MiD51 Regulates Bax-Mediated Cell Death Hongxu Xian1，Yih-Cherng Liou1,2,* 1Department of Biological Sciences, Faculty of Science, National University of Singapore, 14 Science Drive 4, 117543, Singapore 2NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117573, Singapore Mitochondria play crucial roles in cell death. Upon apoptotic stimuli, Bax, a key member of Bcl-2 protein family, translocates to mitochondria and accelerates cell death. The oligomerization of Bax mediates mitochondrial outer membrane permeabilization and apoptosis by stimulating cytochrome C/Smac release. Mitochondrial fusion inhibits cell death whereas fission induces apoptosis. However, the underlying mechanisms of how mitochondrial dynamics associates with apoptosis are still poorly understood. Interestingly, in this study we found staurosporine (STS) significantly induces the degradation of MiD51 (mitochondrial dynamics proteins of 51 kDa) through the ubiquitin-proteasome pathway. Mitochondrial dynamics proteins of 49 kDa (MiD49) and 51 kDa (MiD51) have previously been reported to promote mitochondrial fission through mediating the recruitment of Drp1 onto mitochondria. More recently, the observation that the loss of MiD51 could prevent cristae remodeling and inhibit Drp1-dependent cytochrome C release was reported (Otera et al., 2016). However, here we unravel a novel but divergent role of MiD51 in which it regulates cell death through mediating Bax translocation onto mitochondria. Knocking down of MiD51 sensitizes cells to intrinsic and extrinsic apoptotic stimuli-induced cell death. Furthermore, depletion of MiD51 induces the assembly of Bax foci on mitochondria, which can be rescued by the overexpression of Bcl-xL. However, knocking down of MiD51 cannot further promote cell death in Bcl-xL-depleted cells, suggesting that MiD51 may directly regulate Bax-dependent cell death on mitochondria. In MiD51-depleted cells, Bax translocation onto mitochondria is followed by the decrease of mitochondrial membrane potential (Δψm) and Smac release from mitochondria. Furthermore, we also uncover that the induction of mitochondrial fusion by either depletion of Drp1 or overexpression of Drp1K38A, a defective GTPase mutant, fails to rescue the apoptotic phenotypes in MiD51-depleted cells, indicating that the pivotal role of MiD51 in regulating apoptosis could be through a Drp1-independent pathway, probably a separate role of it in mitochondrial dynamics. Taken together, our finding may shed light on the new role of MiD51 in the regulation of cell survival and fate.
References Otera, H., Miyata, N., Kuge, O., Mihara, K., 2016. Drp1-dependent mitochondrial fission via MiD49/51 is essential for apoptotic cristae remodeling. J Cell Biol.
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