OMA1

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.{{cite journal | vauthors = Levytskyy RM, Bohovych I, Khalimonchuk O | title = Metalloproteases of the Inner Mitochondrial Membrane | journal = Biochemistry | volume = 56 | issue = 36 | pages = 4737–4746 | date = September 2017 | pmid = 28806058 | pmc = 5792295 | doi = 10.1021/acs.biochem.7b00663 }}

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.{{cite journal | vauthors = Baker MJ, Lampe PA, Stojanovski D, Korwitz A, Anand R, Tatsuta T, Langer T | title = Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics | journal = The EMBO Journal | volume = 33 | issue = 6 | pages = 578–93 | date = March 2014 | pmid = 24550258 | pmc = 3989652 | doi = 10.1002/embj.201386474 }} OMA1 has a HEXXH Zn²⁺-binding motive and the MEROPS database classifies OMA1 as metalloendopeptidase of the M48C-family.{{Cite web|title=MEROPS - the Peptidase Database|url=https://www.ebi.ac.uk/merops/cgi-bin/pepsum?id=M48.017|access-date=2021-10-06|website=www.ebi.ac.uk}} OMA1’s structure has not yet been resolved. Two controversial models describe OMA1 either as membrane-anchored protease or as integral membrane protease.{{cite journal | vauthors = Alavi MV | title = OMA1-An integral membrane protease? | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics| volume = 1869 | issue = 2 | pages = 140558 | date = February 2021 | pmid = 33130089 | pmc = 7770061 | doi = 10.1016/j.bbapap.2020.140558 }} Google's AlphaFold predictions are more aligned with the latter model, but have so far not provided a realistic 3D structure.{{Cite web|title=AlphaFold Protein Structure Database|url=https://alphafold.ebi.ac.uk/entry/Q96E52|access-date=2021-10-06|website=alphafold.ebi.ac.uk}} OMA1’s context-dependent regulation is not understood. The mammalian protein has an extended carboxy-terminus, which may be involved in its regulation.{{cite journal | vauthors = Zhang K, Li H, Song Z | title = Membrane depolarization activates the mitochondrial protease OMA1 by stimulating self-cleavage | journal = EMBO Reports | volume = 15 | issue = 5 | pages = 576–85 | date = May 2014 | pmid = 24719224 | pmc = 4210089 | doi = 10.1002/embr.201338240 }}

OMA1’s function evolved over time with distinct substrates in invertebrates and mammals.{{cite journal | vauthors = Duvezin-Caubet S, Koppen M, Wagener J, Zick M, Israel L, Bernacchia A, Jagasia R, Rugarli EI, Imhof A, Neupert W, Langer T, Reichert AS | display-authors = 6 | title = OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria | journal = Molecular Biology of the Cell | volume = 18 | issue = 9 | pages = 3582–90 | date = September 2007 | pmid = 17615298 | pmc = 1951777 | doi = 10.1091/mbc.e07-02-0164 }} Initially described in yeast as "a novel component of the quality control system in the inner membrane of mitochondria," mammalian OMA1 is responsible for stress-dependent OPA1 cleavage. 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.{{cite journal | vauthors = Jiang X, Jiang H, Shen Z, Wang X | title = Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 41 | pages = 14782–7 | date = October 2014 | pmid = 25275009 | pmc = 4205663 | doi = 10.1073/pnas.1417253111 | bibcode = 2014PNAS..11114782J | doi-access = free }}{{cite journal | vauthors = Richter U, Lahtinen T, Marttinen P, Suomi F, Battersby BJ | title = Quality control of mitochondrial protein synthesis is required for membrane integrity and cell fitness | journal = The Journal of Cell Biology | volume = 211 | issue = 2 | pages = 373–89 | date = October 2015 | pmid = 26504172 | pmc = 4621829 | doi = 10.1083/jcb.201504062 }} The DELE1 protein is another OMA1 substrate, which is released upon cleavage into the cytosol, where it can activate the integrated stress response. OMA1 and the i-AAA protease share the OPA1 substrate and were suggested to regulate each other by reciprocal proteolytic hydrolysis.{{cite journal | vauthors = Anand R, Wai T, Baker MJ, Kladt N, Schauss AC, Rugarli E, Langer T | title = The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission | journal = The Journal of Cell Biology | volume = 204 | issue = 6 | pages = 919–29 | date = March 2014 | pmid = 24616225 | pmc = 3998800 | doi = 10.1083/jcb.201308006 }}{{cite journal | vauthors = Rainbolt TK, Lebeau J, Puchades C, Wiseman RL | title = Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress | journal = Cell Reports | volume = 14 | issue = 9 | pages = 2041–2049 | date = March 2016 | pmid = 26923599 | pmc = 4785047 | doi = 10.1016/j.celrep.2016.02.011 }} OMA1 functionally interacts with the eponymous m-AAA protease and other scaffold proteins in the inner membrane, such as the prohibitins PHB1 and PHB2.{{cite journal | vauthors = Deshwal S, Fiedler KU, Langer T | title = Mitochondrial Proteases: Multifaceted Regulators of Mitochondrial Plasticity | journal = Annual Review of Biochemistry | volume = 89 | pages = 501–528 | date = June 2020 | pmid = 32075415 | doi = 10.1146/annurev-biochem-062917-012739 | s2cid = 211216115 }}

