Tying trafficking to fusion and fission at the mighty mitochondria

The mitochondrion is a unique organelle that serves as the main site of ATP generation needed for energy in the cell. However, mitochondria also play essential roles in cell death through apoptosis and necrosis, as well as a variety of crucial functions related to stress regulation, autophagy, lipid synthesis and calcium storage. There is a growing appreciation that mitochondrial function is regulated by the dynamics of its membrane fusion and fission; longer, fused mitochondria are optimal for ATP generation, whereas fission of mitochondria facilitates mitophagy and cell division. Despite the significance of mitochondrial homeostasis for such crucial cellular events, the intricate regulation of mitochondrial fusion and fission is only partially understood. Until very recently, only a single mitochondrial fission protein had been identified. Moreover, only now have researchers turned to address the upstream machinery that regulates mitochondrial fusion and fission proteins. Herein, we review the known GTPases involved in mitochondrial fusion and fission, but also highlight recent studies that address the mechanisms by which these GTPases are regulated. In particular, we draw attention to a substantial new body of literature linking endocytic regulatory proteins, such as the retromer VPS35 cargo selection complex subunit, to mitochondrial homeostasis. These recent studies suggest that relationships and cross-regulation between endocytic and mitochondrial pathways may be more widespread than previously assumed.