Otera et al. reveal that the mitochondrial fission factor Drp1 and its receptors MiD49 and MiD51 promote apoptosis by remodeling mitochondrial cristae.
Early in apoptosis, mitochondrial cristae are remodeled so that cytochrome c enters the space between the inner and outer mitochondrial membranes, from where it can be released into the cytoplasm to initiate caspase activation and cell death. Cristae remodeling is facilitated by mitochondrial fission, a process driven by the dynamin-like GTPase Drp1 and its receptors on the outer mitochondrial membrane. Whether Drp1-mediated fission is required for cytochrome c release remains unclear, however.
Otera et al. found that three Drp1 receptors—Mff, MiD49, and MiD51—have redundant roles in recruiting Drp1 and promoting mitochondrial fission. Knocking out Mff had little effect on cytochrome c release in apoptotic cells, but deleting MiD49, MiD51, or Drp1 itself prevented cristae remodeling and cytochrome c release during the early stages of apoptosis.
Cristae are thought to be stabilized by protein complexes containing long and short isoforms of the GTPase OPA1, and apoptotic signals are thought to induce cristae remodeling by initiating the proteolytic processing and disassembly of these complexes. Surprisingly, however, OPA1 complexes were still disrupted in remodeling-resistant MiD49/MiD51 knockout cells, indicating that OPA1 processing isn’t sufficient to induce cristae reorganization.
Instead, says senior author Katsuyoshi Mihara, the results demonstrate a critical role for Drp1-mediated mitochondrial fission. The authors now want to investigate how MiD49 and MiD51 might interact with the cristae remodeling machinery.