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.{{cite journal | vauthors = Daoud H, Valdmanis PN, Gros-Louis F, Belzil V, Spiegelman D, Henrion E, Diallo O, Desjarlais A, Gauthier J, Camu W, Dion PA, Rouleau GA | display-authors = 6 | title = Resequencing of 29 candidate genes in patients with familial and sporadic amyotrophic lateral sclerosis | journal = Archives of Neurology | volume = 68 | issue = 5 | pages = 587–93 | date = May 2011 | pmid = 21220648 | doi = 10.1001/archneurol.2010.351 | doi-access = free }} Whole exome sequencing of 1,000 individuals with heart failure revealed an association with the coding polymorphism rs17117699 (OMA1 p.Phe211Cys).{{cite journal | vauthors = Hu D, Li S, Hu S, Sun Y, Xiao L, Li C, Wang J, Wang Y, Ni L, Zhao C, Wang DW | display-authors = 6 | title = A Common Missense Variant in OMA1 Associated with the Prognosis of Heart Failure | journal = Cardiovascular Drugs and Therapy | volume = 34 | issue = 3 | pages = 345–356 | date = June 2020 | pmid = 32236861 | doi = 10.1007/s10557-020-06960-8 | s2cid = 214715802 }} 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.{{cite journal | vauthors = Sekine S, Wang C, Sideris DP, Bunker E, Zhang Z, Youle RJ | title = Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1 | journal = Molecular Cell | volume = 73 | issue = 5 | pages = 1028–1043.e5 | date = March 2019 | pmid = 30733118 | doi = 10.1016/j.molcel.2019.01.002 | s2cid = 73450413 | doi-access = free }} Conditional OMA1 activation in neurons led to neurodegeneration with tau hyperphosphorylation in mice.{{cite journal | vauthors = Korwitz A, Merkwirth C, Richter-Dennerlein R, Tröder SE, Sprenger HG, Quirós PM, López-Otín C, Rugarli EI, Langer T | display-authors = 6 | title = Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria | journal = The Journal of Cell Biology | volume = 212 | issue = 2 | pages = 157–66 | date = January 2016 | pmid = 26783299 | pmc = 4738383 | doi = 10.1083/jcb.201507022 }} OMA1 knockout mice by contrast show mild energy-metabolic alterations without apparent impact on survival or lifespan.{{cite journal | vauthors = Quirós PM, Ramsay AJ, Sala D, Fernández-Vizarra E, Rodríguez F, Peinado JR, Fernández-García MS, Vega JA, Enríquez JA, Zorzano A, López-Otín C | display-authors = 6 | title = Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice | journal = The EMBO Journal | volume = 31 | issue = 9 | pages = 2117–33 | date = May 2012 | pmid = 22433842 | pmc = 3343468 | doi = 10.1038/emboj.2012.70 }} OMA1 was also suggested to be relevant for cancer given OMA1’s energy-metabolic regulation and stress-dependent signaling.{{cite journal | vauthors = Alavi MV | title = Targeted OMA1 therapies for cancer | journal = International Journal of Cancer | volume = 145 | issue = 9 | pages = 2330–2341 | date = November 2019 | pmid = 30714136 | doi = 10.1002/ijc.32177 | s2cid = 73438438 | doi-access = free }}

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