Mitochondrial unfolded protein response

The mitochondrial unfolded protein response (UPRmt) is a mitochondria-to-nucleus signaling pathway that raises the expression of nuclear genes encoding mitochondrial chaperones and proteases when mitochondrial protein homeostasis is disturbed. Its executing transcription factor is a bZIP protein of the ATF4/ATF5 family that is partitioned between mitochondria and the nucleus: nematode ATFS-1 and its mammalian functional counterpart ATF5 both carry a mitochondrial targeting sequence, are kept in mitochondria in unstressed cells, and activate chaperone and protease genes when mitochondrial function fails; ATF5 rescues UPRmt signaling in atfs-1 mutant worms. The induced matrix chaperones, the HSP60 chaperonin and the mitochondrial HSP70, are both the classic reporters and the protective output of the response. How mitochondrial stress is relayed to the transcription factor differs between lineages. In Caenorhabditis elegans, where the pathway was defined, the key regulatory point is the import efficiency of ATFS-1: misfolded matrix proteins are degraded by the ClpP protease CLPP-1, the inner-membrane ABC transporter HAF-1 exports the resulting peptides and attenuates protein import under moderate stress, and ATFS-1 that escapes import reaches the nucleus. A nematode chromatin arm (DVE-1/UBL-5 together with the MET-2/LIN-65 H3K9 methylation machinery and the JMJD-3.1 H3K27 demethylase) acts alongside ATFS-1. In mammals, mitochondrial stress such as depolarization, import defects or iron deficiency activates the inner-membrane protease OMA1, which cleaves DELE1; the released DELE1 fragment activates the eIF2alpha kinase HRI (EIF2AK1) in the cytosol, and the resulting integrated stress response raises translation of ATF4 and ATF5. Mammalian CLPP is not required for the UPRmt, so the ClpP peptide signal is not a conserved part of the pathway.

MODULE:mitochondrial_uprDRAFTCONCRETESignaling Pathwaymodules/mitochondrial_upr.yaml
mitochondrial unfolded protein responseGO:0034514
PMID:15280428
Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.
Defines the C. elegans UPRmt: hsp-6 and hsp-60 are selectively induced by perturbed mitochondrial protein handling, and not by heat shock or ER stress.
hsp-6 and hsp-60 induction was specific to perturbed mitochondrial protein handling, as neither heat-shock nor endoplasmic reticulum stress nor manipulations that impair mitochondrial steps in intermediary metabolism or ATP synthesis activated the mitochondrial chaperone genes.
PMID:27426517
The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.
ATF5 is regulated like ATFS-1, induces a similar transcriptional response, and rescues UPRmt signaling in atfs-1-deficient worms, so UPRmt regulation is conserved from worms to mammals.
Here, we describe a mammalian transcription factor, ATF5, which is regulated similarly to ATFS-1 and induces a similar transcriptional response. ATF5 expression can rescue UPR(mt) signaling in atfs-1-deficient worms requiring the same UPR(mt) promoter element identified in C. elegans.
PMID:20188671
The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans.
Model of the nematode sensing arm: ClpP generates peptides from misfolded matrix proteins, and their HAF-1-dependent export contributes to UPRmt signaling.
perturbation of the protein-folding environment in the mitochondrial matrix promotes ClpP-mediated generation of peptides whose haf-1-dependent export from the matrix contributes to UPR(mt) signaling across the mitochondrial inner membrane.
PMID:22700657
Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation.
In C. elegans the key regulatory point is the mitochondrial import efficiency of ATFS-1.
We found that the key point of regulation is the mitochondrial import efficiency of ATFS-1.
PMID:32132707
Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
In mammalian cells mitochondrial stress is relayed to ATF4 through OMA1-dependent DELE1 cleavage and HRI activation.
Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2α kinase activity of HRI.
PMID:27154400
Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt.
Lineage difference: mammalian CLPP is neither required for nor a regulator of the UPRmt, unlike C. elegans CLPP-1.
Remarkably, our results clearly show that mammalian CLPP is neither required for, nor it regulates the UPR(mt) in mammals.
PMID:22719267
Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.
In C. elegans a GCN-2/eIF2alpha translational arm protects mitochondria during stress and is complementary to, not part of, HAF-1/ATFS-1 chaperone induction.
Our data demonstrate that GCN-2-dependent translational control acts in a mitochondrial protective signaling pathway complementary to the regulation of mitochondrial chaperone gene expression mediated by HAF-1 and ATFS-1.
file:genes/worm/atfs-1/atfs-1-ai-review.yaml
worm atfs-1 gene review
Core functions: RNA polymerase II-specific transcription activator in the nucleoplasm for the UPRmt and for defense against Gram-negative bacteria, and mitochondrial transcription factor activity in the matrix.
file:genes/human/ATF5/ATF5-ai-review.yaml
human ATF5 gene review
Core function: RNA polymerase II-specific DNA-binding transcription activator in the nucleus acting in the mitochondrial unfolded protein response.
file:genes/human/CLPP/CLPP-ai-review.yaml
human CLPP gene review
Core function: serine-type endopeptidase of the matrix ClpXP protease in mitochondrial protein catabolism and quality control; the review records PMID:27154400 as the caveat against transferring the worm CLPP-1 UPRmt signaling role to mammals.

