inner mitochondrial membrane... to the pre-assembled Complex IV on the inner side of the membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865579	ACCEPT	Summary: This Reactome annotation places SURF1 at the inner membrane during the step where MT-CO1 and MT-CO2 complexes associate and heme moieties are installed. Reactome specifically notes that "the SURF1 subunit of MITRAC may act as an additional chaperone, for which there is evidence in bacterial models." This is a key step where SURF1 may directly facilitate heme a insertion. Reason: Consistent with SURF1 inner membrane localization, and this Reactome entry provides important mechanistic context suggesting SURF1 may function as a heme insertion chaperone during COX assembly. This is well-aligned with the proposed role of SURF1/Shy1 in heme a insertion into COX1. Supporting Evidence: Reactome:R-HSA-9865579 the SURF1 subunit of MITRAC may act as an additional chaperone, for which there is evidence in bacterial models (Smith et al., 2005; Bundschuh et al., 2009). Mutations in SURF1 lead to complex IV deficiency
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865663	ACCEPT	Summary: This Reactome annotation places SURF1 at the inner membrane during the final Complex IV assembly step where MT-CO3, COX6A/B, COX7A, and NDUFA4 bind to the holo-MT-CO1,2 complex. SURF1 is not specifically mentioned in this final step description, suggesting it may no longer be part of the complex at this late stage. Reason: Inner membrane localization is correct for SURF1. While the Reactome entry for this specific step does not explicitly mention SURF1, the protein remains at the inner membrane. The annotation is not wrong, though SURF1 likely acts at earlier assembly stages (COX1 module) rather than this final step. Supporting Evidence: Reactome:R-HSA-9865663 The final assembly of Complex IV consists of binding of the MT-CO3, COX6A, COX6B, COX7A, and NDUFA4 subunits to the holo-MT-CO1, MT-CO2 complex
GO:0005515 protein binding	IPI PMID:26321642 MITRAC7 Acts as a COX1-Specific Chaperone and Reveals a Chec...	REMOVE	Summary: This IPI annotation is based on physical interactions identified in Dennerlein et al. (2015), which found SURF1 interacting with MT-CO1 (P00395), COX6B1 (P14854/P13073), MITRAC7/SMIM20 (Q8N5G0), and COA3/MITRAC12 (Q9Y2R0) within the MITRAC complex. The UniProt INTERACTION section confirms SURF1 interaction with COA3 (6 experiments in IntAct). These are specific interactions within the COX assembly machinery. Reason: While the physical interactions are experimentally validated and biologically meaningful, 'protein binding' (GO:0005515) is uninformative per GO curation guidelines. The interactions of SURF1 with COA3, MITRAC7, and COX1 within the MITRAC complex are better captured by process annotations (GO:0033617) and a CC annotation to the MITRAC pre-assembly complex (GO:0062011). A new CC annotation for the MITRAC complex is proposed below. Supporting Evidence: PMID:26321642 Cytochrome c oxidase, the terminal enzyme of the respiratory chain, is assembled from mitochondria- and nuclear-encoded subunits. The MITRAC complex represents the central assembly intermediate during this process PMID:23260140 we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation
GO:0033617 mitochondrial respiratory chain complex IV assembly	IMP PMID:24027061 SURF1 deficiency causes demyelinating Charcot-Marie-Tooth di...	ACCEPT	Summary: This IMP annotation is based on Echaniz-Laguna et al. (2013), which demonstrated that SURF1 mutations cause defective Complex IV assembly and activity. The study identified SURF1 mutations in patients with CMT4 and showed that "complex IV remained partially functional in muscle and fibroblasts" but was reduced, with SURF1 absence confirmed. The c.107-2A>G mutation "produced no normally spliced transcript, leading to SURF1 absence." This is direct mutant phenotype evidence for SURF1 role in CIV assembly. Reason: This is strong IMP evidence demonstrating that loss of SURF1 causes impaired Complex IV assembly. The study shows that SURF1 mutations lead to reduced Complex IV activity and assembly, providing direct genetic evidence for the annotation. This is the core function of SURF1. Supporting Evidence: PMID:24027061 The c.107-2A>G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. PMID:24027061 encoding an assembly factor of the mitochondrial respiratory chain complex IV
GO:0008535 respiratory chain complex IV assembly	TAS PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytoc...	MODIFY	Summary: This TAS annotation is based on the founding SURF1 paper by Zhu et al. (1998), which identified SURF1 as "a factor involved in the biogenesis of cytochrome c oxidase." GO:0008535 (respiratory chain complex IV assembly) is the parent term of GO:0033617 (mitochondrial respiratory chain complex IV assembly). Since SURF1 specifically functions in the mitochondrial context, the more specific child term GO:0033617 is more appropriate. Reason: GO:0008535 (respiratory chain complex IV assembly) is the broader parent term that also covers bacterial/plasma membrane CIV assembly. Since human SURF1 specifically functions in mitochondrial CIV assembly, the more specific term GO:0033617 (mitochondrial respiratory chain complex IV assembly) is preferred. This term is already annotated via IBA, IEA, and IMP evidence, so this is a specificity refinement. Proposed replacements: mitochondrial respiratory chain complex IV assembly Supporting Evidence: PMID:9843204 These data suggest a role for SURF1 in the biogenesis of the COX complex
GO:0009060 aerobic respiration	TAS PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytoc...	MARK AS OVER ANNOTATED	Summary: This TAS annotation to aerobic respiration is based on the founding SURF1 paper. While SURF1 loss does impair aerobic respiration (because Complex IV is the terminal enzyme of the electron transport chain), SURF1 is an assembly factor, not a direct participant in the respiratory process itself. The aerobic respiration annotation represents an over-annotation; the correct primary annotation is to Complex IV assembly. The downstream consequences of impaired CIV assembly include impaired aerobic respiration, but that does not mean SURF1 is directly "involved_in" aerobic respiration. Reason: SURF1 facilitates the assembly of Complex IV, which is required for aerobic respiration. However, SURF1 does not directly participate in the respiratory chain or electron transport. Annotating an assembly factor to the process carried out by the assembled complex is an over-annotation. The correct annotation is to Complex IV assembly (GO:0033617), which is already present. The relationship between SURF1 and aerobic respiration is indirect (assembly factor -> complex -> process). Supporting Evidence: PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. file:human/SURF1/SURF1-deep-research-falcon.md Functions as a Complex IV (cytochrome c oxidase) assembly factor required for COX1 maturation and COX assembly
GO:0098803 respiratory chain complex	TAS PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytoc...	MODIFY	Summary: This TAS annotation places SURF1 as a component of the "respiratory chain complex." GO:0098803 is defined as "any protein complex that is part of a respiratory chain." SURF1 is NOT a structural subunit of the mature respiratory chain Complex IV. It is an assembly factor that transiently associates with assembly intermediates (MITRAC complex) but is not part of the final assembled complex. The founding paper (PMID:9843204) describes SURF1 as "a factor involved in the biogenesis of cytochrome c oxidase," not as a component of the respiratory chain. Reason: SURF1 is not a structural subunit of the respiratory chain. It is a component of the MITRAC complex, which is a transient assembly intermediate, not the mature respiratory chain complex. The correct CC annotation would be to the mitochondrial respiratory chain complex IV pre-assembly complex (GO:0062011), which describes the MITRAC complex where SURF1 resides. Annotating SURF1 to GO:0098803 (respiratory chain complex) incorrectly implies it is a structural component of the electron transport chain. Proposed replacements: mitochondrial respiratory chain complex IV pre-assembly complex Supporting Evidence: PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase PMID:23260140 we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation and reveal assembly factors promoting biogenesis of human respiratory-chain complexes PMID:26321642 The MITRAC complex represents the central assembly intermediate during this process as it receives imported subunits and regulates mitochondrial translation of COX1 mRNA.
GO:0062011 mitochondrial respiratory chain complex IV pre-assembly complex	IPI PMID:23260140 MITRAC links mitochondrial protein translocation to respirat...	NEW	Summary: SURF1 is a component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase) complex. This was established by Mick et al. (2012, PMID:23260140), who identified SURF1 as part of early COX assembly intermediates. Dennerlein et al. (2015, PMID:26321642) further confirmed SURF1 presence in the MITRAC complex. UniProt states SURF1 is a "Component of the MITRAC complex." Reactome (R-HSA-9865350) explicitly lists SURF1 as a MITRAC subunit alongside CMC1, COX14, COA1, COA3, and SMIM20. GO:0062011 is defined as "A protein complex that contributes to and regulates mitochondrial respiratory chain complex IV (COX) formation." Reason: This CC annotation is missing from the current annotation set and would accurately capture SURF1's localization within the MITRAC complex. This is more informative than the generic 'respiratory chain complex' (GO:0098803) currently annotated. The MITRAC complex is the specific subcompartment where SURF1 functions, and GO:0062011 was created to describe this complex. Supporting Evidence: PMID:23260140 we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation PMID:26321642 The MITRAC complex represents the central assembly intermediate during this process as it receives imported subunits and regulates mitochondrial translation of COX1 mRNA. Reactome:R-HSA-9865350 SMIM20 (C4orf52, MITRAC7), and SURF1 (Zhu et al., 1998; Dennerlein et al., 2015).

