Protease OMA1 modulates mitochondrial bioenergetics and ultrastructure through dynamic association with MICOS complex

Abstract

Summary Remodeling of mitochondrial ultrastructure is a process that is critical for organelle physiology and apoptosis. Although the key players in this process—mitochondrial contact site and cristae junction organizing system (MICOS) and Optic Atrophy 1 (OPA1)—have been characterized, the mechanisms behind its regulation remain incompletely defined. Here, we found that in addition to its role in mitochondrial division, metallopeptidase OMA1 is required for the maintenance of intermembrane connectivity through dynamic association with MICOS. This association is independent of OPA1, mediated via the MICOS subunit MIC60, and is important for stability of MICOS and the intermembrane contacts. The OMA1-MICOS relay is required for optimal bioenergetic output and apoptosis. Loss of OMA1 affects these activities; remarkably it can be alleviated by MICOS-emulating intermembrane bridge. Thus, OMA1-dependent ultrastructure support is required for mitochondrial architecture and bioenergetics under basal and stress conditions, suggesting a previously unrecognized role for OMA1 in mitochondrial physiology.

Mitochondrial Contact Site and Cristae Organizing System (MICOS) Machinery Supports Heme Biosynthesis by Enabling Optimal Performance of Ferrochelatase

“…While an active role of MICOS in intermediate porphyrinogen transport seems unlikely, the complex may aid the process through bridging the OM and IM to create a proximity conduit between these membranes. Our results showing the rescue of oxidative stress tolerance in Hem15-overexpressing mic60D cells co-expressing a synthetic mitoT (48) tether are consistent with this idea. Alternatively, in mammalian cells, MICOS might be required for spatial organization of coproporphyrinogen III and protoporphyrinogen IX transporters in the OM and IM, respectively.…”

“…To test whether restoring intermembrane connectivity in MICOS-deficient cells could mitigate some of these cytotoxic effects, an artificial IM-OM tether, mitoT, was generated (48) (Fig. 6D and 6E).…”

Emerging Roles of the MICOS Complex in Cristae Dynamics and Biogenesis

“…An increasing number of interacting partners of MICOS subunits are being found, and there has been a debate over whether some of them belong to the MICOS complex or act as auxiliary components. The list includes proteins such as CHCHD10 [36], CHCHD2 [37], DNAJC11 [38], ARMC1 [39], DISC1 [40], VDAC, SLC25A46 [41], OPA1 [28], PINK1 [42], Miro [43], TFAM [44] and OMA1 [45]. The variety of functions that MICOS could perform, apart from cristae biogenesis, could be attributed to its interaction with the proteins mentioned.…”

SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10S59L-related disease

“…OPA1 physically interacts with Mitofilin/MIC60, a core MICOS component, and together they control the maintenance of mitochondrial cristae (Glytsou et al, 2016). More recently, it has been proposed that OMA1 control mitochondrial ultrastructure through its interaction with Mitofilin, independently of OPA1 (Viana et al, 2021). We previously found a destabilization of the MICOS complex with abnormal cristae in patient fibroblasts expressing the CHCHD10 S59L variant (Genin et al, 2016).…”