Boundary. The module covers the conserved UPRmt trunk (stress relay, an ATF4/ATF5-family bZIP transcription factor partitioned between mitochondria and nucleus, and induced matrix chaperones), with the relay modeled as a lineage variant set. It is set at Metazoa (NCBITaxon:33208): the ATFS-1/ATF5 logic is documented in nematodes and mammals, and the HSP60 and mtHSP70 outputs are conserved across animals. The two variants are the two documented relays, not an exhaustive survey; insect UPRmt wiring is not modeled. Lineage differences. (a) Nematode: CLPP-1 proteolysis, HAF-1 peptide export and ATFS-1 import competition, plus a chromatin arm (DVE-1/UBL-5, LIN-65, MET-2, JMJD-3.1) that is described only in C. elegans. HAF-1 is needed under moderate stress, not under severe stress that blocks import directly; it is thought to dampen import rather than to be part of the import machinery (see the haf-1 review). (b) Mammalian: OMA1-DELE1-HRI-eIF2alpha drives the integrated stress response, which raises ATF4 and ATF5 translation. DELE1 is a messenger for mitochondrial stress in general (depolarization, import failure, iron deficiency), not specifically a sensor of misfolded proteins. Mammalian CLPP is the same PANTHER subfamily as CLPP-1 (PTHR10381:SF11) but is not required for the mammalian UPRmt (PMID:27154400), so it is not given the CLPP-1 signaling role and is not a member of the mammalian variant. Its ATFS-1-like mitochondrial partitioning is recorded on the ATF5 member of the shared transcription factor part. ATF4 is in the same PANTHER family but does not rescue atfs-1 worms (PMID:27426517); it is modeled as the ISR transcription factor of the mammalian variant. Left out. The C. elegans GCN-2/eIF2alpha arm is complementary to and independent of ATFS-1 activation (PMID:22719267) and is left to the integrated stress response; the gcn-2 review lists it as a core UPRmt process, which is recorded here only as context. The neuronal and germline signals that switch on the intestinal UPRmt cell-non-autonomously (serotonin, the retromer-dependent Wnt EGL-20 signal, PMID:30057120) are not modeled. JMJD-1.2 acts with JMJD-3.1 (PMID:27133168) but has no review and is only named. ULP-4 and the NuRD/HDA-1 regulators (PMID:30642431, PMID:32789178, PMID:32934238) are modulators. The matrix LON protease that degrades imported ATFS-1 (and LONP1, which degrades imported DELE1) is not modeled. Innate immunity and lifespan extension are outputs of the transcriptional program and are not module processes. ATFS-1 dual targeting. ATFS-1 appears twice: in the nematode variant as the matrix pool that binds mitochondrial DNA (mitochondrial transcription factor activity) before degradation, and in the shared part as the nuclear RNA polymerase II activator. The import checkpoint negatively regulates the nuclear part. PANTHER grounding. ATFS-1 (PTHR13044:SF12) and ATF5 (PTHR13044:SF3) are in PTHR13044 and both inherit DNA-binding transcription activator activity from PAINT node PTN000315883 (Opisthokonta); that node is a generic bZIP activator node, not a UPRmt-specific one. HSP-60 and HSPD1 are in PTHR45633:SF17; the family's PAINT node PTN000143510 carries the UPRmt process (seeded by worm hsp-60). HSP-6 and HSPA9 are in the mitochondrial HSP70 subfamily PTHR19375:SF184 and both inherit from the mitochondrial HSP70 node PTN000452554. Related modules. ATFS-1-dependent transcription of mitophagy genes is treated in MODULE:mitophagy, the cytosolic heat shock response in MODULE:heat_shock_response and the ER UPR in MODULE:er_unfolded_protein_response.

13Nodes
10Parts
1Variant Sets
2Variants
16Annotons
12Connections

Derived QC

Recommended-field compliance

74.2% recommended fields populated
  • knowledge_gaps[0].provenance[0] · reference_section_type (0/1)
  • knowledge_gaps[1] · boundary (0/1)
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  • knowledge_gaps[2] · boundary (0/1)
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  • knowledge_gaps[3] · boundary (0/1)
  • knowledge_gaps[3].provenance[0] · reference_section_type (0/1)
  • knowledge_gaps[4].provenance[0] · reference_section_type (0/1)

Module deep research

✗ none found

No MODULE:mitochondrial_upr deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