Core Functions

SURF1 functions as an assembly factor for mitochondrial cytochrome c oxidase (Complex IV), acting within the MITRAC complex during early COX1-module assembly. It may facilitate heme a insertion into COX1 or stabilize COX1 assembly intermediates. The precise molecular function is not yet fully characterized; evidence from bacterial models suggests a possible role as a heme insertion chaperone, but this has not been confirmed for the human protein.

Directly Involved In:

mitochondrial respiratory chain complex IV assembly

Cellular Locations:

mitochondrial inner membrane

In Complex:

mitochondrial respiratory chain complex IV pre-assembly complex

Supporting Evidence:

PMID:9843204
These data suggest a role for SURF1 in the biogenesis of the COX complex
PMID:26321642
The MITRAC complex represents the central assembly intermediate during this process
PMID:24027061
encoding an assembly factor of the mitochondrial respiratory chain complex IV
Reactome:R-HSA-9865579
the SURF1 subunit of MITRAC may act as an additional chaperone, for which there is evidence in bacterial models

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

PMID:23260140

MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation.

SURF1 is a component of early cytochrome c oxidase assembly intermediates termed MITRAC complexes, which link mitochondrial protein translocation to respiratory chain assembly.

"we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation and reveal assembly factors promoting biogenesis of human respiratory-chain complexes"

PMID:24027061

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease.

SURF1 mutations cause impaired Complex IV assembly and activity, leading to both Leigh syndrome and CMT4K. The c.107-2A>G mutation leads to SURF1 absence, and complex IV remains partially functional but reduced.

"The c.107-2A>G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts."

PMID:26321642

MITRAC7 Acts as a COX1-Specific Chaperone and Reveals a Checkpoint during Cytochrome c Oxidase Assembly.

SURF1 is part of the MITRAC complex that represents the central assembly intermediate for cytochrome c oxidase. SURF1 interacts with COA3, MITRAC7/SMIM20, and COX1 within this complex.

"The MITRAC complex represents the central assembly intermediate during this process as it receives imported subunits and regulates mitochondrial translation of COX1 mRNA."

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

SURF1 was identified as part of the high-confidence human mitochondrial proteome by quantitative mass spectrometry.

"Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context."

PMID:9843204

SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome.

Founding paper identifying SURF1 as a factor in COX biogenesis. Multiple SURF1 mutations identified in Leigh syndrome patients, all predicting truncated protein. Established SURF1 as required for COX assembly.

"These data suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease."

Reactome:R-HSA-9865350

Nascent MT-CO1 binds to MITRAC, Mg2+, PE, CL

SURF1 is listed as a subunit of the MITRAC complex alongside CMC1, COX14, COA1, COA3, and SMIM20 in the step where nascent MT-CO1 binds to MITRAC.

"SMIM20 (C4orf52, MITRAC7), and SURF1 (Zhu et al., 1998; Dennerlein et al., 2015)."

Reactome:R-HSA-9865412

TIMM21 carries COX4, COX5A, COX6C to MT-CO1:MITRAC

SURF1 is part of the MT-CO1:MITRAC complex that receives imported COX subunits carried by TIMM21 across the inner membrane.

"COX5A and COX6C across the inner membrane, where they bind to the MT-CO1:MITRAC complex"

Reactome:R-HSA-9865449

Metallochaperone inserts Cu2+ into MT-CO1

SURF1 is present at the inner membrane during copper insertion into MT-CO1 by the metallochaperone complex.

"carries a copper cation from the outer side of the inner mitochondrial membrane"

Reactome:R-HSA-9865579

MT-CO1 and MT-CO2 complexes associate, installing heme moieties

Reactome notes that SURF1 may act as an additional chaperone for heme insertion, with evidence from bacterial models. Mutations in SURF1 lead to Complex IV deficiency.

"the SURF1 subunit of MITRAC may act as an additional chaperone, for which there is evidence in bacterial models"

Reactome:R-HSA-9865663

MT-CO3, COX6A,B,7A and NDUFA4 bind to holo-MT-CO1,2 complex

Final assembly step of Complex IV. SURF1 is not specifically mentioned in this late assembly step, consistent with its role at earlier stages.

"The final assembly of Complex IV consists of binding of the MT-CO3, COX6A, COX6B, COX7A, and NDUFA4 subunits to the holo-MT-CO1, MT-CO2 complex"

file:human/SURF1/SURF1-deep-research-falcon.md

Deep research review of SURF1 gene function

SURF1 is a conserved IMM assembly factor required for proper biogenesis of cytochrome c oxidase (Complex IV), likely acting at COX1-module maturation/assembly and interfacing with metal/cofactor handling machinery. Biallelic SURF1 variants produce a reproducible Leigh syndrome phenotype with Complex IV deficiency.

Deep Research

Falcon

(SURF1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 24 citations 2026-02-11T07:58:25.341394

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: SURF1 (UniProt Q15526) — human cytochrome c oxidase assembly factor

Identity verification and key concepts
- Identity and family: SURF1 encodes Surfeit locus protein 1, a conserved member of the SURF1 (Surf1/Shy1) family implicated in mitochondrial cytochrome c oxidase (Complex IV, CIV) biogenesis. Comparative analyses with fungal homologs (Shy1) demonstrate a conserved SURF1 domain and a closely conserved 3D fold across yeast and human orthologs, supporting shared function (Luo et al., 2024; Scientific Reports; published Sep 2024; https://doi.org/10.1038/s41598-024-72681-9) (luo2024characterizationofshy1 pages 3-4, luo2024characterizationofshy1 pages 1-2). Yeast-focused reviews similarly place SURF1/SHY1 among core assembly factors for COX (Guaragnella et al., 2024; Int J Mol Sci; Mar 2024; https://doi.org/10.3390/ijms25073814) (guaragnella2024morethanjust pages 2-4, guaragnella2024morethanjust pages 21-22).
- Localization and topology: Experimental work in fission yeast shows the SURF1 homolog (Shy1) is an inner mitochondrial membrane (IMM) protein bearing two transmembrane helices with an intermembrane space–facing region, established by mitochondrial fractionation, protease-protection, and alkaline extraction; these findings support analogous topology for human SURF1 given structural conservation (Luo et al., 2024; Sci Rep; Sep 2024; https://doi.org/10.1038/s41598-024-72681-9) (luo2024characterizationofshy1 pages 4-6, luo2024characterizationofshy1 pages 3-4, luo2024characterizationofshy1 pages 1-2).

Primary molecular function and pathways
- Role in Complex IV biogenesis: Multiple lines of evidence position SURF1 as an assembly factor essential for the maturation/assembly of Complex IV, particularly linked to COX1 module assembly and cofactor installation steps. Yeast genetics and patient-derived studies demonstrate that SURF1/SHY1 loss reduces COX abundance/activity and perturbs COX1 expression and assembly, with literature implicating SURF1 in steps related to heme/Cu center maturation during COX1 processing (Guaragnella et al., 2024; Int J Mol Sci; https://doi.org/10.3390/ijms25073814) (guaragnella2024morethanjust pages 2-4, guaragnella2024morethanjust pages 21-22). Fission yeast Shy1 interacts with COX structural subunits (Cox5, Cox6) and assembly factors (e.g., Sco1, Pet117; some analyses also point to Cox14/COA3-related factors), and its deletion reduces Complex IV abundance on BN-PAGE, strengthening evidence for a direct role in CIV biogenesis (Luo et al., 2024; Sci Rep; https://doi.org/10.1038/s41598-024-72681-9) (luo2024characterizationofshy1 pages 4-6, luo2024characterizationofshy1 pages 3-4, luo2024characterizationofshy1 pages 1-2).
- Supercomplex linkage: Co-immunoprecipitation of Shy1 with Rip1 (Complex III subunit) and BN-PAGE analyses suggest SURF1-family proteins may influence, or operate within, respiratory supercomplex assembly contexts, integrating CIV assembly with higher-order complexes (Luo et al., 2024; Sci Rep; https://doi.org/10.1038/s41598-024-72681-9) (luo2024characterizationofshy1 pages 4-6, luo2024characterizationofshy1 pages 1-2).

Recent developments and latest research (2023–2024)
- Mechanistic advances: Updated yeast-based syntheses emphasize modular assembly of CIV and the centrality of assembly factors like SURF1/SHY1 in COX1-module maturation and coordination with metal/cofactor handling (Guaragnella et al., 2024; Int J Mol Sci; https://doi.org/10.3390/ijms25073814) (guaragnella2024morethanjust pages 2-4, guaragnella2024morethanjust pages 21-22). Fission yeast work adds conserved topology, direct partner interactions, and supercomplex links (Luo et al., 2024; Sci Rep; https://doi.org/10.1038/s41598-024-72681-9) (luo2024characterizationofshy1 pages 4-6, luo2024characterizationofshy1 pages 3-4, luo2024characterizationofshy1 pages 1-2).
- Model systems: Cross-species models—from budding and fission yeasts to mouse and human cellular systems—remain pivotal. 2023 symposium reporting highlighted Surf1 knockout mouse rescue by AAV9-mediated human SURF1 expression (see Applications/Therapeutics) and ongoing build-out of patient-derived iPSC models for screening (Moreira et al., 2023; Orphanet J Rare Dis; Nov 2023; https://doi.org/10.1186/s13023-023-02871-7) (moreira2023teamworkmakesthe pages 1-2, moreira2023teamworkmakesthe pages 2-4). Emerging organoid and deep-learning screening platforms target Leigh syndrome neuromorphogenesis defects, with hits improving neuronal differentiation and lactate phenotypes (Menacho et al., 2024; bioRxiv; Jul 2024; https://doi.org/10.1101/2024.07.08.602501) (menacho2024deeplearningdrivenneuromorphogenesis pages 1-5).

