SUMO wrestling with Drp1 at mitochondria.

Mitochondria undergo dynamic fission and fusion events, and disruptions in this balance can lead to cellular dysfunction or death. New work by Henley and colleagues identifies a key role for the SUMO protease SENP3 and its target Drp1, a key mediator of mitochondrial fission, in ischaemia. The term mitochondrion is derived from the Greek mitos (thread) and khondrion (small grain), emphasizing the fundamental nature of its varied tubular and vesicular appearances within cells. Even this description belies the highly dynamic nature of mitochondria, which undergo continuous cycles of fission and fusion. Maintaining the proper balance between these competing processes is crucial for cellular homeostasis, and a variety of regulatory mechanisms fine tune this balance in different cellular contexts. The key players in mitochondrial fusion in metazoans are large, membrane-bound GTPases in the dynamin superfamily— mitofusin-1 and -2 and optic atrophy-1 (OPA1). Although a number of proteins including Mff, MiD49/51, Fis1, and actin cytoskeletal proteins have been implicated in the regulation of fission, they appear to do so predominantly through their effects on the dynamin-related GTPase Drp1, a protein present mostly in the cytoplasm that is specifically recruited to the mitochondrial outer membrane. After recruitment, Drp1 functions through a complex cycle comprising higher-order oligomerization to form a fission complex, GTPase-dependent constriction that triggers mitochondrial fission, and subsequent Drp1 disassembly and return to the cytoplasm as dimers/tetramers (Otera et al, 2013). Post-translational modifications of Drp1 play important regulatory roles in mitochondrial fission. Known modifications include protein phosphorylation mediated by multiple different kinases, SUMOylation, ubiquitylation, S-nitrosylation, and O-linked-N-acetyl-glucosamine glycosylation. Each Drp1 protomer has four major domains: an N-terminal GTPase domain, a middle assembly domain, a B (or variable) domain, and a C-terminal GTPase-effector domain (GED). Interestingly, the majority of modification sites are found on residues within the variable B domain, with a smaller number in the adjacent GED domain. To add further complexity, there are several known differentially spliced mRNA cassettes within the variable B domain in human Drp1. These modifications can be altered in numerous physiologic and pathologic states, including cell division, neurodegenerative diseases, starvation, and programmed cell death, with often profound effects on the cellular mitochondrial fission/fusion balance (Chang and Blackstone, 2010; Strack and Cribbs, 2012; Otera et al, 2013).