Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1

Abstract

Mitochondria in cells comprise a tubulovesicular network shaped continuously by complementary fission and fusion events. The mammalian Drp1 protein plays a key role in fission, while Mfn1, Mfn2, and OPA1 are required for fusion. Shifts in the balance between these opposing processes can occur rapidly, indicating that modifications to these proteins may regulate mitochondrial membrane dynamics. We highlight posttranslational modifications of the mitochondrial fission protein Drp1, for which these regulatory mechanisms are best characterized. This dynamin-related GTPase undergoes a number of steps to mediate mitochondrial fission, including translocation from cytoplasm to the mitochondrial outer membrane, higher-order assembly into spirals, GTP hydrolysis associated with a conformational change and membrane deformation, and ultimately disassembly. Many of these steps may be influenced by covalent modification of Drp1. We discuss the dynamic nature of Drp1 modifications and how they contribute not only to the normal regulation of mitochondrial division, but also to neuropathologic processes.

Figure 1

Drp1 localization on mitochondria. Endogenous Drp1 puncta (green) are present in COS7 cells at discrete sites along mitochondrial tubules, which are visualized using MitoTracker Red CMXRos. Although some Drp1 foci are clearly evident at sites of fission (arrows in enlargements), not all foci represent sites of fission. Scale bar, 20 μm. Adapted from Zhu et al.

Figure 2

Schematic domain model of Drp1 showing identified sites of posttranslational modifications. Sumoylation sites are indicated by red line segments, and protein phosphorylation sites are identified by black arrows. An orange arrowhead identifies a site of S-nitrosylation. Sites of ubiquitination have not been identified. Boundary amino acid residues for the indicated domains are along the top. All amino acid numbering is based on the human Drp1 splice variant 1 sequence.