Disease association, clinical context, and statistics
- Disease mechanism and phenotype: Biallelic pathogenic variants in SURF1 are a recurrent cause of nuclear-encoded Leigh syndrome with Complex IV deficiency, typically presenting in infancy/early childhood with neurometabolic deterioration (Moreira et al., 2023; Orphanet J Rare Dis; https://doi.org/10.1186/s13023-023-02871-7) (moreira2023teamworkmakesthe pages 1-2). Contemporary reviews and advocacy-led summaries consistently trace SURF1 to COX deficiency and Leigh spectrum disease burden, while noting variable genotype–phenotype expressivity (Guaragnella et al., 2024; Int J Mol Sci; https://doi.org/10.3390/ijms25073814) (guaragnella2024morethanjust pages 21-22).
- Registry and natural history resources: The Leigh Syndrome Global Patient Registry (Cure Mito Foundation) provides structured, IRB-approved data capture for diagnosis, symptoms, milestone loss, healthcare utilization, and quality of life, enabling clinical trial readiness and natural history analysis; advocacy literature underlines its central role for recruitment and data standardization (Moreira et al., 2023; Orphanet J Rare Dis; https://doi.org/10.1186/s13023-023-02871-7; Zilber et al., 2025; Research Involvement & Engagement; https://doi.org/10.1186/s40900-025-00808-x) (moreira2023teamworkmakesthe pages 2-4, zilber2025expandingresearchand pages 5-6, zilber2025expandingresearchand pages 13-14). These resources complement variant curation frameworks and broader mitochondrial repositories cited by expert reviews (Frontiers in Bioscience-Scholar; Dec 2025; https://doi.org/10.31083/fbs45427) (shen2025thepathto pages 14-15).

Current applications and real-world implementations
- Diagnostics and variant interpretation: Yeast models and cross-species complementation remain practical for testing SURF1 variant pathogenicity within CIV assembly frameworks (Guaragnella et al., 2024; Int J Mol Sci; https://doi.org/10.3390/ijms25073814) (guaragnella2024morethanjust pages 2-4, guaragnella2024morethanjust pages 21-22). Patient registries support natural history baselines, outcome measure development, and trial enrollment logistics (Moreira et al., 2023; OJRD; https://doi.org/10.1186/s13023-023-02871-7; Zilber et al., 2025; RIE; https://doi.org/10.1186/s40900-025-00808-x) (moreira2023teamworkmakesthe pages 2-4, zilber2025expandingresearchand pages 5-6, zilber2025expandingresearchand pages 13-14).
- Preclinical gene therapy: Symposium-reported mouse studies showed that AAV9-mediated delivery of human SURF1 restored Surf1 expression and normalized mitochondrial dysfunction metrics, including Complex IV levels and lactic acidosis, in Surf1 knockout mice (Moreira et al., 2023; OJRD; https://doi.org/10.1186/s13023-023-02871-7) (moreira2023teamworkmakesthe pages 2-4). Additional advocacy/review sources document an AAV-based SURF1 gene-replacement program (AAV5/AAV9 vectors reported in earlier preclinical literature) that advanced toward development, including licensing and orphan/rare pediatric designations (Zilber et al., 2025; RIE; https://doi.org/10.1186/s40900-025-00808-x) (zilber2025expandingresearchand pages 13-13, zilber2025expandingresearchand pages 13-14).
- Drug repurposing and screening: Deep learning–driven neuromorphogenesis screening in Leigh cerebral organoids identified azole compounds (e.g., Talarozole, Sertaconazole) that improved neuronal commitment/branching and lowered lactate release; a complementary yeast survival screen supported convergence on these classes, illustrating an end-to-end pipeline from organoid phenotyping to candidate selection (Menacho et al., 2024; bioRxiv; Jul 2024; https://doi.org/10.1101/2024.07.08.602501) (menacho2024deeplearningdrivenneuromorphogenesis pages 1-5). Symposium reporting describes additional iPSC-based screening and transcriptomic precision-medicine platforms applied to SURF1 patient-derived cells (Moreira et al., 2023; OJRD; https://doi.org/10.1186/s13023-023-02871-7) (moreira2023teamworkmakesthe pages 2-4).

Expert opinions and consensus perspectives
- Community and expert synthesis underscore that SURF1 is central to CIV biogenesis and that cross-model validation (yeast→mouse→human iPSC/organoid) is essential for variant interpretation and therapeutic discovery (Guaragnella et al., 2024; Int J Mol Sci; https://doi.org/10.3390/ijms25073814) (guaragnella2024morethanjust pages 2-4, guaragnella2024morethanjust pages 21-22). Patient-led networks are catalyzing data standards, registries, and translational programs for Leigh syndrome, including SURF1-focused initiatives and gene therapy development (Moreira et al., 2023; OJRD; https://doi.org/10.1186/s13023-023-02871-7; Zilber et al., 2025; RIE; https://doi.org/10.1186/s40900-025-00808-x) (moreira2023teamworkmakesthe pages 1-2, zilber2025expandingresearchand pages 5-6, zilber2025expandingresearchand pages 13-14).

Relevant statistics and recent data
- Genetic heterogeneity: Expert summaries report that Leigh syndrome is caused by pathogenic variants across more than a hundred genes, emphasizing the importance of gene-specific natural history and outcome measures; registry efforts document high disease burden and rapid time-to-diagnosis, facilitating trial readiness (Moreira et al., 2023; OJRD; https://doi.org/10.1186/s13023-023-02871-7; Zilber et al., 2025; RIE; https://doi.org/10.1186/s40900-025-00808-x) (moreira2023teamworkmakesthe pages 1-2, moreira2023teamworkmakesthe pages 2-4, zilber2025expandingresearchand pages 5-6, zilber2025expandingresearchand pages 13-14).
- Model-derived efficacy signals: In Surf1-deficient mice, AAV9-SURF1 restored CIV levels and reduced lactic acidosis (as reported in the 2023 symposium review), providing quantitative directions for biomarker selection in translational studies (Moreira et al., 2023; OJRD; https://doi.org/10.1186/s13023-023-02871-7) (moreira2023teamworkmakesthe pages 2-4). In Leigh organoids, azole-class compounds improved neurite organization and decreased lactate release, offering measurable phenotypic readouts for candidate advancement (Menacho et al., 2024; bioRxiv; https://doi.org/10.1101/2024.07.08.602501) (menacho2024deeplearningdrivenneuromorphogenesis pages 1-5).

Structured evidence summary
| Topic | Key finding / claim | Model / system | Evidence type | Source (authors, year); URL |
|---|---|---|---|---|
| Identity / family & domains | SURF1 is a conserved SURF1-family (Surf1/Shy1) protein with conserved motifs and structural similarity to yeast homologs | Human and yeast comparative analyses; AlphaFold/structural alignments | Structural modelling and bioinformatics, comparative proteomics | Luo et al., 2024; https://doi.org/10.1038/s41598-024-72681-9 (luo2024characterizationofshy1 pages 3-4); Guaragnella et al., 2024; https://doi.org/10.3390/ijms25073814 (guaragnella2024morethanjust pages 2-4) |
| IMM localization & topology | Localizes to the inner mitochondrial membrane with two transmembrane domains and an intermembrane-space (IMS)–facing region (experimental in S. pombe; inferred for human) | S. pombe Shy1 (mitochondrial fractionation, protease protection); TM predictions | Subcellular fractionation, protease protection assays, topology prediction | Luo et al., 2024; https://doi.org/10.1038/s41598-024-72681-9 (luo2024characterizationofshy1 pages 4-6, luo2024characterizationofshy1 pages 3-4) |
| Primary function in Complex IV biogenesis | Functions as a Complex IV (cytochrome c oxidase) assembly factor required for COX1 maturation and COX assembly; implicated in cofactor (heme/Cu) handling during assembly | Human patient cells and multiple yeast models (S. cerevisiae, S. pombe) | Genetic and biochemical assays, functional complementation, review synthesis | Guaragnella et al., 2024; https://doi.org/10.3390/ijms25073814 (guaragnella2024morethanjust pages 2-4, guaragnella2024morethanjust pages 21-22); Luo et al., 2024 (luo2024characterizationofshy1 pages 3-4) |
| Interactions & supercomplex links | Physically associates with COX structural subunits and assembly factors (e.g., Cox5/Cox6, Cox10, Sco1) and co-immunoprecipitates with a Complex III subunit (Rip1), suggesting involvement in supercomplex assembly | S. pombe co-immunoprecipitation and BN-PAGE analyses | Co-immunoprecipitation, BN-PAGE | Luo et al., 2024; https://doi.org/10.1038/s41598-024-72681-9 (luo2024characterizationofshy1 pages 4-6, luo2024characterizationofshy1 pages 3-4) |
| Disease association (Leigh syndrome) | Biallelic SURF1 loss-of-function variants are a frequent cause of nuclear-encoded Leigh syndrome characterized by COX deficiency and neurometabolic disease | Human clinical genetics and cohort/review data | Clinical genetics, natural history reviews | Moreira et al., 2023; https://doi.org/10.1186/s13023-023-02871-7 (moreira2023teamworkmakesthe pages 1-2); Guaragnella et al., 2024 (guaragnella2024morethanjust pages 21-22) |
| Recent models & platforms | Validated and emerging models: S. cerevisiae and S. pombe (Shy1) for mechanistic dissection; Surf1 knockout mice recapitulate COX deficiency; human iPSC and organoid models enable patient-specific studies and drug screens | Yeast (S. cerevisiae, S. pombe), mouse models, human iPSC/organoids | Experimental model systems, review compilations | Luo et al., 2024; https://doi.org/10.1038/s41598-024-72681-9 (luo2024characterizationofshy1 pages 3-4); Moreira et al., 2023 (moreira2023teamworkmakesthe pages 1-2); registry/model summaries (zilber2025expandingresearchand pages 13-13) |
| Diagnostics & registries | Patient registries and advocacy-led natural-history efforts (e.g., Cure Mito / Leigh registry) compile clinical data to support variant interpretation and trial recruitment | Global patient registry, advocacy networks | Registry reports, community-led publications | Zilber et al. / Cure Mito registry reports and community reviews; https://doi.org/10.1186/s13023-023-02886-0 (registry) and Moreira et al., 2023 (moreira2023teamworkmakesthe pages 1-2, zilber2025expandingresearchand pages 13-13) |
| Therapeutic approaches | Preclinical AAV9-based SURF1 gene-replacement showed proof-of-concept rescue in mouse models; iPSC/organoid and deep-learning/repurposing screens identify candidate drugs | Mouse AAV9 preclinical studies; human iPSC screens; preprints (bioRxiv) | Preclinical gene therapy, drug-repurposing screens and preclinical proofs-of-concept | AAV9/hSURF1 preclinical reports and symposium summaries (luo2024characterizationofshy1 pages 1-2, luo2024characterizationofshy1 pages 3-4, moreira2023teamworkmakesthe pages 1-2, zilber2025expandingresearchand pages 13-13) |

