All the Little Pieces - Regulation of Mitochondrial Fusion and Fission by Ubiquitin and Small Ubiquitin-Like Modifier and Their Potential Relevance in the Heart -

Abstract

Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maintain their function. The process of mitochondrial fusion has the effect of mixing their content, allowing complementation of protein components, mtDNA repair, and distribution of metabolic intermediates. Fission, on the other hand, enables mitochondria to increase in number and capacity, and to segregate mitochondria for autophagy by the lysosome ("mitophagy"). Disruption of these protein quality control mechanisms has recently been identified in multiple cardiac diseases, including cardiac hypertrophy, heart failure, dilated cardiomyopathy, and ischemic heart disease, and is intimately tied to mitochondrial control of apoptosis. Proteins that regulate mitochondrial fusion and fission have been discovered, including Mfn1, Mfn2, and Opa1 (fusion) and Drp1 and Fis1 (fission). In this review, we discuss how these proteins are regulated by post-translational modification with ubiquitin and SUMO (small ubiquitin-like modifier). We then present what is known about the ubiquitin and SUMO ligases that regulate these post-translational modifications and regulation of mitochondrial fusion and fission, exploring their potential as therapeutic targets of cardiac disease. (Circ J 2011; 75: 2513 - 2521

The Ubiquitin-Like SUMO System and Heart Function

“…Increased expression of SENP5 is linked to alterations in mitochondrial dynamics and mitochondrial fission, which is assumed to rely on enhanced recruitment of mitochondria and oligomerization of the dynamin-related protein (DRP1). 133 Several lines of evidence indicate that transient SUMOylation of DRP1 controls the dynamic association of DRP1 with mitochondria. McBride and co-workers proposed that SUMO1 conjugation enhances retention of DRP1 on the membrane after recruitment of DRP1 to mitochondria, followed by disassembly of the DRP1 oligomer via de-SUMOylation once fission is complete.…”

BECN1s, a short splice variant of BECN1, functions in mitophagy

“…[1][2][3][4] Thus, maintaining a healthy population of mitochondria is essential for cellular homeostasis. Selective autophagy of mitochondria, known as mitophagy, which mediates the selective removal of damaged mitochondria, plays an important role in mitochondrial quality control.…”

Coordination of Cellular Localization-Dependent Effects of Sumoylation in Regulating Cardiovascular and Neurological Diseases

“…In Cos7 and Hela cells, DRP1 SUMO1 modification stimulates mitochondrial fission by enhancing retention of DRP1 on the membrane after its recruitment to mitochondria, followed by disassembly of the Drp1 oligomer via de-SUMOylation (SUMO1) once fission is completed(Wasiak et al, 2007, Zunino et al, 2007, Zunino et al, 2009). Mitochondrial-anchored protein ligase (MAPL) is a 40 kDa protein located on the outer mitochondrial membrane(Zungu et al, 2011) (Fig. 9).…”

“…Although MAPL can participate into the process of both ubiquination and SUMOylation, under physiologic conditions MAPL preferentially functions as a SUMO E3 ligase for DRP1 SUMOylation (SUMO1)(Braschi et al, 2009). MAPL-mediated DRP1 SUMOylation (SUMO1) increases mitochondrial fission and hyper-fragmentation(Zungu et al, 2011, Braschi et al, 2009, Neuspiel et al, 2008). MAPL-mediated DRP1 SUMOylation (SUMO1) has also been identified to play a role in apoptosis.…”