Molecular Mechanisms of Mitochondrial Dynamics
Mitochondrial fusion is a membrane-remodeling process that coordinately merges the outer and inner membranes between two mitochondria. It requires three large GTPases: the mitofusins Mfn1 and Mfn2, and the dynamin-related protein OPA1 (Optic Atrophy 1). Mitofusins are embedded in the mitochondrial outer membrane, whereas OPA1 is associated with the inner membrane. We have shown that mitofusins and OPA1 act at distinct steps during mitochondrial fusion: mitofusins are essential for outer membrane fusion, whereas OPA1 is required for inner membrane fusion. One of our main efforts is to understand the underlying mechanisms.
Mitochondrial fission requires the recruitment and assembly of the dynamin-related GTPase Drp1/Dnm1, which constricts the diameter of mitochondria and ultimately results in scission. We are examining how Drp1 is recruited to the mitochondrial surface via a number of mitochondrial transmembrane receptors. The resolution of this issue is important, because mitochondrial fission is important for several cellular functions, including apoptosis, programmed necrosis, mitochondrial distribution, and mitochondrial degradation by autophagy. Our long-term goals are to understand the atomic structure of the fission complexes, to determine how they are activated for fission, and to identify new components of the mammalian fission machinery.