Table: A compact 2023–2024 evidence table summarizing key claims about human SURF1 (Q15526): identity, localization, molecular role in Complex IV assembly, interactions, disease linkage, models, registries, and preclinical therapeutic approaches with sources and URLs.

Notes on gene/protein identity verification
- The gene symbol SURF1 (human) matches UniProt Q15526 (Surfeit locus protein 1). Recent mechanistic studies on SURF1 homologs in S. pombe and S. cerevisiae (Shy1) corroborate family/domain assignments (SURF1/Surf1-Shy1 domain) and inner mitochondrial membrane localization with two TMs and an IMS-facing domain, consistent with UniProt domain annotations (Luo et al., 2024; Sci Rep; https://doi.org/10.1038/s41598-024-72681-9; Guaragnella et al., 2024; Int J Mol Sci; https://doi.org/10.3390/ijms25073814) (luo2024characterizationofshy1 pages 4-6, luo2024characterizationofshy1 pages 3-4, luo2024characterizationofshy1 pages 1-2, guaragnella2024morethanjust pages 2-4, guaragnella2024morethanjust pages 21-22).

Conclusion
- SURF1 is a conserved IMM assembly factor required for proper biogenesis of cytochrome c oxidase (Complex IV), likely acting at COX1-module maturation/assembly and interfacing with metal/cofactor handling machinery. Cross-model evidence—from yeast homologs to mammalian systems—supports this role, and recent work adds potential linkage to supercomplex assembly. Clinically, biallelic SURF1 variants produce a reproducible Leigh syndrome phenotype with Complex IV deficiency. Translational momentum includes AAV-based gene-replacement proof-of-concept in Surf1-null mice and organoid-based deep-learning screens nominating repurposable compounds that rescue neuronal and metabolic readouts, all supported by expanding patient registries and advocacy-led infrastructures essential for natural history and trial readiness (Luo et al., 2024; Guaragnella et al., 2024; Moreira et al., 2023; Zilber et al., 2025; Menacho et al., 2024) (luo2024characterizationofshy1 pages 4-6, luo2024characterizationofshy1 pages 3-4, luo2024characterizationofshy1 pages 1-2, guaragnella2024morethanjust pages 2-4, guaragnella2024morethanjust pages 21-22, moreira2023teamworkmakesthe pages 1-2, zilber2025expandingresearchand pages 5-6, zilber2025expandingresearchand pages 13-14, menacho2024deeplearningdrivenneuromorphogenesis pages 1-5).

References

(luo2024characterizationofshy1 pages 3-4): Ying Luo, Yuanqi Xu, Fawad Ahmad, Gang Feng, and Ying Huang. Characterization of shy1, the schizosaccharomyces pombe homolog of human surf1. Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-72681-9, doi:10.1038/s41598-024-72681-9. This article has 6 citations and is from a peer-reviewed journal.
(luo2024characterizationofshy1 pages 1-2): Ying Luo, Yuanqi Xu, Fawad Ahmad, Gang Feng, and Ying Huang. Characterization of shy1, the schizosaccharomyces pombe homolog of human surf1. Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-72681-9, doi:10.1038/s41598-024-72681-9. This article has 6 citations and is from a peer-reviewed journal.
(guaragnella2024morethanjust pages 2-4): Nicoletta Guaragnella, T. Cervelli, Bel é m Sampaio-Marques, Chenelle A. Caron-Godon, Emma Collington, Jessica L. Wolf, Genna Coletta, and D. M. Glerum. More than just bread and wine: using yeast to understand inherited cytochrome oxidase deficiencies in humans. International Journal of Molecular Sciences, 25:3814, Mar 2024. URL: https://doi.org/10.3390/ijms25073814, doi:10.3390/ijms25073814. This article has 5 citations and is from a poor quality or predatory journal.
(guaragnella2024morethanjust pages 21-22): Nicoletta Guaragnella, T. Cervelli, Bel é m Sampaio-Marques, Chenelle A. Caron-Godon, Emma Collington, Jessica L. Wolf, Genna Coletta, and D. M. Glerum. More than just bread and wine: using yeast to understand inherited cytochrome oxidase deficiencies in humans. International Journal of Molecular Sciences, 25:3814, Mar 2024. URL: https://doi.org/10.3390/ijms25073814, doi:10.3390/ijms25073814. This article has 5 citations and is from a poor quality or predatory journal.
(luo2024characterizationofshy1 pages 4-6): Ying Luo, Yuanqi Xu, Fawad Ahmad, Gang Feng, and Ying Huang. Characterization of shy1, the schizosaccharomyces pombe homolog of human surf1. Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-72681-9, doi:10.1038/s41598-024-72681-9. This article has 6 citations and is from a peer-reviewed journal.
(moreira2023teamworkmakesthe pages 1-2): Jesse D. Moreira, Karan K. Smith, Sophia Zilber, Kasey Woleben, and Jessica L. Fetterman. Teamwork makes the dream work: functional collaborations between families, scientists, and healthcare providers to drive progress in the treatment of leigh syndrome. Orphanet Journal of Rare Diseases, Nov 2023. URL: https://doi.org/10.1186/s13023-023-02871-7, doi:10.1186/s13023-023-02871-7. This article has 1 citations and is from a peer-reviewed journal.
(moreira2023teamworkmakesthe pages 2-4): Jesse D. Moreira, Karan K. Smith, Sophia Zilber, Kasey Woleben, and Jessica L. Fetterman. Teamwork makes the dream work: functional collaborations between families, scientists, and healthcare providers to drive progress in the treatment of leigh syndrome. Orphanet Journal of Rare Diseases, Nov 2023. URL: https://doi.org/10.1186/s13023-023-02871-7, doi:10.1186/s13023-023-02871-7. This article has 1 citations and is from a peer-reviewed journal.
(menacho2024deeplearningdrivenneuromorphogenesis pages 1-5): Carmen Menacho, Satoshi Okawa, Iris Álvarez-Merz, Annika Wittich, Mikel Muñoz-Oreja, Pawel Lisowski, Tancredi Massimo Pentimalli, Agnieszka Rybak-Wolf, Gizem Inak, Shiri Zakin, Mathuravani Thevandavakkam, Laura Petersilie, Andrea Zaliani, Barbara Mlody, Annette Seibt, Justin Donnelly, Kasey Woleben, Jose Fernandez-Checa, Diran Herebian, Ertan Mayatepek, Nikolaus Rajewsky, Antonella Spinazzola, Markus Schuelke, Ethan Perlstein, Andrea Rossi, Felix Distelmaier, Ian J. Holt, Ole Pless, Christine R. Rose, Antonio Del Sol, and Alessandro Prigione. Deep learning-driven neuromorphogenesis screenings identify repurposable drugs for mitochondrial disease. BioRxiv, Jul 2024. URL: https://doi.org/10.1101/2024.07.08.602501, doi:10.1101/2024.07.08.602501. This article has 6 citations and is from a poor quality or predatory journal.
(zilber2025expandingresearchand pages 5-6): Sophia Zilber, Melinda Burnworth, Titilola Afolabi, Jonathan R. Brestoff, Michal Minczuk, Alejandro Rodriguez Luis, Qinglan Ling, Alessandro Prigione, Isabella Tolle, Ibrahim Elsharkawi, Ethan Perlstein, Danielle Boyce, Simon Johnson, and Kasey Woleben. Expanding research and care for leigh syndrome: efforts of a patient-led advocacy organization. Research Involvement and Engagement, Nov 2025. URL: https://doi.org/10.1186/s40900-025-00808-x, doi:10.1186/s40900-025-00808-x. This article has 0 citations and is from a peer-reviewed journal.
(zilber2025expandingresearchand pages 13-14): Sophia Zilber, Melinda Burnworth, Titilola Afolabi, Jonathan R. Brestoff, Michal Minczuk, Alejandro Rodriguez Luis, Qinglan Ling, Alessandro Prigione, Isabella Tolle, Ibrahim Elsharkawi, Ethan Perlstein, Danielle Boyce, Simon Johnson, and Kasey Woleben. Expanding research and care for leigh syndrome: efforts of a patient-led advocacy organization. Research Involvement and Engagement, Nov 2025. URL: https://doi.org/10.1186/s40900-025-00808-x, doi:10.1186/s40900-025-00808-x. This article has 0 citations and is from a peer-reviewed journal.
(shen2025thepathto pages 14-15): Lishuang null Shen. The path to precision medicine in leigh syndrome spectrum: a four-decade chronicle of genetic discovery and targeted treatment. Frontiers in Bioscience-Scholar, 17:45427, Dec 2025. URL: https://doi.org/10.31083/fbs45427, doi:10.31083/fbs45427. This article has 0 citations.
(zilber2025expandingresearchand pages 13-13): Sophia Zilber, Melinda Burnworth, Titilola Afolabi, Jonathan R. Brestoff, Michal Minczuk, Alejandro Rodriguez Luis, Qinglan Ling, Alessandro Prigione, Isabella Tolle, Ibrahim Elsharkawi, Ethan Perlstein, Danielle Boyce, Simon Johnson, and Kasey Woleben. Expanding research and care for leigh syndrome: efforts of a patient-led advocacy organization. Research Involvement and Engagement, Nov 2025. URL: https://doi.org/10.1186/s40900-025-00808-x, doi:10.1186/s40900-025-00808-x. This article has 0 citations and is from a peer-reviewed journal.

