MICOS10 (MIC10, MINOS1) encodes a 78-amino-acid integral protein of the mitochondrial inner membrane and is a core subunit of the mitochondrial contact site and cristae organizing system (MICOS). It has two closely spaced hydrophobic segments, each carrying a conserved glycine-rich (GxGxGxG) motif, separated by a short basic loop, and is thought to span the membrane as a hairpin with its C terminus in the intermembrane space. MIC10 is the most widespread MICOS subunit across eukaryotes. Together with MIC13, MIC26 and MIC27 it forms the MIC10 subcomplex, which joins the MIC60-MIC19-MIC25 subcomplex at crista junctions in a MIC13-dependent step; through MIC60 the complex associates with the outer membrane SAMM50-metaxin machinery and DNAJC11 to form the intermembrane space bridging (MIB) complex. In yeast, Mic10 oligomerises through its glycine motifs and bends lipid membranes, and this membrane-sculpting activity is needed to form crista junctions. Human cells lacking MIC10 lose most crista junctions and lamellar cristae, which are replaced by tube-like, onion-like or spherical inner membrane structures, while MIC60 subcomplexes persist. Biallelic loss-of-function variants cause a hepatocerebral mitochondrial DNA depletion syndrome with abnormal cristae and impaired respiration, rescued in patient fibroblasts by re-expression of MIC10.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001401 SAM complex | HDA PMID:26477565 Evolution and structural organization of the mitochondrial c... | REMOVE | Summary: Complexome profiling found MICOS subunits co-migrating with SAMM50, MTX2 and MTX3 in a membrane bridging subcomplex and with DNAJC11 and MTX1 in the full MIB complex. The SAM complex term was projected onto MIC10 from that co-migration. Reason: The SAM complex (GO:0001401) is defined as an outer membrane complex that sorts and assembles imported outer membrane proteins. MIC10 is an integral inner membrane protein and is not a SAM subunit; the cited paper places it in MICOS and in the larger MIB bridging assemblies that contain SAM components. The evidence is captured correctly by the MIB complex (GO:0140275) row from the same paper, which is accepted. The same SAM complex row is removed in the APOO and APOOL reviews for the same reason. Supporting Evidence: PMID:26477565 We find three main forms of the complex: A) The MICOS complex, containing all the MICOS proteins, B) a membrane bridging subcomplex, containing in addition SAMM50, MTX2 and the previously uncharacterized MTX3, and C) the complete MIB complex containing in addition DNAJC11 and MTX1. PMID:22114354 Thus we concluded that MINOS1 was an integral membrane protein of the inner membrane in human mitochondria. |
| GO:0005515 protein binding | IPI PMID:25764979 The non-glycosylated isoform of MIC26 is a constituent of th... | REMOVE | Summary: Co-immunoprecipitation of MIC10 with MIC60/IMMT (Q16891) in the MIC26 study. Reason: The interaction is genuine; it is an intra-complex association between MICOS subunits and is already represented by the MICOS complex (GO:0061617) annotations. Bare protein binding adds no functional information and no more informative MF term is supported for this pair. Supporting Evidence: PMID:25764979 The latter isoform spans the mitochondrial inner membrane and physically interacts with several MICOS complex subunits such as MIC60, MIC27, and MIC10. |
| GO:0005515 protein binding | IPI PMID:25764979 The non-glycosylated isoform of MIC26 is a constituent of th... | REMOVE | Summary: Co-immunoprecipitation of MIC10 with MIC27/APOOL (Q6UXV4). Reason: Genuine intra-MICOS interaction within the MIC10 subcomplex, captured by the MICOS complex annotations. Bare protein binding is uninformative. Supporting Evidence: PMID:25764979 The latter isoform spans the mitochondrial inner membrane and physically interacts with several MICOS complex subunits such as MIC60, MIC27, and MIC10. |
| GO:0005515 protein binding | IPI PMID:25764979 The non-glycosylated isoform of MIC26 is a constituent of th... | REMOVE | Summary: Co-immunoprecipitation of MIC10 with the non-glycosylated mitochondrial form of MIC26/APOO (Q9BUR5). Reason: Genuine intra-MICOS interaction within the MIC10 subcomplex, captured by the MICOS complex annotations. Bare protein binding is uninformative. Supporting Evidence: PMID:25764979 The latter isoform spans the mitochondrial inner membrane and physically interacts with several MICOS complex subunits such as MIC60, MIC27, and MIC10. |
