Sensing the Stress: A Role for the UPR(mt) and UPR(am) in the Quality Control of Mitochondria

Mitochondria exist as compartmentalized units, surrounded by a selectively permeable double membrane. Within is contained the mitochondrial genome and protein synthesis machinery, required for the synthesis of OXPHOS components and ultimately, ATP production. Despite their physical barrier, mitochondria are tightly integrated into the cellular environment. A constant flow of information must be maintained to and from the mitochondria and the nucleus, to ensure mitochondria are amenable to cell metabolic requirements and also to feedback on their functional state. This review highlights the pathways by which mitochondrial stress is signaled to the nucleus, with a particular focus on the mitochondrial unfolded protein response (UPR(mt)) and the unfolded protein response activated by the mistargeting of proteins (UPR(am)). Although these pathways were originally discovered to alleviate proteotoxic stress from the accumulation of mitochondrial-targeted proteins that are misfolded or unimported, we review recent findings indicating that the UPR(mt) can also sense defects in mitochondrial translation. We further discuss the regulation of OXPHOS assembly and speculate on a possible role for mitochondrial stress pathways in sensing OXPHOS biogenesis.