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Remodeling of mitochondrial ultrastructure is a complex dynamic process that is critical for a variety of mitochondrial functions and apoptosis. Although the key regulators of this process - mitochondrial contact site and cristae junction organizing system (MICOS) and GTPase Optic Atrophy 1 (OPA1) have been characterized, the mechanisms behind this regulation remain incompletely defined. Here, we found that in addition to its role in mitochondrial division, metallopeptidase OMA1 is required for maintenance of contacts between the inner and outer membranes through a dynamic association with MICOS. This association is independent of OPA1, appears to be mediated via the MIC60 MICOS subunit, and is important for stability of MICOS machinery and the inner-outer mitochondrial membrane contacts. We find that such molecular organization is required for stability of respiratory supercomplexes, optimal bioenergetic output in response to cellular insults, and apoptosis. Loss of OMA1 affects these activities; remarkably it can be partially compensated for by an artificial MICOS-emulating tether protein that bridges the inner and outer mitochondrial membranes. Our data show that OMA1-mediated support of mitochondrial ultrastructure is required for maintenance of mitochondrial architecture and bioenergetics under both basal and homeostasis-challenging conditions and suggest a previously unrecognized role for this protease in mitochondrial physiology.
Advisor: Oleh Khalimonchuk