Abstract 2479 Biogenesis of mitochondrial outer membrane proteins

Mitochondria are membrane bound organelles that play a central role in cellular metabolism and signaling. During their evolution from an endosymbiotic bacterium to a bona fide organelle, 99% of mitochondrial proteins became encoded by the nuclear genome, and thus must be accurately recognized in the cytosol, targeted, and inserted into the correct mitochondrial compartment. Despite more than four decades of research defining how proteins are imported into mitochondria, one critical question remains unanswered: how are a-helical proteins inserted into the outer membrane, particularly in mammalian mitochondria? Outer membrane proteins have evolved to mediate communication with the host cell, and its members have now expanded to regulate key aspects of cell physiology including apoptosis, innate immunity, and mitochondrial transport, fusion, and fission. We have answered this long-standing question: we identified the central factor for insertion of diverse a-helical proteins into the outer mitochondrial membrane, MTCH2. We show that MTCH2 is both necessary and sufficient for the insertion of tail-anchored proteins, and is the defining member of a new class of insertases that exploit the solute carrier 25 fold (SCL25) and are found throughout holozoa. Further, we found that modulating the function of MTCH2, either by changing its expression level or with mutations that alter its insertase activity, we can affect the localization of substrates to the ER vs mitochondria, and sensitize cells to apoptosis. This work also provides a biochemical rationalization for the enigmatic phenotypes associated with MTCH2, which range from defects in lipogenesis and apoptosis, to associations with Alzheimer's disease and leukemias.