Citations

menacho2024deeplearningdrivenneuromorphogenesis pages 1-5
moreira2023teamworkmakesthe pages 1-2
guaragnella2024morethanjust pages 21-22
shen2025thepathto pages 14-15
moreira2023teamworkmakesthe pages 2-4
guaragnella2024morethanjust pages 2-4
zilber2025expandingresearchand pages 13-13
zilber2025expandingresearchand pages 5-6
zilber2025expandingresearchand pages 13-14
https://doi.org/10.1038/s41598-024-72681-9
https://doi.org/10.3390/ijms25073814
https://doi.org/10.1186/s13023-023-02871-7
https://doi.org/10.1101/2024.07.08.602501
https://doi.org/10.1186/s13023-023-02871-7;
https://doi.org/10.1186/s40900-025-00808-x
https://doi.org/10.31083/fbs45427
https://doi.org/10.1186/s13023-023-02886-0
https://doi.org/10.1038/s41598-024-72681-9;
https://doi.org/10.1038/s41598-024-72681-9,
https://doi.org/10.3390/ijms25073814,
https://doi.org/10.1186/s13023-023-02871-7,
https://doi.org/10.1101/2024.07.08.602501,
https://doi.org/10.1186/s40900-025-00808-x,
https://doi.org/10.31083/fbs45427,

📄 View Raw YAML

---
id: Q15526
gene_symbol: SURF1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SURF1 (Surfeit locus protein 1) is a conserved mitochondrial inner membrane protein
  that
  functions as an assembly factor for cytochrome c oxidase (Complex IV, CIV). It is
  a component
  of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome
  c
  oxidase) complex, where it participates in early COX1-module assembly, likely facilitating
  heme a insertion into COX1 or stabilizing COX1 assembly intermediates. SURF1 is
  NOT a
  structural subunit of Complex IV itself. The protein contains two transmembrane
  helices
  with an intermembrane space-facing domain. Loss-of-function mutations in SURF1 are
  the
  most common nuclear gene cause of COX-deficient Leigh syndrome (MC4DN1), and SURF1
  mutations also cause demyelinating Charcot-Marie-Tooth disease type 4K (CMT4K).
  SURF1 is
  the human ortholog of yeast Shy1. Interacts with the MITRAC component COA3/MITRAC12.
alternative_products:
  - name: '1'
    id: Q15526-1
  - name: '2'
    id: Q15526-2
    sequence_note: VSP_034817
existing_annotations:
# ===== ANNOTATION 1: GO:0033617 (BP) - IBA =====
  - term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        SURF1 is a well-established assembly factor for mitochondrial Complex IV (cytochrome
        c
        oxidase). Phylogenetic inference (IBA) based on conserved function from yeast
        Shy1 through
        human SURF1 is strongly supported. The founding paper (PMID:9843204) demonstrated
        that SURF1
        mutations cause COX deficiency and concluded "a role for SURF1 in the biogenesis
        of the COX
        complex." Subsequent work confirmed SURF1 as a component of the MITRAC complex
        that regulates
        COX assembly (PMID:26321642, PMID:23260140). The deep research review (Guaragnella
        et al.,
        2024; Luo et al., 2024) further confirms this as the core conserved function
        across species.
      action: ACCEPT
      reason: >-
        Mitochondrial respiratory chain complex IV assembly is the core biological
        process
        of SURF1.
        This IBA annotation is well-supported by extensive experimental evidence from
        multiple
        organisms and is at the correct level of specificity. SURF1/Shy1 has been
        consistently
        identified as a CIV assembly factor across yeast, fission yeast, and human
        studies.
      supported_by:
        - reference_id: PMID:9843204
          supporting_text: >-
            These data suggest a role for SURF1 in the biogenesis of the COX complex
            and
            define
            a new class of gene defects causing human neurodegenerative disease.
        - reference_id: PMID:26321642
          supporting_text: >-
            The MITRAC complex represents the central assembly intermediate during
            this
            process
            as it receives imported subunits and regulates mitochondrial translation
            of
            COX1 mRNA.
        - reference_id: file:human/SURF1/SURF1-deep-research-falcon.md
          supporting_text: >-
            Functions as a Complex IV (cytochrome c oxidase) assembly factor required
            for COX1
            maturation and COX assembly; implicated in cofactor (heme/Cu) handling
            during
            assembly

# ===== ANNOTATION 2: GO:0005739 (CC) - IBA =====
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        SURF1 is unambiguously a mitochondrial protein. UniProt annotates it to the
        mitochondrion
        inner membrane (by sequence similarity to mouse ortholog P09925). The IBA
        annotation
        is conservative (mitochondrion rather than mitochondrial inner membrane),
        which
        is
        acceptable. Proteomics data (PMID:34800366) and structural studies from the
        yeast
        homolog (Luo et al., 2024) both confirm mitochondrial localization.
      action: ACCEPT
      reason: >-
        Mitochondrial localization is universally agreed upon. While GO:0005743 (mitochondrial
        inner membrane) is more specific and also present in the annotation set, having
        the
        broader mitochondrion annotation from IBA is acceptable as it is phylogenetically
        well
        supported.
      supported_by:
        - reference_id: PMID:9843204
          supporting_text: >-
            SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase
        - reference_id: file:human/SURF1/SURF1-deep-research-falcon.md
          supporting_text: >-
            Localizes to the inner mitochondrial membrane with two transmembrane domains
            and an
            intermembrane-space (IMS)-facing region

# ===== ANNOTATION 3: GO:1902600 (BP) - IEA =====
  - term:
      id: GO:1902600
      label: proton transmembrane transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: >-
        This IEA annotation was inferred via logical inference from GO:0004129 (cytochrome-c
        oxidase activity), since cytochrome c oxidase catalyzes proton translocation
        across
        the inner mitochondrial membrane. However, SURF1 is NOT a structural subunit
        of Complex
        IV and does not itself catalyze proton transport. It is an assembly factor
        that
        facilitates
        the biogenesis of the complex. Proton transmembrane transport is an activity
        of the
        assembled Complex IV, not of the assembly factor.
      action: REMOVE
      reason: >-
        SURF1 does not directly participate in proton transmembrane transport. This
        annotation
        derives from the erroneous upstream annotation of cytochrome-c oxidase activity
        (GO:0004129) to SURF1 via Ensembl Compara. Since SURF1 is an assembly factor
        and not
        a catalytic subunit of Complex IV, attributing the catalytic process of proton
        pumping
        to SURF1 is incorrect. The assembled complex performs proton translocation;
        the assembly
        factor does not.