17 gene-function check(s) reflected in core functions · 0 conflict(s) · 4 evidence or coverage gap(s) (21 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
clpp1_matrix_protease CLPP-1
UniProtKB:Q27539
Gene 		ATP-dependent peptidase activity
GO:0004176 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
haf1_peptide_exporter HAF-1
UniProtKB:O45278
Gene 		ABC-type peptide transporter activity
GO:0015440 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atfs1_matrix ATFS-1
UniProtKB:Q23272
Gene 		mitochondrial transcription factor activity
GO:0034246 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dve1_activator DVE-1
UniProtKB:Q86MI0
Gene 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ubl5_coactivator UBL-5
UniProtKB:P91302
Gene 		transcription coactivator activity
GO:0003713 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
met2_h3k9_methyltransferase MET-2
UniProtKB:P34544
Gene 		histone H3K9 dimethyltransferase activity
GO:0140942 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
jmjd31_demethylase JMJD-3.1
UniProtKB:Q95QK3
Gene 		histone H3K27me2/H3K27me3 demethylase activity
GO:0071558 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
oma1_protease OMA1
UniProtKB:Q96E52
Gene 		metalloendopeptidase activity
GO:0004222 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dele1_kinase_activator DELE1
UniProtKB:Q14154
Gene 		protein serine/threonine kinase activator activity
GO:0043539 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hri_eif2a_kinase HRI (EIF2AK1)
UniProtKB:Q9BQI3
Gene 		eukaryotic translation initiation factor 2alpha kinase activity
GO:0004694 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hri_heme_sensor HRI (EIF2AK1)
UniProtKB:Q9BQI3
Gene 		heme binding
GO:0020037 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atf4_activator ATF4
UniProtKB:P18848
Gene 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atfs1_atf5_activator ATFS-1 (worm)
UniProtKB:Q23272
Family Representative 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atfs1_atf5_activator ATF5 (human)
UniProtKB:Q9Y2D1
Family Representative 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mthsp70_chaperone HSP-6 (worm)
UniProtKB:P11141
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mthsp70_chaperone HSPA9 (human)
UniProtKB:P38646
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
hsp60_chaperonin HSP-60 (worm)
UniProtKB:P50140
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsp60_chaperonin HSPD1 (human)
UniProtKB:P10809
Family Representative 		ATP-dependent protein folding chaperone
GO:0140662 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atfs1_atf5_activator ATFS-1/ATF5 mitochondria-partitioned bZIP factors
PANTHER:PTHR13044
Family 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR13044.
mthsp70_chaperone mitochondrial HSP70 (mtHSP70/mortalin) chaperones
PANTHER:PTHR19375:SF184
Family 		ATP-dependent protein folding chaperone
GO:0140662 		Family Function Unreviewed
Family review leaves GO:0140662 UNRESOLVED. Canonical Hsp70/DnaK folding activity remains positive, including direct denatured-luciferase reactivation evidence for yeast Ssa1. A universal grant across this heterogeneous family is not justified. The current term requires ATP-driven assistance to protein folding; HscA ATPase stimulation, client capture and cluster transfer do not alone establish that endpoint. E. coli HscA stabilizes disordered IscU and has model-client antiaggregation activity. The full PMID9852006 study separately reports failure to restore denatured-luciferase activity in the tested Hsc66 partner combinations, with a positive DnaK control. Together these observations make generic folding assignments over-annotated for the E. coli target without proving impossibility for every substrate or transferring a negative experiment to the Pseudomonas and Azotobacter homologs. Their folding endpoints remain unresolved. The negative Hsp110 judgment for HSPH1/Q92598 remains: it acts as a nucleotide-exchange factor and holdase rather than an independent ATP-driven folding chaperone. The exact former exception object is archived because live member exceptions cannot qualify an UNRESOLVED universal scope; no negative HscA exception, loss event or new broad ATPase grant is added. HSPA13 and other divergent proteins remain member-level questions.
hsp60_chaperonin mitochondrial HSP60 chaperonins
PANTHER:PTHR45633:SF17
Family 		ATP-dependent protein folding chaperone
GO:0140662 		Family Function Unreviewed
Family review leaves GO:0140662 UNRESOLVED. Hsp60/GroEL uses ATP-dependent folding cycles, whereas Tcm62 is a divergent chaperonin-related assembly and antiaggregation factor whose ATP-dependent folding mechanism is not established. Mitochondrial residence, antigenicity and particular imported substrates are lineage-specific contexts; chaperone-assisted import is not membrane-channel activity. ATP-dependent folding cannot be granted family-wide without resolving the Tcm62 boundary and defining the supported chaperonin branches.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • atfs1_import_checkpoint ⊣ uprmt_transcription_factor [input]
    atfs1_import_checkpoint is a negative regulator with no upstream edge (not described as feedback)
  • matrix_signal_generation ⊣ atfs1_import_checkpoint [input]
    matrix_signal_generation is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (17/17 grounded genes reviewed)

12 complete review(s) · 14 with deep research · 0 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
ATF4 P18848 ✓ 215/216 ✓
ATF5 Q9Y2D1 ✓ ✓ ✗
atfs-1 Q23272 ✓ ✓ ✓
clpp-1 Q27539 ✓ ✓ ✓
DELE1 Q14154 ✓ ✓ ✗
dve-1 Q86MI0 ✓ 29/30 ✓
EIF2AK1 Q9BQI3 ✓ ✓ ✗
haf-1 O45278 ✓ ✓ ✓
hsp-6 P11141 ✓ ✓ ✓
hsp-60 P50140 ✓ 20/21 ✓
HSPA9 P38646 ✓ ✓ ✓
HSPD1 P10809 ✓ 173/178 ✓
jmjd-3.1 Q95QK3 ✓ 18/19 ✓
lin-65 Q95XN0 ✓ ✓ ✓
met-2 P34544 ✓ ✓ ✓
OMA1 Q96E52 ✓ ✓ ✓
ubl-5 P91302 ✓ ✓ ✓

Details

Context
MetazoaNCBITaxon:33208
mitochondrial protein-folding or proteostasis stress (e.g. spg-7 or hsp-6 RNAi in worms; respiratory chain inhibition, mtDNA depletion, misfolded matrix protein expression, depolarization in mammalian cells)
Mitochondrial unfolded protein responseSignaling Pathwaymitochondrial_upr

