OMA1

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]