Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control

The mitochondrial contact site and cristae organizing system (MICOS) and Optic atrophy 1 (OPA1) control cristae shape, thus affecting mitochondrial function and apoptosis. Whether and how they physically and functionally interact is unclear. Here, we provide evidence that OPA1 is epistatic to MICOS in the regulation of cristae shape. Proteomic analysis identifies multiple MICOS components in native OPA1-containing high molecular weight complexes disrupted during cristae remodeling. MIC60, a core MICOS protein, physically interacts with OPA1, and together, they control cristae junction number and stability, OPA1 being epistatic to MIC60. OPA1 defines cristae width and junction diameter independently of MIC60. Our combination of proteomics, biochemistry, genetics, and electron tomography provides a unifying model for mammalian cristae biogenesis by OPA1 and MICOS.We thank Drs. F. Caicci and F. Boldrin (EM Facility, Department of Biology, University of Padova) for EM and ALEMBIC, San Raffaele Scientific Institute, for tomography. L.S. is a senior scientist of the Dulbecco-Telethon Institute. Support was provided by Telethon-Italy (GGP15091 and GGP14187), AIRC Italy (ERC FP7-282280), FP7 CIG (PCIG13-GA-2013-618697), the Italian Ministry of Research (FIRB RBAP11Z3YA\_005), the Italian Ministry of Health (GR-2009-1600051 to L.S.), a University of Padua grant for a postdoctoral fellowship (2015 to M.E.S.), and an International Brain Research Organization-International Society for Neurochemistry research fellowship (2016 to A.M.).S