OMA1
Identifiers
Aliases	OMA1, 2010001O09Rik, DAB1, MPRP-1, YKR087C, ZMPpeptidase, OMA1 zinc metallopeptidase, MPRP1
External IDs	OMIM: 617081 MGI: 1914263 HomoloGene: 12070 GeneCards: OMA1
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p32.2-p32.1 Start 58,415,384 bp[1] End 58,546,802 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4|4 C6 Start 103,171,009 bp[2] End 103,229,065 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in bronchial epithelial cell Achilles tendon bone marrow cells right uterine tube corpus callosum caput epididymis renal medulla right adrenal gland superior surface of tongue rectum Top expressed in interventricular septum right ventricle myocardium of ventricle sternocleidomastoid muscle digastric muscle temporal muscle epithelium of stomach vastus lateralis muscle tibialis anterior muscle extraocular muscle More reference expression data BioGPS n/a
Gene ontology Molecular function peptidase activity hydrolase activity metallopeptidase activity metal ion binding metalloendopeptidase activity Cellular component membrane integral component of membrane mitochondrial membranes mitochondrion mitochondrial inner membrane Biological process mitochondrial protein processing energy homeostasis response to stress mitochondrion organization cristae formation protein quality control for misfolded or incompletely synthesized proteins negative regulation of mitochondrial fusion proteolysis lipid metabolism glucose metabolic process diet induced thermogenesis regulation of apoptotic process positive regulation of cold-induced thermogenesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 4: 103.17 – 103.23 Mb PubMed search [3] [4]
Wikidata
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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

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

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

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

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