Mitochondria-to-nucleus pathway in which a lineage-specific relay (nematode ClpP peptide export and ATFS-1 import competition, or mammalian OMA1-DELE1-HRI integrated stress response signaling) activates an ATFS-1/ATF5-family bZIP transcription factor that induces mitochondrial chaperone genes.

mitochondrial unfolded protein responseGO:0034514
Context
MetazoaNCBITaxon:33208
mitochondrial protein-folding or proteostasis stress (e.g. spg-7 or hsp-6 RNAi in worms; respiratory chain inhibition, mtDNA depletion, misfolded matrix protein expression, depolarization in mammalian cells)

Connections

Either relay increases the nuclear activity of the ATFS-1/ATF5 factor: by releasing ATFS-1 from import in worms, or by raising ATF5 synthesis through eIF2alpha phosphorylation in mammals.
Nematode variant: efficient mitochondrial import and degradation of ATFS-1 keeps it out of the nucleus; reduced import releases the nuclear pool.
Mammalian variant: eIF2alpha phosphorylation favours ATF5 synthesis.
Nuclear ATFS-1 or ATF5 induces HSP60 and mtHSP70 transcription.
chromatin_arm -> chaperone_output Positively Regulates
Nematode variant: DVE-1/UBL-5 and the chromatin regulators are required for hsp-60 and hsp-6 induction.
Part 1: relay of mitochondrial stress to the UPRmt transcription factor
Mitochondrial stress relayBiological Processmitochondrial_stress_relay

Converts loss of mitochondrial proteostasis or import capacity into activation of the UPRmt transcription factor. Implemented differently in nematodes and mammals.

Variant set: Stress relay route by taxon / sensing mechanism (Exactly One)
PMID:27154400
Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt.
CLPP plays a central role in worm UPRmt activation, but the assumption that it does the same in mammals does not hold.
The mitochondrial matrix protease CLPP plays a central role in the activation of the mitochondrial unfolded protein response (UPR(mt)) in Caenorhabditis elegans

The nematode route reads mitochondrial import capacity directly through ATFS-1 import competition, with a ClpP/HAF-1 peptide signal under moderate stress. The mammalian route is the OMA1-DELE1-HRI branch of the integrated stress response. Neither DELE1 nor an OMA1-DELE1 relay is known in C. elegans, and mammalian CLPP is dispensable for the UPRmt (PMID:27154400). EXACTLY_ONE is kept although it is open whether mammalian ATF5 is also controlled by import competition (see knowledge gaps). The variants are lineage routes: the nematode variant is the CLPP-1/HAF-1/ATFS-1 relay, which mammals do not use because CLPP is dispensable there. A mammalian ATF5 import checkpoint, if it is shown, would be a new part of the mammalian variant or a further variant, not the nematode one. No organism is known to use both documented routes, so ONE_OR_MORE would assert a co-occurrence that has not been shown.

Nematode ATFS-1 import-competition routeBiological Processnematode_atfs1_import_route

CLPP-1 peptide generation and HAF-1 export attenuate mitochondrial import, so that ATFS-1 escapes import and degradation; a nematode-specific chromatin arm prepares target loci.

Context
Caenorhabditis elegansNCBITaxon:6239

Connections

HAF-1 (with CLPP-1-generated peptides) is thought to dampen mitochondrial import during moderate stress, so less ATFS-1 is imported; in haf-1 mutants the stress- induced drop in import is not seen. How exported peptides act on import is not known.
matrix_signal_generation -> chromatin_arm Positively Regulates
CLPP-1 is required for DVE-1 nuclear redistribution and promoter binding.
Part 1: matrix stress signal generation and export
CLPP-1 proteolysis and HAF-1 peptide exportBiological Processmatrix_signal_generation

Misfolded matrix proteins are degraded by the CLPP-1 protease and the resulting peptides are exported across the inner membrane by HAF-1. Both are genetically required for nuclear accumulation of ATFS-1 and for activation of the hsp-60 and hsp-6 reporters. Peptide efflux from isolated mitochondria is ATP-dependent and needs both HAF-1 and ClpP.

Context
mitochondrial matrixGO:0005759

Annotons

CLPP-1 matrix ATP-dependent protease
clpp1_matrix_protease
Participant: Gene Product: CLPP-1
Gene Product:
CLPP-1UniProtKB:Q27539

Function

ATP-dependent peptidase activityGO:0004176 Proteolytic chamber of the ClpXP protease, following the clpp-1 review core function. The ATPase partner (CLPX) is not modeled.
Substrates: misfolded mitochondrial matrix proteins
Products: peptides

Processes

mitochondrial unfolded protein responseGO:0034514 protein quality control for misfolded or incompletely synthesized proteinsGO:0006515

Locations

mitochondrial matrixGO:0005759

Generates the peptide signal from misfolded matrix proteins. Reduced clpp-1 activity attenuates DVE-1 nuclear redistribution, promoter binding and the downstream UPRmt. This signaling role is nematode-specific: mammalian CLPP (same subfamily) is not required for the UPRmt (PMID:27154400).