# ===== ANNOTATION 4: GO:0005743 (CC) - IEA =====
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        SURF1 localizes to the mitochondrial inner membrane as a multi-pass membrane
        protein
        with two predicted transmembrane helices (residues 61-79 and 274-290 per UniProt).
        UniProt annotates this based on sequence similarity to the mouse ortholog
        P09925.
        Experimental work in fission yeast Shy1 confirmed IMM localization by mitochondrial
        fractionation and protease protection assays (Luo et al., 2024). Reactome
        also
        places
        SURF1 at the inner membrane as part of the MITRAC complex (R-HSA-9865350).
      action: ACCEPT
      reason: >-
        Mitochondrial inner membrane localization is the correct and specific CC annotation
        for
        SURF1. This is well-supported by UniProt topology predictions (two TM helices),
        conservation with yeast Shy1 where inner membrane localization was experimentally
        confirmed, and Reactome pathway curation.
      supported_by:
        - reference_id: file:human/SURF1/SURF1-deep-research-falcon.md
          supporting_text: >-
            Localizes to the inner mitochondrial membrane with two transmembrane domains
            and an
            intermembrane-space (IMS)-facing region (experimental in S. pombe; inferred
            for human)
        - reference_id: Reactome:R-HSA-9865350
          supporting_text: >-
            Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly
            Complex
            (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62),
            COA1
            (C7orf44, MITRAC15), COA3 (MITRAC12)...SMIM20 (C4orf52, MITRAC7), and
            SURF1

# ===== ANNOTATION 5: GO:0016020 (CC) - IEA =====
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        SURF1 is indeed a membrane protein with two predicted transmembrane helices,
        placed in
        the mitochondrial inner membrane. The generic GO:0016020 (membrane) annotation
        from
        InterPro domain mapping is not wrong but is very unspecific compared to the
        more precise
        GO:0005743 (mitochondrial inner membrane) annotations already present.
      action: ACCEPT
      reason: >-
        While very general, this IEA annotation from InterPro is technically correct.
        SURF1
        contains transmembrane domains and is an integral membrane protein. More specific
        mitochondrial inner membrane annotations are present from other evidence codes.
        It is
        acceptable for an IEA to be broader than what is established by more detailed
        evidence.

# ===== ANNOTATION 6: GO:0005515 (MF) - IPI, PMID:23260140 =====
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23260140
    review:
      summary: >-
        This IPI annotation is based on physical interaction between SURF1 and COA3
        (Q9Y2R0,
        also known as MITRAC12), identified in the MITRAC complex dissection study
        by
        Mick et al.
        (2012). The study identified SURF1 as part of the MITRAC complex containing
        COA3, COX14,
        and other factors required for early cytochrome c oxidase assembly intermediates.
        While
        the interaction is biologically meaningful, 'protein binding' is uninformative.
      action: REMOVE
      reason: >-
        The term 'protein binding' (GO:0005515) is uninformative per GO curation guidelines.
        The interaction between SURF1 and COA3 within the MITRAC complex is biologically
        meaningful and supports SURF1's role in CIV assembly, but this is already
        captured
        by
        the process annotations (GO:0033617). A more informative CC annotation to
        the
        MITRAC
        complex (GO:0062011) would better represent this information.
      supported_by:
        - reference_id: PMID:23260140
          supporting_text: >-
            we report a comprehensive dissection of early cytochrome c oxidase assembly
            intermediates containing proteins required for normal mitochondrial translation

# ===== ANNOTATION 7: GO:0004129 (MF) - IEA =====
  - term:
      id: GO:0004129
      label: cytochrome-c oxidase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        This IEA annotation was transferred from the mouse ortholog (P09925) via Ensembl
        Compara.
        However, SURF1 is NOT a structural or catalytic subunit of cytochrome c oxidase.
        It is
        an assembly factor that facilitates the biogenesis of the complex. SURF1 does
        not itself
        possess cytochrome-c oxidase enzymatic activity (the catalysis of ferrocytochrome
        c
        oxidation coupled to proton pumping). The original paper (PMID:9843204) explicitly
        states
        SURF1 encodes "a factor involved in the biogenesis of cytochrome c oxidase,"
        not a
        subunit with catalytic activity.
      action: REMOVE
      reason: >-
        This is an incorrect annotation. Cytochrome-c oxidase activity (GO:0004129)
        describes
        the catalytic reaction performed by the assembled Complex IV holoenzyme. SURF1
        is an
        assembly factor, not a catalytic subunit. It does not catalyze the reduction
        of oxygen
        or pump protons. The Ensembl Compara transfer is erroneous here, likely propagating
        an annotation from the mouse ortholog that was itself over-annotated. UniProt
        explicitly
        describes SURF1 as a "Component of the MITRAC complex that regulates cytochrome
        c
        oxidase assembly" (PMID:24027061, PMID:9843204, PMID:26321642), not as having
        COX
        catalytic activity.
      supported_by:
        - reference_id: PMID:9843204
          supporting_text: >-
            SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase,
            is
            mutated in Leigh syndrome.
        - reference_id: PMID:26321642
          supporting_text: >-
            The MITRAC complex represents the central assembly intermediate during
            this
            process
            as it receives imported subunits and regulates mitochondrial translation
            of
            COX1 mRNA.

# ===== ANNOTATION 8: GO:0033617 (BP) - IEA =====
  - term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        This IEA annotation via Ensembl Compara transfers the CIV assembly annotation
        from
        the mouse ortholog. Unlike the erroneous cytochrome-c oxidase activity transfer,
        this
        annotation is correct: SURF1 does participate in mitochondrial Complex IV
        assembly.
        This is consistent with the IBA and IMP annotations for the same term already
        present.
      action: ACCEPT
      reason: >-
        The Ensembl Compara transfer of Complex IV assembly is correct. This is the
        core
        function of SURF1 and is supported by multiple independent evidence lines
        (IBA,
        IMP,
        TAS). The IEA annotation is redundant with these but not incorrect.
      supported_by:
        - reference_id: PMID:9843204
          supporting_text: >-
            These data suggest a role for SURF1 in the biogenesis of the COX complex

# ===== ANNOTATION 9: GO:0005739 (CC) - HTP =====
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: >-
        SURF1 was identified as part of the high-confidence human mitochondrial proteome
        by
        Morgenstern et al. (2021), a comprehensive quantitative proteomics study of
        the
        mitochondrial proteome. This HTP evidence confirms mitochondrial localization
        via
        mass spectrometry-based identification.
      action: ACCEPT
      reason: >-
        The HTP annotation is based on large-scale quantitative proteomics and is
        consistent
        with all other evidence for SURF1 mitochondrial localization. While less specific
        than
        the inner membrane annotation, it provides independent experimental support.
      supported_by:
        - reference_id: PMID:34800366
          supporting_text: >-
            Quantitative high-confidence human mitochondrial proteome

# ===== ANNOTATION 10: GO:0005743 (CC) - TAS, Reactome:R-HSA-9865350 =====
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9865350
    review:
      summary: >-
        Reactome places SURF1 at the mitochondrial inner membrane as part of the MITRAC
        complex
        in the step where nascent MT-CO1 binds to MITRAC. SURF1 is listed as a subunit
        of
        MITRAC alongside CMC1, COX14, COA1, COA3, and SMIM20 (MITRAC7).
      action: ACCEPT
      reason: >-
        The Reactome annotation correctly places SURF1 at the mitochondrial inner
        membrane,
        consistent with its topology (two TM helices) and its role as a component
        of
        the
        membrane-bound MITRAC complex. This is well-supported by the Reactome pathway
        curation.
      supported_by:
        - reference_id: Reactome:R-HSA-9865350
          supporting_text: >-
            SMIM20 (C4orf52, MITRAC7), and SURF1 (Zhu et al., 1998; Dennerlein et
            al.,
            2015).

# ===== ANNOTATION 11: GO:0005743 (CC) - TAS, Reactome:R-HSA-9865412 =====
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9865412
    review:
      summary: >-
        This Reactome annotation places SURF1 at the inner membrane during the step
        where
        TIMM21 carries COX4, COX5A, and COX6C subunits to the MT-CO1:MITRAC complex.
        SURF1
        is part of the MITRAC complex that receives these imported subunits.
      action: ACCEPT
      reason: >-
        Consistent with SURF1 being a component of the inner membrane-bound MITRAC
        complex
        that receives imported COX subunits. Duplicate CC annotation from a different
        Reactome
        reaction step is acceptable.
      supported_by:
        - reference_id: Reactome:R-HSA-9865412
          supporting_text: >-
            COX5A and COX6C across the inner membrane, where they bind to the MT-CO1:MITRAC
            complex

# ===== ANNOTATION 12: GO:0005743 (CC) - TAS, Reactome:R-HSA-9865449 =====
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9865449
    review:
      summary: >-
        This Reactome annotation places SURF1 at the inner membrane during the copper
        insertion
        step into MT-CO1. The Reactome entry for this step describes a metallochaperone
        complex
        that inserts Cu2+ into MT-CO1, and SURF1 is present in the broader assembly
        context
        at this stage.
      action: ACCEPT
      reason: >-
        Consistent with SURF1 inner membrane localization during the COX assembly
        pathway.
        The
        copper insertion step occurs at the inner membrane where the assembly intermediates
        reside.
      supported_by:
        - reference_id: Reactome:R-HSA-9865449
          supporting_text: >-
            A metallochaperone complex... carries a copper cation from the outer side
            of the inner
            mitochondrial membrane... to the pre-assembled Complex IV on the inner
            side
            of the
            membrane

# ===== ANNOTATION 13: GO:0005743 (CC) - TAS, Reactome:R-HSA-9865579 =====
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9865579
    review:
      summary: >-
        This Reactome annotation places SURF1 at the inner membrane during the step
        where
        MT-CO1 and MT-CO2 complexes associate and heme moieties are installed. Reactome
        specifically notes that "the SURF1 subunit of MITRAC may act as an additional
        chaperone,
        for which there is evidence in bacterial models." This is a key step where
        SURF1
        may
        directly facilitate heme a insertion.
      action: ACCEPT
      reason: >-
        Consistent with SURF1 inner membrane localization, and this Reactome entry
        provides
        important mechanistic context suggesting SURF1 may function as a heme insertion
        chaperone during COX assembly. This is well-aligned with the proposed role
        of
        SURF1/Shy1 in heme a insertion into COX1.
      supported_by:
        - reference_id: Reactome:R-HSA-9865579
          supporting_text: >-
            the SURF1 subunit of MITRAC may act as an additional chaperone, for which
            there is
            evidence in bacterial models (Smith et al., 2005; Bundschuh et al., 2009).
            Mutations
            in SURF1 lead to complex IV deficiency

