OMA1

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OMA1
Identifiers
AliasesOMA1, 2010001O09Rik, DAB1, MPRP-1, YKR087C, ZMPpeptidase, OMA1 zinc metallopeptidase, MPRP1
External IDsOMIM: 617081 MGI: 1914263 HomoloGene: 12070 GeneCards: OMA1
Orthologs
SpeciesHumanMouse
Entrez

115209

67013

Ensembl

ENSG00000162600

ENSMUSG00000035069

UniProt

Q96E52

Q9D8H7

RefSeq (mRNA)

NM_145243

NM_025909

RefSeq (protein)

NP_660286

NP_080185

Location (UCSC)Chr 1: 58.42 – 58.55 MbChr 4: 103.17 – 103.23 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Metalloendopeptidase OMA1, mitochondrial is an enzyme that in humans is encoded by the OMA1 gene.[5][6] OMA1 is a Zn2+-dependent metalloendopeptidase in the inner membrane of mitochondria. The OMA1 acronym was derived from overlapping proteolytic activity with m-AAA protease 1.[6]

The OMA1 protease acts at the intersection of a mitochondrial quality control system and energy metabolism, whereby its activation correlates with outer membrane permeabilization and cytochrome c release in the context of apoptosis.

Mammalian OMA1 can cleave the inner-membrane shaping protein OPA1 and the signaling peptide DELE1 in a context-dependent manner.[7][8][9][10]

Gene[edit]

The human OMA1 gene spans with 9 exons 66 kb of the reverse strand of the short arm of chromosome 1 (1p32.2-p32.1). OMA1 is conserved and homologues have been identified in model organisms, such as mice and yeast. Yet, no homologous have been found in C. elegans and drosophila.[11]

Structure[edit]

The human OMA1 protein comprises 524 amino acids. The nuclear encoded protein exhibits an amino-terminal mitochondrial import sequence, which is removed upon import giving rise to a 43.8 kDa mature protease.[12] OMA1 has a HEXXH Zn2+-binding motive and the MEROPS database classifies OMA1 as metalloendopeptidase of the M48C-family.[13] OMA1’s structure has not yet been resolved. Two controversial models describe OMA1 either as membrane-anchored protease[11] or as integral membrane protease.[14] Google's AlphaFold predictions are more aligned with the latter model, but have so far not provided a realistic 3D structure.[15] OMA1’s context-dependent regulation is not understood. The mammalian protein has an extended carboxy-terminus, which may be involved in its regulation.[16]

Function[edit]

OMA1’s function evolved over time with distinct substrates in invertebrates and mammals.[17] Initially described in yeast as "a novel component of the quality control system in the inner membrane of mitochondria,"[6] mammalian OMA1 is responsible for stress-dependent OPA1 cleavage.[7][8] Apoptotic stimuli, such as Bax and Bak, as well as other factors can trigger OMA1 activation and OPA1 processing, which are correlated with outer membrane permeabilization and cytochrome c release.[18][19] The DELE1 protein is another OMA1 substrate, which is released upon cleavage into the cytosol, where it can activate the integrated stress response.[9][10] OMA1 and the i-AAA protease share the OPA1 substrate and were suggested to regulate each other by reciprocal proteolytic hydrolysis.[20][21] OMA1 functionally interacts with the eponymous m-AAA protease and other scaffold proteins in the inner membrane, such as the prohibitins PHB1 and PHB2.[22]

Clinical significance[edit]