PMID:17925224
ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans.
DVE-1 nuclear redistribution, promoter binding and the UPRmt are attenuated when clpp-1 activity is reduced.
These events and the downstream UPR(mt) are attenuated in animals with reduced activity of clpp-1, which encodes a mitochondrial matrix protease homologous to bacterial ClpP.
HAF-1 inner-membrane peptide exporter
haf1_peptide_exporter
Participant: Gene Product: HAF-1
Gene Product:
HAF-1UniProtKB:O45278

Function

ABC-type peptide transporter activityGO:0015440 Inferred from ATP-dependent, HAF-1-dependent peptide efflux from isolated mitochondria; transport by purified HAF-1 has not been reconstituted.
Substrates: CLPP-1-generated matrix peptides

Processes

mitochondrial unfolded protein responseGO:0034514

Locations

mitochondrial inner membraneGO:0005743

Mitochondria-localized ABC protein required for UPRmt signaling and for nuclear localization of ATFS-1 under moderate mitochondrial stress, but not under severe stress that blocks import directly. It is thought to attenuate mitochondrial protein import during stress rather than to be part of the import machinery.

PMID:20188671
The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans.
Peptide efflux from isolated mitochondria needs ATP, HAF-1 and ClpP.
Peptide efflux from isolated mitochondria was ATP dependent and required HAF-1 and the protease ClpP.
PMID:20188671
The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans.
haf-1 deletion blocks nuclear localization of ATFS-1 (ZC376.7) under stress.
Defective UPR(mt) signaling in the haf-1-deleted worms was associated with failure of the bZIP protein, ZC376.7, to localize to nuclei in worms with perturbed mitochondrial protein folding
PMID:22719267
Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.
HAF-1 is localized to the mitochondrial inner membrane.
the mitochondrial inner membrane-localized peptide transporter HAF-1

Connections

CLPP-1-generated peptides are the proposed HAF-1 export cargo.
Part 2: ATFS-1 mitochondrial import checkpoint
ATFS-1 mitochondrial import and matrix activityRegulatory Stepatfs1_import_checkpoint

ATFS-1 has an N-terminal mitochondrial targeting sequence that is essential for UPRmt repression. In unstressed cells ATFS-1 is efficiently imported into mitochondria and degraded, so it does not reach the nucleus. The import efficiency of ATFS-1 thus reports the capacity of mitochondrial protein import. Imported ATFS-1 also binds OXPHOS gene promoters in mitochondrial DNA and limits OXPHOS transcript accumulation during stress.

Annotons

ATFS-1 in the mitochondrial matrix
atfs1_matrix
Participant: Gene Product: ATFS-1
Gene Product:
ATFS-1UniProtKB:Q23272

Function

mitochondrial transcription factor activityGO:0034246
Targets: mtDNA OXPHOS gene promoters

Processes

mitochondrial transcriptionGO:0006390

Locations

mitochondrial matrixGO:0005759

Import of ATFS-1 into the matrix, followed by its degradation, keeps the nuclear response off. The matrix pool binds mtDNA and tunes OXPHOS transcript levels.

PMID:22700657
Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation.
ATFS-1 has an MTS and an NLS; the MTS is essential for UPRmt repression.
In addition to a nuclear localization sequence, ATFS-1 has an N-terminal mitochondrial targeting sequence that is essential for UPR(mt) repression. Normally, ATFS-1 is imported into mitochondria and degraded.
PMID:25773600
Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).
ATFS-1 binds OXPHOS gene promoters in both nuclear and mitochondrial genomes.
ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes.
Part 3: chromatin arm that makes UPRmt target genes accessible
DVE-1/UBL-5 and chromatin reorganizationBiological Processchromatin_arm

Mitochondrial stress causes DVE-1 and UBL-5 to form a complex and accumulate in nuclei, where DVE-1 binds mitochondrial chaperone promoters. In parallel, MET-2 with its nuclear cofactor LIN-65 deposits H3K9me2 and compacts most of the genome, while the regions that stay open are bound by DVE-1. The H3K27 demethylase JMJD-3.1 is needed for full UPRmt induction and for mitochondrial stress-induced longevity.

Context
nucleusGO:0005634

Annotons

DVE-1 homeodomain transcription factor
dve1_activator
Participant: Gene Product: DVE-1
Gene Product:
DVE-1UniProtKB:Q86MI0

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228
Targets: hsp-60 and other mitochondrial chaperone gene promoters

Processes

mitochondrial unfolded protein responseGO:0034514

Locations

nucleusGO:0005634

SATB-like homeodomain factor whose nuclear redistribution and enhanced binding to chaperone promoters accompany UPRmt activation; it binds the chromatin regions left open after MET-2/LIN-65-dependent compaction.

PMID:17925224
ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans.
UPRmt activation correlates with DVE-1 nuclear redistribution and enhanced binding to mitochondrial chaperone promoters.
Activation of the UPR(mt) correlates temporally and spatially with nuclear redistribution of DVE-1 and with its enhanced binding to the promoters of mitochondrial chaperone genes.
UBL-5 DVE-1-associated coactivator
ubl5_coactivator
Participant: Gene Product: UBL-5
Gene Product:
UBL-5UniProtKB:P91302

Function

transcription coactivator activityGO:0003713 In the ubl-5 review GO:0003713 is a NEW proposal (no GOA row), and it is the second core function. The primary core MF there is splicing factor binding (GO:1990935), for the essential spliceosome role, which is outside this module. Only the UPRmt coactivator role is modeled here.

Processes

mitochondrial unfolded protein responseGO:0034514

Locations

nucleusGO:0005634

Ubiquitin-like protein that complexes with DVE-1 under mitochondrial stress and accumulates in nuclei. It is not a conjugated modifier (it lacks the C-terminal di-glycine).

