(200b) A New Regulator of Mitochondrial Metabolism That Has Different Functions in Spatially Distinct Subcellular Locations, the Mitochondria and the Nucleus

Mitochondrial energy production is closely regulated to conserve the cell’s most valuable currency, ATP. Dysfunction in energy production and its regulation is associated with a variety of pathologic conditions that range from debilitating to major life-threatening diseases. Regulation includes communication between spacially distinct loci, in this case signaling from the nucleus to the mitochondria and retrograde regulation from the mitochondria back to the nucleus. Our understanding of stress-associated regulatory mechanisms for mitochondria in energy production and cell survival remains incomplete. We now report that we have discovered a new regulator of mitochondrial metabolism, the coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (CHCHD2). It functions in a novel way by acting via different modes in the two cellular compartments. In normally growing cells most CHCHD2 is located in the mitochondria; during stress the amount of CHCHD2 in mitochondria decreases and the amount in the nucleus increases. In the mitochondria, CHCHD2 is imported by a Mia40-mediated pathway to the intermembrane space where, upon phosphorylation at Tyr-99, it binds to cytochrome c oxidase (COX), the terminal complex of the respiratory chain. This association is required for full COX activity; when CHCHD2 levels are lowered, such as by oxidative or hypoxic stress, widespread dysfunction is observed including reduction of COX activity, of membrane potential, and of growth rate whereas there are increased radical species (ROS) and mitochondrial fragmentation. In the nucleus, however, CHCHD2 acts as a transcription factor, one of whose targets is a COX subunit 4 isoform, COX4i2, which is transcriptionally stimulated by hypoxia and by the deacetylation of CHCHD2 by Sirt1. This CHCHD2-mediated stress response may provide an important survival mechanism for cells under conditions of oxidative or hypoxic stress, both in the acute phase by altering mitochondrial oxygen utilizing activity and in the chronic phase by promoting remodeling of COX. Supported by Henry L. Brasza endowment.