Pathway Human Homo sapiens

Mitochondrial unfolded protein response (UPRmt)

R-HSA-9841251 in Reactome release 97: under Cellular responses to stress, with 18 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-9841251 (mouse), R-RNO-9841251 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-9841251.1
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2024-09-11
Events inside: 21, counted from the record

Misfolded proteins in mitochondria activate the mitochondrial unfolded protein response (mtUPR), a program of gene expression that increases capacities for protein folding and protein degradation within the mitochondria (Zhao et al. 2002, Aldridge et al. 2007, reviewed in Cilleros-Holgado et al. 2023). Four interrelated pathways that regulate the mtUPR have been delineated: activation of Heat Shock Factor 1 (HSF1) by dissociation from HSPA1A,B (HSP70) (Sutandy et al. 2023), enhanced translocation of ATF5 to the nucleus (Fiorese et al. 2016), activation of the estrogen receptor alpha (ESR1) by phosphorylation, and activation of FOXO3 by deacetylation (reviewed in Kenny and Germain 2017, Munch 2018, Shpilka and Haynes 2018, Zhou et al. 2022).

The mtUPR appears to be initiated by the accumulation of reactive oxygen species (ROS) and mitochondrial precursor proteins in the cytosol (Sutandy et al. 2023). The ROS oxidize cysteine residues on DNAJA1, causing DNAJA1 to displace HSF1 from the chaperone HSPA1A,B (HSP70). HSF1 then transits to the nucleus, trimerizes, and activates expression of genes encoding chaperones (Sutandy et al. 2023).

The transcription factor ATF5, which is normally imported into mitochondria, instead accumulates in the cytosol and transits to the nucleus (Fiorese et al. 2016), where it acts with HSF1 to increase expression of chaperone genes (Fiorese et al. 2016, Sutandy et al. 2023). ATF5 may act downstream of HSF1, as ATF5 is not required to initiate the mtUPR (Sutandy et al. 2023).

ROS also activate the protein kinase AKT1 (PKB) (Papa and Germain 2011), which phosphorylates the estrogen receptor ESR1 (Campbell et al. 2001, Papa and Germain 2011). Phosphorylated ESR1 transits to the nucleus and, independently of estrogen, activates the expression of HTRA2 (OMI), NRF1, and other genes involved in mitochondrial homeostasis as part of the mitochondrial unfolded response (Papa and Germain 2011).

Through an uncharacterized mechanism, ROS cause increased expression of the deacetylase SIRT3, which directly or indirectly causes the deacetylation of the transcription factor FOXO3. Deacetylated FOXO3 in the nucleus increases expression of the antioxidant enzymes mitochondrial superoxide dismutase (SOD2, MnSOD) and peroxisomal catalase (CAT) in the mitochondrial unfolded response (Papa and Germain 2014).

Though ATF4 and CHOP are also key regulators of the mtUPR (Zhao et al. 2002, Quiros et al. 2017), the mechanisms that activate them in response to unfolded protein are not well characterized and may involve the phosphorylation of the EIF2S1 subunit of the translation factor eIF2alpha; however, none of the four known EIF2S1 kinases (GCN2, HRI, PERK, and PKR) are required for activation of CHOP (Munch and Harper 2016).

Literature Reactome attaches

The different axes of the mammalian mitochondrial unfolded protein responseBMC Biol, 2018, vol. 16, p. 81PubMed 30049264
The mitochondrial UPR: mechanisms, physiological functions and implications in ageingNat Rev Mol Cell Biol, 2018, vol. 19, p. 109-120PubMed 29165426
From discovery of the CHOP axis and targeting ClpP to the identification of additional axes of the UPRmt driven by the estrogen receptor and SIRT3J Bioenerg Biomembr, 2017, vol. 49, p. 297-305PubMed 28799020
mtDNA, Metastasis, and the Mitochondrial Unfolded Protein Response (UPR<sup>mt</sup>)Front Cell Dev Biol, 2017, vol. 5, p. 37PubMed 28470001
Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elementsPLoS One, 2007, vol. 2, p. e874PubMed 17849004
A mitochondrial specific stress response in mammalian cellsEMBO J, 2002, vol. 21, p. 4411-9PubMed 12198143
The mitochondrial unfolded protein response: A multitasking giant in the fight against human diseases

Reactome's record lists 14 orthologous events, R-MMU-9841251 (Mus musculus), R-RNO-9841251 (Rattus norvegicus) among the species this site serves, and 12 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-30 ET · Reactome pathway browser"Mitochondrial unfolded protein response (UPRmt)". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9841251 with StableID: R-HSA-9841251.1 (accessed 2026-09-30 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 18 genes in this human pathway; showing 1 to 18, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneAKT1	AuthorityHGNC:391	Mapping file id207 NCBI file	EvidenceTAS
GeneATF5	AuthorityHGNC:790	Mapping file id22809 NCBI file	EvidenceIEA, TAS
GeneCAT	AuthorityHGNC:1516	Mapping file id847 NCBI file	EvidenceTAS
GeneDEFA5	AuthorityHGNC:2764	Mapping file id1670 NCBI file	EvidenceTAS
GeneDNAJA1	AuthorityHGNC:5229	Mapping file id3301 NCBI file	EvidenceTAS
GeneESR1	AuthorityHGNC:3467	Mapping file id2099 NCBI file	EvidenceTAS
GeneFOXO3	AuthorityHGNC:3821	Mapping file id2309 NCBI file	EvidenceTAS
GeneHSF1	AuthorityHGNC:5224	Mapping file id3297 NCBI file	EvidenceTAS
GeneHSPA1A	AuthorityHGNC:5232	Mapping file id3303 NCBI file	EvidenceTAS
GeneHSPA1B	AuthorityHGNC:5233	Mapping file id3304 NCBI file	EvidenceTAS
GeneHSPA9	AuthorityHGNC:5244	Mapping file id3313 NCBI file	EvidenceTAS
GeneHSPD1	AuthorityHGNC:5261	Mapping file id3329 NCBI file	EvidenceTAS
GeneHSPE1	AuthorityHGNC:5269	Mapping file id3336 NCBI file	EvidenceTAS
GeneHTRA2	AuthorityHGNC:14348	Mapping file id27429 NCBI file	EvidenceTAS
GeneLONP1	AuthorityHGNC:9479	Mapping file id9361 NCBI file	EvidenceTAS
GeneNRF1	AuthorityHGNC:7996	Mapping file id4899 NCBI file	EvidenceTAS
GeneSIRT3	AuthorityHGNC:14931	Mapping file id23410 NCBI file	EvidenceTAS
GeneSOD2	AuthorityHGNC:11180	Mapping file id6648 NCBI file	EvidenceTAS

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Cellular responses to stressR-HSA-2262752815 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.