PMID:17925224
ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans.
Mitochondrial unfolded protein stress correlates with DVE-1-UBL-5 complex formation.
Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5
PMID:16816413
Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response.
UBL-5 accumulates in nuclei under mitochondrial stress and acts in a nuclear step of the UPRmt.
Induction of mitochondrial stress promotes accumulation of GFP-tagged UBL-5 in nuclei of transgenic worms, suggesting that UBL-5 effects a nuclear step required for mounting a response to the threat of mitochondrial protein misfolding.
MET-2 H3K9 dimethyltransferase
met2_h3k9_methyltransferase
Participant: Gene Product: MET-2
Gene Product:
MET-2UniProtKB:P34544

Function

histone H3K9 dimethyltransferase activityGO:0140942 The met-2 review MODIFYs its methyltransferase rows to the parent histone H3K9 methyltransferase activity (GO:0046974), and proposes this child term as a NEW core function. The child is used here because the UPRmt evidence is specifically for H3K9 dimethylation (PMID:27133166).

Processes

mitochondrial unfolded protein responseGO:0034514 heterochromatin formationGO:0031507

Locations

nucleusGO:0005634

SETDB1-family methyltransferase whose H3K9 dimethylation is required for UPRmt activation; it silences bulk chromatin while selected loci open for DVE-1.

PMID:27133166
Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPR(mt).
UPRmt activation requires H3K9 dimethylation by MET-2 and the nuclear cofactor LIN-65.
Mitochondrial stress response activation requires the di-methylation of histone H3K9 through the activity of the histone methyltransferase met-2 and the nuclear co-factor lin-65.
LIN-65 nuclear cofactor of MET-2
lin65_cofactor
Participant: Gene Product: LIN-65
Gene Product:
LIN-65UniProtKB:Q95XN0

Processes

mitochondrial unfolded protein responseGO:0034514

Locations

nucleusGO:0005634

Nuclear cofactor required with MET-2 for stress-induced H3K9 dimethylation and UPRmt. No molecular function is asserted, in line with the lin-65 review: how LIN-65 supports MET-2 activity is not known.

PMID:27133166
Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPR(mt).
Remaining open chromatin is bound by DVE-1 after global silencing.
While globally the chromatin becomes silenced by these marks, remaining portions of the chromatin open up, at which point the binding of canonical stress responsive factors such as DVE-1 occurs.
JMJD-3.1 H3K27 demethylase
jmjd31_demethylase
Participant: Gene Product: JMJD-3.1
Gene Product:
JMJD-3.1UniProtKB:Q95QK3

Function

histone H3K27me2/H3K27me3 demethylase activityGO:0071558

Processes

mitochondrial unfolded protein responseGO:0034514

Locations

nucleusGO:0005634

JMJD3-family demethylase that, with JMJD-1.2, positively regulates UPRmt induction and mitochondrial stress-induced longevity.

PMID:27133168
Two Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity.
Loss of jmjd-1.2 or jmjd-3.1 suppresses UPRmt induction and longevity.
Reduction of function of the demethylases potently suppresses longevity and UPR(mt) induction, while gain of function is sufficient to extend lifespan in a UPR(mt)-dependent manner.

Connections

MET-2/LIN-65-dependent chromatin compaction leaves selected regions open for DVE-1 binding.
Mammalian OMA1-DELE1-HRI integrated stress response routeSignaling Pathwaymammalian_oma1_dele1_hri_route

Mitochondrial stress activates the inner-membrane protease OMA1, which cleaves DELE1. The DELE1 C-terminal fragment accumulates in the cytosol, binds and activates the eIF2alpha kinase HRI, and eIF2alpha phosphorylation raises translation of the uORF-regulated bZIP factors ATF4 and ATF5. Under iron deficiency, arrested DELE1 import stabilizes DELE1 on the mitochondrial surface and activates HRI by the same route.

Context
Homo sapiensNCBITaxon:9606

Connections

oma1_dele1_cleavage -> dele1_hri_activation Positively Regulates
OMA1 cleavage releases the DELE1 fragment that activates HRI.
DELE1 binds and activates HRI.
eIF2alpha phosphorylation favours translation of ATF4.
Part 1: OMA1 cleavage of DELE1
OMA1 stress-activated cleavage of DELE1Reactionoma1_dele1_cleavage

Annotons

OMA1 inner-membrane metalloprotease
oma1_protease
Participant: Gene Product: OMA1
Gene Product:
OMA1UniProtKB:Q96E52

Function

metalloendopeptidase activityGO:0004222
Substrates: DELE1 (also OPA1)
Products: DELE1 C-terminal short form (S-DELE1)

Processes

mitochondrial protein processingGO:0034982

Locations

mitochondrial inner membraneGO:0005743

Stress-activated protease whose cleavage of DELE1 releases the signaling fragment; the same activation drives OPA1 processing.

