MUL1-A new potential for a therapeutic target for Parkinson's disease a commentary on “MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin” by Yun and colleagues (eLife 2014; 3: 1-26)

Abstract

Mitochondrial dysfunction, impaired protein degradation, oxidative damage, and impaired mitophagy all have important roles in the pathogenesis of Parkinson's disease (PD). Familial PD studies advanced our understanding of PD pathogenesis. For example, mutations in relevant genes PINK1 (PTEN-induced putative kinase) and parkin cause autosomal recessive young-onset PD; PINK1 activates Parkin (E3-ubiquitin ligase), which then phosphorylates ubiquitin, 1 leading to the elimination of damaged mitochondria (mitophagy). PINK1 and parkin mutations disrupt this pathway, 1 and parkin enhancement is a proposed therapeutic approach in PD. In mice, loss of PINK1 and parkin results only in subtle PD signs, 2 unlike in humans where levodoparesponsive parkinsonism develops. Intriguingly, 1 patient with parkin homozygous mutation and confirmed functional parkin loss surprisingly did not develop PD even by age 66. Furthermore, ubiquitination of fusion mediator-mitofusin (mfn2; 4 part of the mitochondrial network and mitophagy cascade), was impaired in this patient, and there was no observed compensation for the impaired mfn2 ubiquitination. 3 This suggests the existence of other compensatory proteins or pathways that may prove useful for PD therapeutics.Yun and colleagues identified a novel ligase that rescues the defects caused by mutations in PINK1 and parkin mutations in Drosophila called MUL1 (Mitochondrial E3-Ubiquitin Protein Ligase 1). MUL1 guards mitochondrial homeostasis and promotes fragmentation of mitochondria by stabilizing dynamin-related protein (drp1) or degrading mitofusin (mfn). It is not known if increased mfn/decreased drp1 alone causes mutant phenotypes. MUL1 seems to act in parallel with PINK1 and parkin. Loss of PINK1 or parkin combined with additional loss of MUL1 results in exaggerated mitochondrial damage and more severe PD phenotype in flies when compared with loss of PINK1 or parkin alone. When MUL1 is absent, any compensation for PINK1 or parkin defects is impossible. Moreover, decreased mfn ubiquitination with an exaggerated phenotype as a result of the loss of both MUL1 and parkin was confirmed in mouse cortical neurons. MUL1 upregulation rescues mitochondrial damage caused by PINK1 or parkin deficit, and ligase activity is crucial for this rescue. Yun and colleagues demonstrated that mitofusin overexpression, but not dynamin-related protein loss, results in mutant phenotypes in Drosophila and mice. MUL1 and parkin can rescue the PINK1 mutants independently.This paper highlights that new PD-targeted therapeutic possibilities involving MUL1 are promising. Moreover, other studies reported MUL1 involvement in regulation of seleniteinduced mitophagy.5 Selenite at low doses is known to induce mitophagy.5 Again, ligase activity is crucial for this process. Selenium role as a chemoprotective agent should be investigated further, and other agents capable of MUL1 upregulation should be sought.In conclusion, the MUL1 pathway may be an important covariable in PINK1 and parkin mutation carriers. Furthermore, MUL...

MUL1‐RING recruits the substrate, p53‐TAD as a complex with UBE2D2–UB conjugate

“…Mitochondrial E3 ubiquitin ligase 1 (MUL1), located in the mitochondrial outer membrane, regulates various biological processes, including mitochondrial dynamics, cell growth, apoptosis, and mitophagy through ubiquitylation and SUMOylation [ 1 ]. It is a potential therapeutic target for Parkinson's disease because its role is similar to that of the PINK1/Parkin pathway [ 2 , 3 ]. MUL1 also has different names, such as mitochondrial‐anchored protein ligase (MAPL) [ 4 ], mitochondrial ubiquitin (UB) ligase activator of NF‐κB (MULAN) [ 5 ], growth inhibition, and death E3 ligase (GIDE) [ 6 ] and Hades [ 7 ].…”