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.[11]

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]

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]

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]