PMID:32132706
A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol.
Stress-activated OMA1 cleaves DELE1 into a short form that accumulates in the cytosol and activates HRI.
Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion.
file:genes/human/OMA1/OMA1-ai-review.yaml
human OMA1 gene review
Core function metalloendopeptidase activity.
Part 2: DELE1 activation of HRI
DELE1 activates HRI in the cytosolMolecular Functiondele1_hri_activation

Annotons

DELE1 cytosolic HRI activator
dele1_kinase_activator
Participant: Gene Product: DELE1
Gene Product:
DELE1UniProtKB:Q14154

Function

protein serine/threonine kinase activator activityGO:0043539
Targets: HRI (EIF2AK1)

Processes

HRI-mediated signalingGO:0140468

Locations

cytosolGO:0005829

Mitochondrial stress messenger. Imported and degraded by LONP1 at steady state; its OMA1-generated fragment (or full-length DELE1 stalled on the outer membrane under iron deficiency) binds and activates HRI. It reports depolarization, import failure and iron deficiency, and is not specifically a sensor of misfolded proteins.

PMID:32132707
Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
Purified DELE1 stimulates HRI eIF2alpha kinase activity.
Using purified HRI, eIF2α and DELE1, we showed that DELE1 stimulates eIF2α kinase activity of HRI in vitro
PMID:37327776
A mitochondrial iron-responsive pathway regulated by DELE1.
Iron chelation arrests DELE1 import and stabilizes it on the mitochondrial surface, where it activates HRI-mediated ISR.
Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR).
file:genes/human/DELE1/DELE1-ai-review.yaml
human DELE1 gene review
Core function protein serine/threonine kinase activator activity in HRI-mediated signaling, cytosol and mitochondrial outer membrane.
Part 3: HRI phosphorylation of eIF2alpha
HRI eIF2alpha kinaseMolecular Functionhri_eif2a_phosphorylation

Annotons

HRI eIF2alpha kinase
hri_eif2a_kinase
Participant: Gene Product: HRI (EIF2AK1)
Gene Product:
HRI (EIF2AK1)UniProtKB:Q9BQI3

Function

eukaryotic translation initiation factor 2alpha kinase activityGO:0004694
Substrates: eIF2alpha (EIF2S1) Ser51

Processes

HRI-mediated signalingGO:0140468

Locations

cytosolGO:0005829

The eIF2alpha kinase necessary and sufficient for relaying mitochondrial stress to ATF4.

PMID:32132707
Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
HRI is the eIF2alpha kinase necessary and sufficient for the relay.
HRI is the eIF2α kinase that is necessary and sufficient for this relay.
HRI heme sensing
hri_heme_sensor
Participant: Gene Product: HRI (EIF2AK1)
Gene Product:
HRI (EIF2AK1)UniProtKB:Q9BQI3

Function

heme bindingGO:0020037

Locations

cytosolGO:0005829

Heme bound to the N-terminal and kinase-insert domains keeps HRI inactive. Heme sensing is a second, DELE1-independent input to the same kinase and is included because it sets HRI responsiveness.

PMID:17110456
Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias.
HRI senses intracellular heme through its heme-binding domains.
In this manner, HRI serves as a feedback inhibitor of globin synthesis by sensing the intracellular concentration of heme through its heme-binding domains.
file:genes/human/EIF2AK1/EIF2AK1-ai-review.yaml
human EIF2AK1 gene review
Core functions eIF2alpha kinase activity in HRI-mediated signaling and heme binding, cytosol.
Part 4: ISR transcription factor ATF4
ATF4 translation and transcriptional activationMolecular Functionatf4_isr_activation

Annotons

ATF4 ISR transcription activator
atf4_activator
Participant: Gene Product: ATF4
Gene Product:
ATF4UniProtKB:P18848

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

HRI-mediated signalingGO:0140468

Locations

nucleusGO:0005634

uORF-regulated bZIP factor whose translation rises after eIF2alpha phosphorylation; it drives the ISR arm of the mammalian mitochondrial stress response. It does not substitute for ATFS-1 in worms.

PMID:32132707
Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
Mitochondrial dysfunction triggers eIF2alpha phosphorylation and induction of ATF4.
In mammalian cells, mitochondrial dysfunction triggers the integrated stress response, in which the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) results in the induction of the transcription factor ATF4
PMID:27426517
The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.
Transgenic ATF4, unlike ATF5, does not rescue hsp-60 reporter induction in atfs-1 worms.
Interestingly, atfs-1-deletion worms expressing transgenic ATF5, but not worms expressing transgenic ATF4, were able to induce the hsp-60pr::gfp reporter during mitochondrial stress
Part 2: UPRmt transcriptional activation by an ATFS-1/ATF5-family bZIP factor
ATFS-1/ATF5 nuclear transcriptional activationMolecular Functionuprmt_transcription_factor

A bZIP factor with both a mitochondrial targeting sequence and a nuclear localization signal is held in mitochondria in unstressed cells. During mitochondrial stress part of the pool reaches the nucleus and activates genes for mitochondrial chaperones and proteases (and, in worms, OXPHOS assembly factors, glycolysis and innate immunity genes) through a conserved UPRmt promoter element.

Annotons

ATFS-1/ATF5 UPRmt transcription activator
atfs1_atf5_activator
Participant: Family: ATFS-1/ATF5 mitochondria-partitioned bZIP factors
Family:
ATFS-1/ATF5 mitochondria-partitioned bZIP factorsPANTHER:PTHR13044 PTHR13044 also contains ATF4, which is not a UPRmt counterpart of ATFS-1 (it fails to rescue atfs-1 worms); the role is restricted to the ATFS-1 (SF12) and ATF5 (SF3) subfamilies.
Representative Members: ATFS-1 (worm)UniProtKB:Q23272 ATF5 (human)UniProtKB:Q9Y2D1

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228
Targets: UPRmt promoter element of HSP60, mtHSP70 (hsp-60, hsp-6), LONP1 and other mitochondrial protective genes

Processes

mitochondrial unfolded protein responseGO:0034514

Locations

nucleoplasmGO:0005654

The transcription factor that executes the UPRmt in the nucleus. In worms, nuclear ATFS-1 is released by reduced import. In mammals ATF5 localizes to mitochondria in the absence of stress, and its synthesis is also raised by eIF2alpha phosphorylation.

