Pathway Human Homo sapiens

Mitochondrial protein degradation

R-HSA-9837999 in Reactome release 97: under Metabolism of proteins, with 98 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-9837999 (mouse), R-RNO-9837999 (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-9837999.2
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2023-12-06
Events inside: 20, counted from the record

Mitochondrial proteases participate in proteostasis, the regulation of proteins to maintain a functional proteome, by degrading unfolded, unassembled, and oxidatively damaged proteins (reviewed in Ng et al. 2021, Song et al. 2021). Degradation of mitochondrial proteins by proteases also serves to regulate transcription by TFAM, oxidative phosphorylation by electron carriers, lipid translocation by PRELID1 and STARD7, and mitochondrial fission and fusion by OPA1 and OMA1 (reviewed in Ahola et al. 2019). Because of the bacterial origin of mitochondria, they contain a number of bacterial type proteases, including LONP1 in the matrix, CLPP:CLPX (CLPXP) in the matrix, HTRA2 (OMI) in the intermembrane space, AFG3L2 in the mitochondrial inner membrane and protruding into the matrix, and YME1L1 in the mitochondrial inner membrane and protruding into the intermembrane space (reviewed in Deshwal et al. 2020, Szczepanowska and Trifunovic 2022).

The hexameric LONP1 complex, which is homologous to Lon proteases of eubacteria such as E. coli, binds substrate proteins in the matrix and inner membrane, unfolds them in an ATP-dependent mechanism, and degrades them (reviewed in Gibellini et al. 2020). LONP1 also acts as an ATP-dependent chaperone that is independent of its protease function (reviewed in Gibellini et al. 2020).

Like LONP1, the CLPXP complex unfolds matrix proteins in an ATP-dependent reaction and degrades them, however, the ATPase/unfolding function and the protease function are performed by separate subunits, with CLPX hexamers unfolding substrate proteins and translocating them to CLPP tetradecamers for processive degradation (reviewed in Mabanglo et al. 2021, Mabanglo and Houry 2022).

AFG3L2 (m-AAA+) forms either homohexamers or heterohexamers with its paralog SPG7 (Paraplegin) that are anchored in the mitochondrial inner membrane and protrude into the matrix (reviewed in Patron et al. 2018, Steele and Glynn 2019, Zhang and Mao 2020). The substrate protein enters the central channel formed by the ATPase domains of AFG3L2 and is unfolded and translocated to the pore formed by the protease domains, where it is degraded (reviewed inZhang and Mao 2020).

Like AFG3L2, YME1L1 (YME1L, i-AAA+) is a homohexameric complex that is anchored in the mitochondrial inner membrane, however, YME1L1 protrudes into the intermembrane space where it unfolds substrate proteins of the intermembrane space and inner membrane in an ATP-dependent reaction and then degrades them (reviewed in Steele and Glynn 2019, Ohba et al. 2020, Zhang and Mao 2020).

HTRA2 (OMI) forms soluble trimeric complexes in the intermembrane space that degrade substrate proteins, notably amyloid precursor proteins that are translocated to the intermembrane space and inner membrane. HTRA2 released from mitochondria into the cytosol also participates in regulating apoptosis (reviewed in Vande Walle et al. 2008).

Mutations in mitochondrial proteases cause diseases, such as spastic paraplegia (SPG7), ataxia (AFG3L2), and Parkinson's Disease (HTRA2), that typically have neurological symptoms among others (reviewed in Su et al. 2019, Gomez-Fabra Gala and Vogtle 2021).

