Slc25a12 regulates Opa1 oligomeric assembly and cristae maintenance which is implicated in cardiac pathophysiology

Cardiomyocytes can adapt their metabolism to sustain ATP biosynthesis using different carbon sources in normal and pathological conditions. Whether and how mitochondrial cristae, the dynamic inner mitochondrial membrane subcompartments that constitute the bioenergetic units of mitochondria, also dynamically adapt to these changing carbon sources remains unexplored. Here, we report that in cardiomyocytes the mitochondrial aspartate-glutamate carrier modulates complex assembly of the key cristae morphology protein Optic Atrophy 1 (OPA1). Complexomic analysis of heart mitochondria pinpointed the aspartate-glutamate carrier (Slc25a12) as a putative interactor of OPA1 multimers in normal, but not apoptotic mitochondria. Genetic ablation of Slc25a12 in C2C12 cells by CRISPR/Cas9 reduced Opa1 protein levels and oligomerization, resulting in a loss of mitochondrial cristae density and an increase in cristae width. Our data reveal a previously unappreciated role for Slc25a12 as a modulator of mitochondrial cristae and respiration through its crosstalk with Opa1.