| GO:0005515 protein binding | IPI PMID:31644573 Armadillo repeat-containing protein 1 is a dual localization... | REMOVE | Summary: FLAG-ARMC1 (Q9NVT9) co-precipitates MIC10 together with MIC60, SAMM50 and metaxin 1; ARMC1 is a peripheral MICOS/MIB-associated protein. Reason: The co-precipitation reflects association of ARMC1 with the MICOS/MIB assembly as a whole, not a defined binary activity of MIC10. ARMC1 knockout does not affect MICOS stability or cristae. Bare protein binding is uninformative and no specific MF follows. Supporting Evidence: PMID:31644573 To confirm the IP data, we performed western blot analysis of the IP samples and found that FLAG-ArmC1 indeed co-precipitated with members of the MICOS/MIB complex Mic60/Mitofilin, Mic10/MINOS1, Sam50, and Metaxin 1, but not with Actin or Hsp60 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI yeast two-hybrid interaction with the mitochondrial pyruvate carrier subunit MPC2 (O95563). Reason: Systematic yeast two-hybrid hit between two small inner membrane proteins with hydrophobic segments, with no follow-up or functional context. Bare protein binding is uninformative; removal does not assert the interaction is false. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI yeast two-hybrid interaction with apolipoprotein C-IV (P55056), a secreted plasma lipoprotein component. Reason: A secreted apolipoprotein and a mitochondrial inner membrane protein do not share a compartment; this is a screen hit with no biological context. Bare protein binding is uninformative. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI yeast two-hybrid interaction with CIDEB (Q9UHD4), a lipid droplet/ER protein. Reason: Screen hit between proteins in different compartments with no follow-up. Bare protein binding is uninformative. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | ACCEPT | Summary: Detected in the phosphoproteome of mitochondria isolated from human skeletal muscle. Reason: Correct, though less specific than the inner membrane and MICOS complex annotations. Supporting Evidence: PMID:22114354 Thus we concluded that MINOS1 was an integral membrane protein of the inner membrane in human mitochondria. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Included in the MitoCoP high-confidence human mitochondrial proteome. Reason: Correct; consistent with the targeted localisation studies. Supporting Evidence: PMID:34800366 We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference at node PTN000480690 for the Mic10 family, seeded by yeast, fission yeast, plant, fly, trypanosome and human members. Reason: Mic10 is the most widely distributed MICOS subunit and is mitochondrial wherever studied; MICOS10 is a canonical member of the family with conserved glycine motifs. Correct, though the inner membrane and MICOS complex terms are more informative. Supporting Evidence: PMID:26477565 Mic10 is the most widespread MICOS gene |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localisation to mitochondria. Reason: Correct; agrees with the immunofluorescence in Vero cells in PMID:22114354. Supporting Evidence: PMID:22114354 These analyses revealed a primarily mitochondrial localization pattern of MINOS1 in Vero cells that could be superimposed on the distribution of the mitochondrial marker cyclophilin D (Figure 1C). |
| GO:0005743 mitochondrial inner membrane | EXP PMID:22114354 MINOS1 is a conserved component of mitofilin complexes and r... | ACCEPT | Summary: Protease protection of mitochondria versus mitoplasts and alkaline carbonate extraction in HEK293T mitochondria show MIC10 is an integral inner membrane protein exposed to the intermembrane space. Reason: Direct experimental evidence for the core location of the protein. Supporting Evidence: PMID:22114354 Thus we concluded that MINOS1 was an integral membrane protein of the inner membrane in human mitochondria. PMID:22114354 We concluded that MINOS1 and Mio10 are integral inner membrane proteins with their C-termini exposed to the IMS. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation from the Mic10 InterPro entry and UniProt subcellular location. Reason: Correct; duplicates the experimental annotation from PMID:22114354. Supporting Evidence: PMID:22114354 Thus we concluded that MINOS1 was an integral membrane protein of the inner membrane in human mitochondria. |