Literature Reactome attaches

Quality control of the mitochondrionDev Cell, 2021, vol. 56, p. 881-905PubMed 33662258
Mitochondrial matrix proteases: quality control and beyondFEBS J, 2022, vol. 289, p. 7128-7146PubMed 33971087
m-AAA proteases, mitochondrial calcium homeostasis and neurodegenerationCell Res, 2018, vol. 28, p. 296-306PubMed 29451229
AAA+ ATPases in Protein Degradation: Structures, Functions and MechanismsBiomolecules, 2020, vol. 10PubMed 32325699
Regulation of mitochondrial plasticity by the i-AAA protease YME1LBiol Chem, 2020, vol. 401, p. 877-890PubMed 32087062
Substrates and interactors of the ClpP protease in the mitochondriaCurr Opin Chem Biol, 2022, vol. 66, p. 102078PubMed 34446368
Mitochondrial proteases in human diseasesFEBS Lett, 2021, vol. 595, p. 1205-1222PubMed 33453058

Reactome's record lists 14 orthologous events, R-MMU-9837999 (Mus musculus), R-RNO-9837999 (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 2026-10-02 ET · Reactome pathway browser"Mitochondrial protein degradation". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9837999 with StableID: R-HSA-9837999.2 (accessed 2026-10-02 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 98 genes in this human pathway; showing 1 to 98, 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
GeneACAD8	AuthorityHGNC:87	Mapping file id27034 NCBI file	EvidenceTAS
GeneACADSB	AuthorityHGNC:91	Mapping file id36 NCBI file	EvidenceTAS
GeneACAT1	AuthorityHGNC:93	Mapping file id38 NCBI file	EvidenceTAS
GeneACO2	AuthorityHGNC:118	Mapping file id50 NCBI file	EvidenceTAS
GeneACOT2	AuthorityHGNC:18431	Mapping file id10965 NCBI file	EvidenceTAS
GeneAFG3L2	AuthorityHGNC:315	Mapping file id10939 NCBI file	EvidenceTAS
GeneALAS1	AuthorityHGNC:396	Mapping file id211 NCBI file	EvidenceTAS
GeneALDH18A1	AuthorityHGNC:9722	Mapping file id5832 NCBI file	EvidenceTAS
GeneALDH1B1	AuthorityHGNC:407	Mapping file id219 NCBI file	EvidenceTAS
GeneALDH2	AuthorityHGNC:404	Mapping file id217 NCBI file	EvidenceTAS
GeneAPP	AuthorityHGNC:620	Mapping file id351 NCBI file	EvidenceTAS
GeneARG2	AuthorityHGNC:664	Mapping file id384 NCBI file	EvidenceTAS
GeneATP5F1A	AuthorityHGNC:823	Mapping file id498 NCBI file	EvidenceTAS
GeneATP5F1B	AuthorityHGNC:830	Mapping file id506 NCBI file	EvidenceTAS
GeneATP5F1C	AuthorityHGNC:833	Mapping file id509 NCBI file	EvidenceTAS
GeneATP5MG	AuthorityHGNC:14247	Mapping file id10632 NCBI file	EvidenceTAS
GeneATP5PD	AuthorityHGNC:845	Mapping file id10476 NCBI file	EvidenceTAS
GeneATP5PF	AuthorityHGNC:847	Mapping file id522 NCBI file	EvidenceTAS
GeneATP5PO	AuthorityHGNC:850	Mapping file id539 NCBI file	EvidenceTAS
GeneBDH1	AuthorityHGNC:1027	Mapping file id622 NCBI file	EvidenceTAS
GeneCHCHD2	AuthorityHGNC:21645	Mapping file id51142 NCBI file	EvidenceIEA
GeneCLPP	AuthorityHGNC:2084	Mapping file id8192 NCBI file	EvidenceTAS
