Molecular Mechanisms of Mitochontrial Dynamics
Mitochondrial membrane remodeling is driven by a specialized set of large, GTP-hydrolyzing enzymes. These mechanochemical machines assemble on the mitochondrial surface and reshape lipid bilayers through nucleotide-dependent conformational changes. Together, they orchestrate the fundamental processes of mitochondrial fusion and fission.
Mitochondrial fusion
Mitochondrial fusion is a coordinated process that merges both the outer and inner membranes of adjacent mitochondria, allowing the exchange of membranes, proteins, and mitochondrial DNA. This process is mediated by three dynamin-related GTPases: the mitofusins Mfn1 and Mfn2, which reside in the outer mitochondrial membrane, and OPA1 (Optic Atrophy 1), which is anchored to the inner membrane.
Our work has shown that these GTPases function at distinct and sequential steps. Mitofusins are required for outer membrane fusion, whereas OPA1 is essential for inner membrane fusion. Loss of either mitofusins or OPA1 effectively blocks mitochondrial mixing and profoundly disrupts mitochondrial physiology.
Mitochondrial fission
Mitochondrial fission is carried out by the dynamin-related GTPase Drp1/Dnm1L, which is recruited from the cytosol to the mitochondrial surface. Upon assembly on mitochondria, Drp1 forms constriction rings that tighten around the organelle, ultimately severing it into separate units. This recruitment is mediated by several mitochondrial outer membrane receptors that provide spatial and temporal control over the fission process.
Mitochondrial fission plays critical roles in cellular homeostasis. Beyond shaping organelle morphology, it is required for apoptosis, programmed necrosis, mitochondrial distribution, and mitophagy, the selective degradation of mitochondria by autophagy.