| GO:0005743 mitochondrial inner membrane | NAS PMID:25997101 QIL1 is a novel mitochondrial protein required for MICOS com... | ACCEPT | Summary: Author statement in the QIL1 paper that the MICOS core resides in the inner membrane at crista junctions. Reason: Correct; supported experimentally by PMID:22114354. Supporting Evidence: PMID:25997101 The MIC10-MIC19-MIC25-MIC26-MIC27-MIC60 complex is thought to reside in the IM at the site of CJs. |
| GO:0007007 inner mitochondrial membrane organization | IC PMID:26477565 Evolution and structural organization of the mitochondrial c... | ACCEPT | Summary: Inferred by curator from membership in the MIB complex. Reason: Correct. MIC10 shapes the inner membrane directly, and human knockouts show loss of crista junctions and lamellar cristae. Cristae formation (GO:0042407), also annotated by IMP, is the more specific process; this parent term is still accurate. Supporting Evidence: PMID:32567732 Compared to WT cells, the occurrence of CJs was reduced by about 25% in Mic26‐KO cells and by more than 70% in Mic10‐, Mic13‐, and Mic19‐KO cells. |
| GO:0042407 cristae formation | IMP PMID:32567732 MICOS assembly controls mitochondrial inner membrane remodel... | ACCEPT | Summary: MIC10 knockout HeLa cells lose most crista junctions and lamellar cristae; their inner membrane forms large tube-like cristae lining the boundary membrane, and re-expression restores cristae. Reason: Core biological process, with knockout and re-expression in human cells. MIC10 does part of the work: it is the membrane-bending subunit of MICOS. The paper argues that the MIC60 subcomplex is what is required for crista junctions per se, while the MIC10 subcomplex is needed for lamellar cristae; both are covered by cristae formation. Supporting Evidence: PMID:32567732 Compared to WT cells, the occurrence of CJs was reduced by about 25% in Mic26‐KO cells and by more than 70% in Mic10‐, Mic13‐, and Mic19‐KO cells. PMID:32567732 Furthermore, the fact that human Mic10‐KO cells still form CJs, but exhibit an aberrant cristae architecture, allowed us to disentangle CJ formation from lamellar cristae formation and to investigate the distinct functions of the two MICOS subcomplexes. |
| GO:0042407 cristae formation | IMP PMID:33130824 OPA1 and MICOS Regulate mitochondrial crista dynamics and fo... | ACCEPT | Summary: Mic10 knockout HeLa cells lose crista junctions and form onion-like and spherical cristae with reduced crista dynamics. Reason: Independent human knockout evidence for the core process. Supporting Evidence: PMID:33130824 As seen by TEM analysis, Mic10 KO, Mic19 KO, or Mic60 knockdown (KD) resulted in a slight decrease in the number of mitochondrial cristae, an increase in abnormal cristae, and a complete loss of mitochondrial CJs |
| GO:0042407 cristae formation | NAS PMID:25997101 QIL1 is a novel mitochondrial protein required for MICOS com... | ACCEPT | Summary: Author statement in the QIL1 paper on the MICOS complex and crista junctions. Reason: Correct; experimentally supported by the IMP annotations. Supporting Evidence: PMID:25997101 The MIC10-MIC19-MIC25-MIC26-MIC27-MIC60 complex is thought to reside in the IM at the site of CJs. |
| GO:0044284 mitochondrial crista junction | NAS PMID:25997101 QIL1 is a novel mitochondrial protein required for MICOS com... | ACCEPT | Summary: Author statement that the MICOS complex resides at crista junctions. Reason: Correct and specific. Yeast Mic10 is localised to crista junctions experimentally, and the human MICOS core is enriched there. Supporting Evidence: PMID:25997101 The MIC10-MIC19-MIC25-MIC26-MIC27-MIC60 complex is thought to reside in the IM at the site of CJs. PMID:25955211 Mic10 oligomerizes to bend mitochondrial inner membranes at cristae junctions. |
| GO:0061617 MICOS complex | HDA PMID:26477565 Evolution and structural organization of the mitochondrial c... | ACCEPT | Summary: Complexome profiling places MIC10 in the MICOS complex. Reason: Core complex membership, also shown by targeted co-immunoprecipitation. Supporting Evidence: PMID:26477565 We find three main forms of the complex: A) The MICOS complex, containing all the MICOS proteins |
