SummaryThe 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.

Highlights d OPA1 is upregulated in response to angiogenic stimuli to limit NFkB signaling d OPA1 controls cytosolic Ca 2+ levels, NFkB signaling, and angiogenic gene expression d Deletion of endothelial Opa1 curtails tumor angiogenesis, growth, and metastatization d MYLS22, first-in-class small molecule, inhibits OPA1 and limits tumor growth

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