GeneCLPX	AuthorityHGNC:2088	Mapping file id10845 NCBI file	EvidenceTAS
GeneCOX4I1	AuthorityHGNC:2265	Mapping file id1327 NCBI file	EvidenceIEA
GeneCOX5A	AuthorityHGNC:2267	Mapping file id9377 NCBI file	EvidenceTAS
GeneCOX5B	AuthorityHGNC:2269	Mapping file id1329 NCBI file	EvidenceTAS
GeneCS	AuthorityHGNC:2422	Mapping file id1431 NCBI file	EvidenceTAS
GeneDBT	AuthorityHGNC:2698	Mapping file id1629 NCBI file	EvidenceTAS
GeneDLD	AuthorityHGNC:2898	Mapping file id1738 NCBI file	EvidenceTAS
GeneECH1	AuthorityHGNC:3149	Mapping file id1891 NCBI file	EvidenceTAS
GeneECI1	AuthorityHGNC:2703	Mapping file id1632 NCBI file	EvidenceTAS
GeneFECH	AuthorityHGNC:3647	Mapping file id2235 NCBI file	EvidenceTAS
GeneFH	AuthorityHGNC:3700	Mapping file id2271 NCBI file	EvidenceTAS
GeneGLUD1	AuthorityHGNC:4335	Mapping file id2746 NCBI file	EvidenceTAS
GeneHADH	AuthorityHGNC:4799	Mapping file id3033 NCBI file	EvidenceTAS
GeneHMGCS2	AuthorityHGNC:5008	Mapping file id3158 NCBI file	EvidenceTAS
GeneHSD17B10	AuthorityHGNC:4800	Mapping file id3028 NCBI file	EvidenceTAS
GeneHSPA9	AuthorityHGNC:5244	Mapping file id3313 NCBI file	EvidenceTAS
GeneHSPD1	AuthorityHGNC:5261	Mapping file id3329 NCBI file	EvidenceTAS
GeneHTRA2	AuthorityHGNC:14348	Mapping file id27429 NCBI file	EvidenceTAS
GeneIARS2	AuthorityHGNC:29685	Mapping file id55699 NCBI file	EvidenceTAS
GeneIDH2	AuthorityHGNC:5383	Mapping file id3418 NCBI file	EvidenceTAS
GeneIDH3A	AuthorityHGNC:5384	Mapping file id3419 NCBI file	EvidenceTAS
GeneLDHD	AuthorityHGNC:19708	Mapping file id197257 NCBI file	EvidenceTAS
GeneLONP1	AuthorityHGNC:9479	Mapping file id9361 NCBI file	EvidenceTAS
GeneMDH2	AuthorityHGNC:6971	Mapping file id4191 NCBI file	EvidenceTAS
GeneME2	AuthorityHGNC:6984	Mapping file id4200 NCBI file	EvidenceTAS
GeneMICU2	AuthorityHGNC:31830	Mapping file id221154 NCBI file	EvidenceIEA
GeneMRPL12	AuthorityHGNC:10378	Mapping file id6182 NCBI file	EvidenceTAS
GeneMRPL32	AuthorityHGNC:14035	Mapping file id64983 NCBI file	EvidenceTAS
GeneMRPS10	AuthorityHGNC:14502	Mapping file id55173 NCBI file	EvidenceTAS
GeneMRPS2	AuthorityHGNC:14495	Mapping file id51116 NCBI file	EvidenceTAS
GeneMT-ATP6	AuthorityHGNC:7414	Mapping file id4508 NCBI file	EvidenceTAS
GeneMT-CO1	AuthorityHGNC:7419	Mapping file id4512 NCBI file	EvidenceTAS
GeneMT-CO2	AuthorityHGNC:7421	Mapping file id4513 NCBI file	EvidenceIEA
GeneMT-ND1	AuthorityHGNC:7455	Mapping file id4535 NCBI file	EvidenceIEA
GeneMT-ND2	AuthorityHGNC:7456	Mapping file id4536 NCBI file	EvidenceIEA
GeneMT-ND5	AuthorityHGNC:7461	Mapping file id4540 NCBI file	EvidenceIEA
GeneMT-ND6	AuthorityHGNC:7462	Mapping file id4541 NCBI file	EvidenceIEA
GeneNADK2	AuthorityHGNC:26404	Mapping file id133686 NCBI file	EvidenceTAS
GeneNDUFA13	AuthorityHGNC:17194	Mapping file id51079 NCBI file	EvidenceTAS