| GO:0061617 MICOS complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from the Mic10 family entry. Reason: Correct; agrees with experimental evidence. Supporting Evidence: PMID:22114354 Accordingly, MINOS1 and Mio10 are conserved components of the MINOS complex in mitochondria. |
| GO:0061617 MICOS complex | NAS PMID:25997101 QIL1 is a novel mitochondrial protein required for MICOS com... | ACCEPT | Summary: The QIL1 paper shows by BN-PAGE and immunoprecipitation that MIC10 is in the ~700 kDa MICOS complex and that QIL1 is needed for its incorporation. Reason: Correct core complex membership; the paper contains direct experimental support. Supporting Evidence: PMID:25997101 Thus, QIL1 appears to be required for incorporation of MIC10, MIC26, and MIC27 into the MICOS complex. |
| GO:0140275 MIB complex | HDA PMID:26477565 Evolution and structural organization of the mitochondrial c... | ACCEPT | Summary: Complexome profiling places MICOS subunits in the full MIB complex with SAMM50, metaxins and DNAJC11. Reason: Correct; also consistent with the human MIC10 co-immunoprecipitation of SAMM50 and metaxins 1 and 2. MIB is the correct term for this bridging assembly (rather than SAM complex). Supporting Evidence: PMID:26477565 C) the complete MIB complex containing in addition DNAJC11 and MTX1. PMID:22114354 In agreement, we found the outer mitochondrial membrane proteins Sam50 and metaxin 1 and 2 to coisolate with MINOS1, indicating that MINOS1 is part of a mitofilin-containing complex that associates with the outer membrane. |
| GO:0180020 membrane bending activity | ISS PMID:25955211 Mic10 oligomerizes to bend mitochondrial inner membranes at ... | NEW | Summary: Proposed new annotation: MIC10 bends lipid membranes through oligomerisation of its glycine-motif transmembrane hairpin. Reason: Purified yeast Mic10 (Q96VH5) induces curvature in model membranes, and glycine-motif oligomerisation mutants lose this activity and fail to form crista junctions in vivo; SGD records this as membrane bending (GO:0097753, IDA). Human MIC10 retains both GxGxGxG motifs (TM1 IGTGFGLGIV, TM2 AFGSGMGLGMA) and the basic inter-TM loop, and simulations of the MIC10 subcomplex support cardiolipin-assisted oligomerisation that stabilises curvature. This is a molecular function performed by MIC10 itself, the activity GO now uses for OPA1 and ESCRT-III proteins. Human protein has not been tested in vitro, hence ISS. Supporting Evidence: PMID:25955211 We show that Mic10 spans the inner membrane in a hairpin topology and that its ability to sculpt membranes depends on oligomerization through a glycine-rich motif. PMID:25955211 Oligomerization mutants fail to induce curvature in model membranes PMID:25955210 The four-glycine motifs are dispensable for interaction of Mic10 with other MICOS subunits but are crucial for the formation of large Mic10 oligomers. PMID:42647630 However, while Mic10 can act alone to form oligomers, which, in turn, causes membrane bending (22, 23), it is not solely responsible for the formation and maintenance of cristae (22). |
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Download this section (compressed HTML)Q: Does purified human MIC10 bend membranes in vitro as yeast Mic10 does, and does this depend on cardiolipin and on the two GxGxGxG motifs?
Q: Does human MIC10, like yeast Mic10, bind dimeric F1Fo-ATP synthase and promote its oligomerisation (PMID:28315355)? A positive result would support mitochondrial proton-transporting ATP synthase complex binding (GO:0140260), which yeast MIC10 already carries.
Q: Is the Cys58Ser variant found in trans to an exon-1 deletion in MICOS10-related hepatocerebral mtDNA depletion syndrome (PMID:39510533) a loss-of-function allele on its own, and how does a cristae defect lead to mtDNA depletion?
Experiment: Reconstitute purified human MIC10 (wild type and glycine-motif mutants) into liposomes of defined cardiolipin content and measure tubulation or curvature by cryo-EM, followed by rescue of MIC10-knockout cells with the same mutants scored for crista junction number.
Experiment: Co-immunoprecipitate or crosslink human MIC10 with ATP synthase from wild-type and MIC10-knockout cells and test ATP synthase oligomer levels by BN-PAGE.
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