The Oxidation Status of Mic19 Regulates MICOS Assembly

The function of mitochondria depends on the proper organization of mitochondrial membranes. The morphology of the inner membrane is regulated by the recently identified mitochondrial contact site and crista organizing system (MICOS) complex. MICOSmutants exhibit alterations in crista formation, leading to mitochondrial dysfunction. However, the mechanisms that underlie MICOS regulation remain poorly understood. MIC19, a peripheral protein of the inner membrane and component of the MICOS complex, was previously reported to be required for the proper function of MICOS inmaintaining the architecture of the inner membrane. Here, we show that human and Saccharomyces cerevisiaeMIC19 proteins undergo oxidation in mito-chondria and require the mitochondrial intermembrane space assembly (MIA) pathway, which couples the oxidation and im-port of mitochondrial intermembrane space proteins for mitochondrial localization. Detailed analyses identified yeast Mic19 in two different redox forms. The form that contains an intramolecular disulfide bond is bound toMic60 of the MICOS complex. Mic19 oxidation is not essential for its integration into the MICOS complex but plays a role in MICOS assembly and the mainte-nance of the proper inner membrane morphology. These findings suggest that Mic19 is a redox-dependent regulator of MICOS function. Mitochondria are essential organelles in eukaryotic cells andplay a key role in many cellular processes, including energy conversion; the synthesis of amino acids, lipids, and heme; and apoptosis. Mitochondria are enveloped by the outer membran