The mitochondrial aspartate-glutamate carrier Slc25a12 regulates Opa1 oligomeric assembly and cristae maintenance in cardiac pathophysiology

Introduction and Aim 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. Methods and Results Here, we report that in cardiomyocytes the mitochondrial aspartate-glutamate carrier modulates complex assembly of the key cristae morphology protein Optic Atrophy 1 (OPA1). Because mitochondrial morphology of C2C12 cells responded to the carbon source they relied on, we inspected if key components of the mitochondria-shaping machinery interacted with substrate carriers. By perusing a proteomic compendium of high molecular weight complexes in heart mitochondria generated in our laboratory we identified the aspartate-glutamate carrier (Slc25a12) as a putative interactor of multimers of OPA1 in heart mitochondria. Genetic ablation of Slc25a12 in C2C12 cells by CRISPR/Cas9 reduced Opa1 oligomerization, resulting in a loss of mitochondrial cristae density and an increase in cristae width. Conclusion Our data reveal a previously unappreciated role for Slc25a12 as a modulator of mitochondrial cristae shape through its crosstalk with Opa1.