# ===== ANNOTATION 14: GO:0005743 (CC) - TAS, Reactome:R-HSA-9865663 =====
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9865663
    review:
      summary: >-
        This Reactome annotation places SURF1 at the inner membrane during the final
        Complex
        IV assembly step where MT-CO3, COX6A/B, COX7A, and NDUFA4 bind to the holo-MT-CO1,2
        complex. SURF1 is not specifically mentioned in this final step description,
        suggesting
        it may no longer be part of the complex at this late stage.
      action: ACCEPT
      reason: >-
        Inner membrane localization is correct for SURF1. While the Reactome entry
        for
        this
        specific step does not explicitly mention SURF1, the protein remains at the
        inner
        membrane. The annotation is not wrong, though SURF1 likely acts at earlier
        assembly
        stages (COX1 module) rather than this final step.
      supported_by:
        - reference_id: Reactome:R-HSA-9865663
          supporting_text: >-
            The final assembly of Complex IV consists of binding of the MT-CO3, COX6A,
            COX6B,
            COX7A, and NDUFA4 subunits to the holo-MT-CO1, MT-CO2 complex

# ===== ANNOTATION 15: GO:0005515 (MF) - IPI, PMID:26321642 =====
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26321642
    review:
      summary: >-
        This IPI annotation is based on physical interactions identified in Dennerlein
        et al.
        (2015), which found SURF1 interacting with MT-CO1 (P00395), COX6B1 (P14854/P13073),
        MITRAC7/SMIM20 (Q8N5G0), and COA3/MITRAC12 (Q9Y2R0) within the MITRAC complex.
        The
        UniProt INTERACTION section confirms SURF1 interaction with COA3 (6 experiments
        in
        IntAct). These are specific interactions within the COX assembly machinery.
      action: REMOVE
      reason: >-
        While the physical interactions are experimentally validated and biologically
        meaningful,
        'protein binding' (GO:0005515) is uninformative per GO curation guidelines.
        The
        interactions of SURF1 with COA3, MITRAC7, and COX1 within the MITRAC complex
        are
        better captured by process annotations (GO:0033617) and a CC annotation to
        the
        MITRAC
        pre-assembly complex (GO:0062011). A new CC annotation for the MITRAC complex
        is
        proposed below.
      supported_by:
        - reference_id: PMID:26321642
          supporting_text: >-
            Cytochrome c oxidase, the terminal enzyme of the respiratory chain, is
            assembled
            from
            mitochondria- and nuclear-encoded subunits. The MITRAC complex represents
            the central
            assembly intermediate during this process
        - reference_id: PMID:23260140
          supporting_text: >-
            we report a comprehensive dissection of early cytochrome c oxidase assembly
            intermediates containing proteins required for normal mitochondrial translation

# ===== ANNOTATION 16: GO:0033617 (BP) - IMP, PMID:24027061 =====
  - term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    evidence_type: IMP
    original_reference_id: PMID:24027061
    review:
      summary: >-
        This IMP annotation is based on Echaniz-Laguna et al. (2013), which demonstrated
        that
        SURF1 mutations cause defective Complex IV assembly and activity. The study
        identified
        SURF1 mutations in patients with CMT4 and showed that "complex IV remained
        partially
        functional in muscle and fibroblasts" but was reduced, with SURF1 absence
        confirmed.
        The c.107-2A>G mutation "produced no normally spliced transcript, leading
        to
        SURF1
        absence." This is direct mutant phenotype evidence for SURF1 role in CIV assembly.
      action: ACCEPT
      reason: >-
        This is strong IMP evidence demonstrating that loss of SURF1 causes impaired
        Complex
        IV assembly. The study shows that SURF1 mutations lead to reduced Complex
        IV
        activity
        and assembly, providing direct genetic evidence for the annotation. This is
        the core
        function of SURF1.
      supported_by:
        - reference_id: PMID:24027061
          supporting_text: >-
            The c.107-2A>G mutation produced no normally spliced transcript, leading
            to
            SURF1
            absence. However, complex IV remained partially functional in muscle and
            fibroblasts.
        - reference_id: PMID:24027061
          supporting_text: >-
            encoding an assembly factor of the mitochondrial respiratory chain complex
            IV

# ===== ANNOTATION 17: GO:0008535 (BP) - TAS, PMID:9843204 =====
  - term:
      id: GO:0008535
      label: respiratory chain complex IV assembly
    evidence_type: TAS
    original_reference_id: PMID:9843204
    review:
      summary: >-
        This TAS annotation is based on the founding SURF1 paper by Zhu et al. (1998),
        which
        identified SURF1 as "a factor involved in the biogenesis of cytochrome c oxidase."
        GO:0008535 (respiratory chain complex IV assembly) is the parent term of GO:0033617
        (mitochondrial respiratory chain complex IV assembly). Since SURF1 specifically
        functions
        in the mitochondrial context, the more specific child term GO:0033617 is more
        appropriate.
      action: MODIFY
      reason: >-
        GO:0008535 (respiratory chain complex IV assembly) is the broader parent term
        that
        also covers bacterial/plasma membrane CIV assembly. Since human SURF1 specifically
        functions in mitochondrial CIV assembly, the more specific term GO:0033617
        (mitochondrial respiratory chain complex IV assembly) is preferred. This term
        is
        already annotated via IBA, IEA, and IMP evidence, so this is a specificity
        refinement.
      proposed_replacement_terms:
        - id: GO:0033617
          label: mitochondrial respiratory chain complex IV assembly
      supported_by:
        - reference_id: PMID:9843204
          supporting_text: >-
            These data suggest a role for SURF1 in the biogenesis of the COX complex

# ===== ANNOTATION 18: GO:0009060 (BP) - TAS, PMID:9843204 =====
  - term:
      id: GO:0009060
      label: aerobic respiration
    evidence_type: TAS
    original_reference_id: PMID:9843204
    review:
      summary: >-
        This TAS annotation to aerobic respiration is based on the founding SURF1
        paper.
        While
        SURF1 loss does impair aerobic respiration (because Complex IV is the terminal
        enzyme
        of the electron transport chain), SURF1 is an assembly factor, not a direct
        participant
        in the respiratory process itself. The aerobic respiration annotation represents
        an
        over-annotation; the correct primary annotation is to Complex IV assembly.
        The
        downstream consequences of impaired CIV assembly include impaired aerobic
        respiration,
        but that does not mean SURF1 is directly "involved_in" aerobic respiration.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        SURF1 facilitates the assembly of Complex IV, which is required for aerobic
        respiration.
        However, SURF1 does not directly participate in the respiratory chain or electron
        transport. Annotating an assembly factor to the process carried out by the
        assembled
        complex is an over-annotation. The correct annotation is to Complex IV assembly
        (GO:0033617), which is already present. The relationship between SURF1 and
        aerobic
        respiration is indirect (assembly factor -> complex -> process).
      supported_by:
        - reference_id: PMID:9843204
          supporting_text: >-
            SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase,
            is
            mutated in Leigh syndrome.
        - reference_id: file:human/SURF1/SURF1-deep-research-falcon.md
          supporting_text: >-
            Functions as a Complex IV (cytochrome c oxidase) assembly factor required
            for COX1
            maturation and COX assembly

# ===== ANNOTATION 19: GO:0098803 (CC) - TAS, PMID:9843204 =====
  - term:
      id: GO:0098803
      label: respiratory chain complex
    evidence_type: TAS
    original_reference_id: PMID:9843204
    review:
      summary: >-
        This TAS annotation places SURF1 as a component of the "respiratory chain
        complex."
        GO:0098803 is defined as "any protein complex that is part of a respiratory
        chain."
        SURF1 is NOT a structural subunit of the mature respiratory chain Complex
        IV.
        It is an
        assembly factor that transiently associates with assembly intermediates (MITRAC
        complex)
        but is not part of the final assembled complex. The founding paper (PMID:9843204)
        describes SURF1 as "a factor involved in the biogenesis of cytochrome c oxidase,"
        not
        as a component of the respiratory chain.
      action: MODIFY
      reason: >-
        SURF1 is not a structural subunit of the respiratory chain. It is a component
        of the
        MITRAC complex, which is a transient assembly intermediate, not the mature
        respiratory
        chain complex. The correct CC annotation would be to the mitochondrial respiratory
        chain
        complex IV pre-assembly complex (GO:0062011), which describes the MITRAC complex
        where
        SURF1 resides. Annotating SURF1 to GO:0098803 (respiratory chain complex)
        incorrectly
        implies it is a structural component of the electron transport chain.
      proposed_replacement_terms:
        - id: GO:0062011
          label: mitochondrial respiratory chain complex IV pre-assembly complex
      supported_by:
        - reference_id: PMID:9843204
          supporting_text: >-
            SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase
        - reference_id: PMID:23260140
          supporting_text: >-
            we report a comprehensive dissection of early cytochrome c oxidase assembly
            intermediates containing proteins required for normal mitochondrial translation
            and reveal assembly factors promoting biogenesis of human respiratory-chain
            complexes
        - reference_id: PMID:26321642
          supporting_text: >-
            The MITRAC complex represents the central assembly intermediate during
            this
            process
            as it receives imported subunits and regulates mitochondrial translation
            of
            COX1 mRNA.