PMID:22700657
Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation.
Reduced import during stress lets ATFS-1 accumulate in the cytosol and reach the nucleus.
during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus.
PMID:25274306
Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection.
Nuclear trafficking of ATFS-1 depends on its NLS and activates a protective transcriptional response.
Because ATFS-1 has a nuclear localization sequence (NLS), it then traffics to the nucleus where it activates a protective transcriptional response
PMID:25773600
Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).
ATFS-1 ChIP-seq targets include chaperone, OXPHOS assembly factor and glycolysis genes.
in addition to regulating mitochondrial chaperone, OXPHOS complex assembly factor, and glycolysis genes
PMID:27426517
The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.
ATF5 localizes to mitochondria in the absence of stress.
Our data support a model that when expressed, ATF5 localizes to mitochondria in the absence of stress.
PMID:27426517
The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.
Increased eIF2alpha phosphorylation favours ATF5 synthesis, linking the UPRmt to the ISR.
our work also suggests an interaction between the UPRmt and the integrated stress response (ISR) because increased eIF2α-phosphorylation results in preferential ATF5 synthesis
file:genes/human/ATF5/ATF5-ai-review.yaml
human ATF5 gene review
Core function GO:0001228 in the nucleus, acting in the mitochondrial unfolded protein response.
Part 3: induced mitochondrial chaperone output
HSP60 and mtHSP70 matrix chaperone outputBiological Processchaperone_output

The chaperonin HSP60 and the mitochondrial HSP70 are the best-characterized induced genes in both worms (hsp-60, hsp-6) and mammals (HSPD1, HSPA9), and the reporters used to define the pathway. Their induction raises matrix folding capacity.

Context
mitochondrial matrixGO:0005759

Annotons

Mitochondrial HSP70 chaperone
mthsp70_chaperone
Participant: Family: mitochondrial HSP70 (mtHSP70/mortalin) chaperones
Family:
mitochondrial HSP70 (mtHSP70/mortalin) chaperonesPANTHER:PTHR19375:SF184 Mitochondrial subfamily of the HSP70 family PTHR19375.
Representative Members: HSP-6 (worm)UniProtKB:P11141 HSPA9 (human)UniProtKB:P38646

Function

ATP-dependent protein folding chaperoneGO:0140662 As in the hsp-6 review core function; the HSPA9 review uses the parent protein folding chaperone (GO:0044183).

Processes

protein foldingGO:0006457

Locations

mitochondrial matrixGO:0005759

Matrix HSP70 induced by the UPRmt. Its depletion is itself a UPRmt trigger in worms. It also drives matrix protein import as the PAM motor.

PMID:15280428
Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.
hsp-6 and hsp-60 encode the matrix HSP70 and HSP60 chaperones and are selectively induced.
We found that the mitochondrial matrix HSP70 and HSP60 chaperones, encoded by the Caenorhabditis elegans hsp-6 and hsp-60 genes, were selectively activated by perturbations that impair assembly of multi-subunit mitochondrial complexes
PMID:27426517
The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.
In human cells, ATF5 knockdown lowers steady-state HSP60, mtHSP70 and LONP1 expression in a cell line with mtDNA lesions.
ATF5 shRNA reduced the steady state expression of HSP60, mtHSP70, LONP1 and impaired cell growth
file:genes/human/HSPA9/HSPA9-ai-review.yaml
human HSPA9 gene review
Core functions protein folding chaperone and ATP hydrolysis activity in the mitochondrial matrix, including protein import into the matrix.
Mitochondrial HSP60 chaperonin
hsp60_chaperonin
Participant: Family: mitochondrial HSP60 chaperonins
Family:
mitochondrial HSP60 chaperoninsPANTHER:PTHR45633:SF17
Representative Members: HSP-60 (worm)UniProtKB:P50140 HSPD1 (human)UniProtKB:P10809

Function

ATP-dependent protein folding chaperoneGO:0140662

Processes

mitochondrial unfolded protein responseGO:0034514

Locations

mitochondrial matrixGO:0005759

Matrix chaperonin (with HSP10) induced by the UPRmt; hsp-60pr::gfp is the standard worm pathway reporter.

PMID:16816413
Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response.
ubl-5 RNAi blocks induction of endogenous hsp-60 and hsp-6.
ubl-5 (RNAi) inhibits the induction of endogenous mitochondrial chaperone encoding genes hsp-60 and hsp-6 and compromises the ability of animals to cope with mitochondrial stress.
PMID:27426517
The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.
Paraquat induces HSP60, mtHSP70 and LONP1 transcription in human cells.
resulted in increased transcription of HSP60, mtHSP70, LONP1 and HD-5, a secreted anti-microbial peptide
file:genes/human/HSPD1/HSPD1-ai-review.yaml
human HSPD1 gene review
Core function ATP-dependent protein folding chaperone in the mitochondrial matrix.