OMA1 is not directly linked to a specific disease. 3 heterozygous coding sequence variants of uncertain significance were identified in the OMA1 gene in a screen of 190 individuals with Amyotrophic Lateral Sclerosis.[23] Whole exome sequencing of 1,000 individuals with heart failure revealed an association with the coding polymorphism rs17117699 (OMA1 p.Phe211Cys).[24] OMA1 may still have disease relevance through its substrates OPA1 and DELE1. Also certain misrouted PINK1 mutants pertaining to Parkinson's disease were found to be digested by OMA1.[25] Conditional OMA1 activation in neurons led to neurodegeneration with tau hyperphosphorylation in mice.[26] OMA1 knockout mice by contrast show mild energy-metabolic alterations without apparent impact on survival or lifespan.[27] OMA1 was also suggested to be relevant for cancer given OMA1’s energy-metabolic regulation and stress-dependent signaling.[28]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000162600 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035069 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: OMA1 zinc metallopeptidase".
  6. ^ a b c Kaser M, Kambacheld M, Kisters-Woike B, Langer T (November 2003). "Oma1, a novel membrane-bound metallopeptidase in mitochondria with activities overlapping with the m-AAA protease". The Journal of Biological Chemistry. 278 (47): 46414–23. doi:10.1074/jbc.m305584200. PMID 12963738.
  7. ^ a b Ehses S, Raschke I, Mancuso G, Bernacchia A, Geimer S, Tondera D, et al. (December 2009). "Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1". The Journal of Cell Biology. 187 (7): 1023–36. doi:10.1083/jcb.200906084. PMC 2806285. PMID 20038678.
  8. ^ a b Head B, Griparic L, Amiri M, Gandre-Babbe S, van der Bliek AM (December 2009). "Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells". The Journal of Cell Biology. 187 (7): 959–66. doi:10.1083/jcb.200906083. PMC 2806274. PMID 20038677.
  9. ^ a b Guo X, Aviles G, Liu Y, Tian R, Unger BA, Lin YT, et al. (March 2020). "Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway". Nature. 579 (7799): 427–432. Bibcode:2020Natur.579..427G. doi:10.1038/s41586-020-2078-2. PMC 7147832. PMID 32132707.
  10. ^ a b Fessler E, Eckl EM, Schmitt S, Mancilla IA, Meyer-Bender MF, Hanf M, et al. (March 2020). "A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol". Nature. 579 (7799): 433–437. Bibcode:2020Natur.579..433F. doi:10.1038/s41586-020-2076-4. PMC 7116715. PMID 32132706.
  11. ^ a b Levytskyy RM, Bohovych I, Khalimonchuk O (September 2017). "Metalloproteases of the Inner Mitochondrial Membrane". Biochemistry. 56 (36): 4737–4746. doi:10.1021/acs.biochem.7b00663. PMC 5792295. PMID 28806058.
  12. ^ Baker MJ, Lampe PA, Stojanovski D, Korwitz A, Anand R, Tatsuta T, Langer T (March 2014). "Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics". The EMBO Journal. 33 (6): 578–93. doi:10.1002/embj.201386474. PMC 3989652. PMID 24550258.
  13. ^ "MEROPS - the Peptidase Database". www.ebi.ac.uk. Retrieved 2021-10-06.
  14. ^ Alavi MV (February 2021). "OMA1-An integral membrane protease?". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1869 (2): 140558. doi:10.1016/j.bbapap.2020.140558. PMC 7770061. PMID 33130089.
  15. ^ "AlphaFold Protein Structure Database". alphafold.ebi.ac.uk. Retrieved 2021-10-06.
  16. ^ Zhang K, Li H, Song Z (May 2014). "Membrane depolarization activates the mitochondrial protease OMA1 by stimulating self-cleavage". EMBO Reports. 15 (5): 576–85. doi:10.1002/embr.201338240. PMC 4210089. PMID 24719224.
  17. ^ Duvezin-Caubet S, Koppen M, Wagener J, Zick M, Israel L, Bernacchia A, et al. (September 2007). "OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria". Molecular Biology of the Cell. 18 (9): 3582–90. doi:10.1091/mbc.e07-02-0164. PMC 1951777. PMID 17615298.
  18. ^ Jiang X, Jiang H, Shen Z, Wang X (October 2014). "Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 111 (41): 14782–7. Bibcode:2014PNAS..11114782J. doi:10.1073/pnas.1417253111. PMC 4205663. PMID 25275009.
  19. ^ Richter U, Lahtinen T, Marttinen P, Suomi F, Battersby BJ (October 2015). "Quality control of mitochondrial protein synthesis is required for membrane integrity and cell fitness". The Journal of Cell Biology. 211 (2): 373–89. doi:10.1083/jcb.201504062. PMC 4621829. PMID 26504172.
  20. ^ Anand R, Wai T, Baker MJ, Kladt N, Schauss AC, Rugarli E, Langer T (March 2014). "The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission". The Journal of Cell Biology. 204 (6): 919–29. doi:10.1083/jcb.201308006. PMC 3998800. PMID 24616225.
  21. ^ Rainbolt TK, Lebeau J, Puchades C, Wiseman RL (March 2016). "Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress". Cell Reports. 14 (9): 2041–2049. doi:10.1016/j.celrep.2016.02.011. PMC 4785047. PMID 26923599.
  22. ^ Deshwal S, Fiedler KU, Langer T (June 2020). "Mitochondrial Proteases: Multifaceted Regulators of Mitochondrial Plasticity". Annual Review of Biochemistry. 89: 501–528. doi:10.1146/annurev-biochem-062917-012739. PMID 32075415. S2CID 211216115.
  23. ^ Daoud H, Valdmanis PN, Gros-Louis F, Belzil V, Spiegelman D, Henrion E, et al. (May 2011). "Resequencing of 29 candidate genes in patients with familial and sporadic amyotrophic lateral sclerosis". Archives of Neurology. 68 (5): 587–93. doi:10.1001/archneurol.2010.351. PMID 21220648.
  24. ^ Hu D, Li S, Hu S, Sun Y, Xiao L, Li C, et al. (June 2020). "A Common Missense Variant in OMA1 Associated with the Prognosis of Heart Failure". Cardiovascular Drugs and Therapy. 34 (3): 345–356. doi:10.1007/s10557-020-06960-8. PMID 32236861. S2CID 214715802.
  25. ^ Sekine S, Wang C, Sideris DP, Bunker E, Zhang Z, Youle RJ (March 2019). "Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1". Molecular Cell. 73 (5): 1028–1043.e5. doi:10.1016/j.molcel.2019.01.002. PMID 30733118. S2CID 73450413.
  26. ^ Korwitz A, Merkwirth C, Richter-Dennerlein R, Tröder SE, Sprenger HG, Quirós PM, et al. (January 2016). "Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria". The Journal of Cell Biology. 212 (2): 157–66. doi:10.1083/jcb.201507022. PMC 4738383. PMID 26783299.
  27. ^ Quirós PM, Ramsay AJ, Sala D, Fernández-Vizarra E, Rodríguez F, Peinado JR, et al. (May 2012). "Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice". The EMBO Journal. 31 (9): 2117–33. doi:10.1038/emboj.2012.70. PMC 3343468. PMID 22433842.
  28. ^ Alavi MV (November 2019). "Targeted OMA1 therapies for cancer". International Journal of Cancer. 145 (9): 2330–2341. doi:10.1002/ijc.32177. PMID 30714136. S2CID 73438438.
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