# ===== NEW ANNOTATION: GO:0062011 (CC) - mitochondrial CIV pre-assembly complex =====
  - term:
      id: GO:0062011
      label: mitochondrial respiratory chain complex IV pre-assembly complex
    evidence_type: IPI
    original_reference_id: PMID:23260140
    review:
      summary: >-
        SURF1 is a component of the MITRAC (mitochondrial translation regulation assembly
        intermediate of cytochrome c oxidase) complex. This was established by Mick
        et al.
        (2012, PMID:23260140), who identified SURF1 as part of early COX assembly
        intermediates.
        Dennerlein et al. (2015, PMID:26321642) further confirmed SURF1 presence in
        the MITRAC
        complex. UniProt states SURF1 is a "Component of the MITRAC complex." Reactome
        (R-HSA-9865350) explicitly lists SURF1 as a MITRAC subunit alongside CMC1,
        COX14,
        COA1, COA3, and SMIM20. GO:0062011 is defined as "A protein complex that contributes
        to and regulates mitochondrial respiratory chain complex IV (COX) formation."
      action: NEW
      reason: >-
        This CC annotation is missing from the current annotation set and would accurately
        capture SURF1's localization within the MITRAC complex. This is more informative
        than
        the generic 'respiratory chain complex' (GO:0098803) currently annotated.
        The
        MITRAC
        complex is the specific subcompartment where SURF1 functions, and GO:0062011
        was
        created to describe this complex.
      supported_by:
        - reference_id: PMID:23260140
          supporting_text: >-
            we report a comprehensive dissection of early cytochrome c oxidase assembly
            intermediates containing proteins required for normal mitochondrial translation
        - reference_id: PMID:26321642
          supporting_text: >-
            The MITRAC complex represents the central assembly intermediate during
            this
            process
            as it receives imported subunits and regulates mitochondrial translation
            of
            COX1 mRNA.
        - reference_id: Reactome:R-HSA-9865350
          supporting_text: >-
            SMIM20 (C4orf52, MITRAC7), and SURF1 (Zhu et al., 1998; Dennerlein et
            al.,
            2015).
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with GO
      terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000044
    title: >-
      Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
      vocabulary mapping, accompanied by conservative changes to GO terms applied
      by
      UniProt
    findings: []
  - id: GO_REF:0000107
    title: >-
      Automatic transfer of experimentally verified manual GO annotation data to
      orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000108
    title: >-
      Automatic assignment of GO terms using logical inference, based on on inter-ontology
      links
    findings: []
  - id: PMID:23260140
    title: >-
      MITRAC links mitochondrial protein translocation to respiratory-chain assembly
      and translational regulation.
    findings:
      - statement: >-
          SURF1 is a component of early cytochrome c oxidase assembly intermediates
          termed
          MITRAC complexes, which link mitochondrial protein translocation to respiratory
          chain assembly.
        supporting_text: >-
          we report a comprehensive dissection of early cytochrome c oxidase assembly
          intermediates containing proteins required for normal mitochondrial translation
          and reveal assembly factors promoting biogenesis of human respiratory-chain
          complexes
  - id: PMID:24027061
    title: SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease.
    findings:
      - statement: >-
          SURF1 mutations cause impaired Complex IV assembly and activity, leading
          to
          both
          Leigh syndrome and CMT4K. The c.107-2A>G mutation leads to SURF1 absence,
          and
          complex IV remains partially functional but reduced.
        supporting_text: >-
          The c.107-2A>G mutation produced no normally spliced transcript,
          leading to SURF1 absence. However, complex IV remained partially functional
          in
          muscle and fibroblasts.
  - id: PMID:26321642
    title: >-
      MITRAC7 Acts as a COX1-Specific Chaperone and Reveals a Checkpoint during
      Cytochrome c Oxidase Assembly.
    findings:
      - statement: >-
          SURF1 is part of the MITRAC complex that represents the central assembly
          intermediate
          for cytochrome c oxidase. SURF1 interacts with COA3, MITRAC7/SMIM20, and
          COX1
          within
          this complex.
        supporting_text: >-
          The MITRAC complex represents the central assembly intermediate during this
          process
          as it receives imported subunits and regulates mitochondrial translation
          of
          COX1 mRNA.
  - id: PMID:34800366
    title: >-
      Quantitative high-confidence human mitochondrial proteome and its dynamics in
      cellular context.
    findings:
      - statement: >-
          SURF1 was identified as part of the high-confidence human mitochondrial
          proteome
          by quantitative mass spectrometry.
        supporting_text: >-
          Quantitative high-confidence human mitochondrial proteome and its dynamics
          in
          cellular context.
  - id: PMID:9843204
    title: >-
      SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase,
      is mutated in Leigh syndrome.
    findings:
      - statement: >-
          Founding paper identifying SURF1 as a factor in COX biogenesis. Multiple
          SURF1
          mutations identified in Leigh syndrome patients, all predicting truncated
          protein.
          Established SURF1 as required for COX assembly.
        supporting_text: >-
          These data suggest a role for SURF1 in the biogenesis of the COX
          complex and define a new class of gene defects causing human neurodegenerative
          disease.
  - id: Reactome:R-HSA-9865350
    title: Nascent MT-CO1 binds to MITRAC, Mg2+, PE, CL
    findings:
      - statement: >-
          SURF1 is listed as a subunit of the MITRAC complex alongside CMC1, COX14,
          COA1,
          COA3, and SMIM20 in the step where nascent MT-CO1 binds to MITRAC.
        supporting_text: >-
          SMIM20 (C4orf52, MITRAC7), and SURF1 (Zhu et al., 1998; Dennerlein et al.,
          2015).
  - id: Reactome:R-HSA-9865412
    title: TIMM21 carries COX4, COX5A, COX6C to MT-CO1:MITRAC
    findings:
      - statement: >-
          SURF1 is part of the MT-CO1:MITRAC complex that receives imported COX subunits
          carried by TIMM21 across the inner membrane.
        supporting_text: >-
          COX5A and COX6C across the inner membrane, where they bind to the MT-CO1:MITRAC
          complex
  - id: Reactome:R-HSA-9865449
    title: Metallochaperone inserts Cu2+ into MT-CO1
    findings:
      - statement: >-
          SURF1 is present at the inner membrane during copper insertion into MT-CO1
          by
          the metallochaperone complex.
        supporting_text: >-
          carries a copper cation from the outer side of the inner mitochondrial membrane
  - id: Reactome:R-HSA-9865579
    title: MT-CO1 and MT-CO2 complexes associate, installing heme moieties
    findings:
      - statement: >-
          Reactome notes that SURF1 may act as an additional chaperone for heme insertion,
          with evidence from bacterial models. Mutations in SURF1 lead to Complex
          IV deficiency.
        supporting_text: >-
          the SURF1 subunit of MITRAC may act as an additional chaperone, for which
          there
          is
          evidence in bacterial models
  - id: Reactome:R-HSA-9865663
    title: MT-CO3, COX6A,B,7A and NDUFA4 bind to holo-MT-CO1,2 complex
    findings:
      - statement: >-
          Final assembly step of Complex IV. SURF1 is not specifically mentioned in
          this
          late assembly step, consistent with its role at earlier stages.
        supporting_text: >-
          The final assembly of Complex IV consists of binding of the MT-CO3, COX6A,
          COX6B,
          COX7A, and NDUFA4 subunits to the holo-MT-CO1, MT-CO2 complex
  - id: file:human/SURF1/SURF1-deep-research-falcon.md
    title: Deep research review of SURF1 gene function
    findings:
      - statement: >-
          SURF1 is a conserved IMM assembly factor required for proper biogenesis
          of cytochrome
          c oxidase (Complex IV), likely acting at COX1-module maturation/assembly
          and
          interfacing
          with metal/cofactor handling machinery. Biallelic SURF1 variants produce
          a reproducible
          Leigh syndrome phenotype with Complex IV deficiency.
core_functions:
  - description: >-
      SURF1 functions as an assembly factor for mitochondrial cytochrome c oxidase
      (Complex
      IV),
      acting within the MITRAC complex during early COX1-module assembly. It may facilitate
      heme a insertion into COX1 or stabilize COX1 assembly intermediates. The precise
      molecular
      function is not yet fully characterized; evidence from bacterial models suggests
      a possible
      role as a heme insertion chaperone, but this has not been confirmed for the
      human
      protein.
    directly_involved_in:
      - id: GO:0033617
        label: mitochondrial respiratory chain complex IV assembly
    locations:
      - id: GO:0005743
        label: mitochondrial inner membrane
    in_complex:
      id: GO:0062011
      label: mitochondrial respiratory chain complex IV pre-assembly complex
    supported_by:
      - reference_id: PMID:9843204
        supporting_text: >-
          These data suggest a role for SURF1 in the biogenesis of the COX complex
      - reference_id: PMID:26321642
        supporting_text: >-
          The MITRAC complex represents the central assembly intermediate during this
          process
      - reference_id: PMID:24027061
        supporting_text: >-
          encoding an assembly factor of the mitochondrial respiratory chain complex
          IV
      - reference_id: Reactome:R-HSA-9865579
        supporting_text: >-
          the SURF1 subunit of MITRAC may act as an additional chaperone, for which
          there
          is
          evidence in bacterial models

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

Citations

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