GeneNDUFA2	AuthorityHGNC:7685	Mapping file id4695 NCBI file	EvidenceTAS
GeneNDUFB6	AuthorityHGNC:7701	Mapping file id4712 NCBI file	EvidenceIEA
GeneNDUFS1	AuthorityHGNC:7707	Mapping file id4719 NCBI file	EvidenceTAS
GeneNDUFS3	AuthorityHGNC:7710	Mapping file id4722 NCBI file	EvidenceTAS
GeneNDUFV1	AuthorityHGNC:7716	Mapping file id4723 NCBI file	EvidenceTAS
GeneNDUFV3	AuthorityHGNC:7719	Mapping file id4731 NCBI file	EvidenceTAS
GeneOGDH	AuthorityHGNC:8124	Mapping file id4967 NCBI file	EvidenceTAS
GeneOMA1	AuthorityHGNC:29661	Mapping file id115209 NCBI file	EvidenceIEA
GeneOPA1	AuthorityHGNC:8140	Mapping file id4976 NCBI file	EvidenceIEA
GeneOXCT1	AuthorityHGNC:8527	Mapping file id5019 NCBI file	EvidenceTAS
GeneOXSM	AuthorityHGNC:26063	Mapping file id54995 NCBI file	EvidenceTAS
GenePCCB	AuthorityHGNC:8654	Mapping file id5096 NCBI file	EvidenceTAS
GenePDHA1	AuthorityHGNC:8806	Mapping file id5160 NCBI file	EvidenceTAS
GenePDHB	AuthorityHGNC:8808	Mapping file id5162 NCBI file	EvidenceTAS
GenePDK1	AuthorityHGNC:8809	Mapping file id5163 NCBI file	EvidenceTAS
GenePMPCA	AuthorityHGNC:18667	Mapping file id23203 NCBI file	EvidenceTAS
GenePRELID1	AuthorityHGNC:30255	Mapping file id27166 NCBI file	EvidenceIEA
GenePRKACA	AuthorityHGNC:9380	Mapping file id5566 NCBI file	EvidenceTAS
GeneSHMT2	AuthorityHGNC:10852	Mapping file id6472 NCBI file	EvidenceTAS
GeneSLC25A5	AuthorityHGNC:10991	Mapping file id292 NCBI file	EvidenceTAS
GeneSLC25A6	AuthorityHGNC:10992	Mapping file id293 NCBI file	EvidenceTAS
GeneSMDT1	AuthorityHGNC:25055	Mapping file id91689 NCBI file	EvidenceTAS
GeneSPG7	AuthorityHGNC:11237	Mapping file id6687 NCBI file	EvidenceTAS
GeneSSBP1	AuthorityHGNC:11317	Mapping file id6742 NCBI file	EvidenceTAS
GeneSTAR	AuthorityHGNC:11359	Mapping file id6770 NCBI file	EvidenceTAS
GeneSTARD7	AuthorityHGNC:18063	Mapping file id56910 NCBI file	EvidenceIEA
GeneSUCLG2	AuthorityHGNC:11450	Mapping file id8801 NCBI file	EvidenceTAS
GeneTFAM	AuthorityHGNC:11741	Mapping file id7019 NCBI file	EvidenceTAS
GeneTIMM10	AuthorityHGNC:11814	Mapping file id26519 NCBI file	EvidenceIEA
GeneTIMM17A	AuthorityHGNC:17315	Mapping file id10440 NCBI file	EvidenceIEA
GeneTIMM22	AuthorityHGNC:17317	Mapping file id29928 NCBI file	EvidenceIEA
GeneTIMM9	AuthorityHGNC:11819	Mapping file id26520 NCBI file	EvidenceIEA
GeneTRIAP1	AuthorityHGNC:26937	Mapping file id51499 NCBI file	EvidenceIEA
GeneTWNK	AuthorityHGNC:1160	Mapping file id56652 NCBI file	EvidenceTAS
GeneUQCRC2	AuthorityHGNC:12586	Mapping file id7385 NCBI file	EvidenceTAS
GeneUQCRQ	AuthorityHGNC:29594	Mapping file id27089 NCBI file	EvidenceTAS
GeneYME1L1	AuthorityHGNC:12843	Mapping file id10730 NCBI file	EvidenceIEA

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

Metabolism of proteinsR-HSA-3924992,148 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.