C-Abl-mediated Drp1 phosphorylation promotes oxidative stress-induced mitochondrial fragmentation and neuronal cell death

Lujun Zhou,Can Peng,Zengqiang Yuan,Lei Sun,Jinbo Cheng,Peng Zhang,Qiang Zhang

doi:10.1038/cddis.2017.524

Abstract

Oxidative stress-induced mitochondrial dysfunction and neuronal cell death have important roles in the development of neurodegenerative diseases. Dynamin related protein 1 (Drp1) is a critical factor in regulating mitochondrial dynamics. A variety of posttranslational modifications of Drp1 have been reported, including phosphorylation, ubiquitination, sumoylation and S-nitrosylation. In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation. Consistently, c-Abl-mediated phosphorylation is important for GTPase activity of Drp1 and mitochondrial fragmentation. Furthermore, we found that Drp1 phosphorylation mediated by c-Abl is required for oxidative stress-induced cell death in primary cortical neurons. Taken together, our findings reveal that c-Abl-Drp1 signaling pathway regulates oxidative stress-induced mitochondrial fragmentation and cell death, which might be a potential target for the treatment of neurodegenerative diseases.

Highlights

Oxidative stress-induced mitochondrial dysfunction and neuronal cell death have been implicated as crucial steps in neurodegenerative diseases.[1,2,3,4,5] Mitochondria are highly dynamic organelles with continuous fission and fusion that are regulated by several
We found that c-Abl phosphorylated Drp[1] at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp[1] and promoted Dynamin related protein 1 (Drp1)-mediated mitochondrial fragmentation
Our findings reveal that c-Abl-Drp[1] signaling pathway regulates oxidative stress-induced mitochondrial fragmentation and cell death, which might be a potential target for the treatment of neurodegenerative diseases

Summary

Cell Death and Disease

C-Abl in mitochondrial dynamics, c-Ablflox/flox mice were crossed with CamKIIα-iCre transgenic mice to generate the mice with c-Abl deletion in neurons. In time-course experiment, Drp1Ser[616] phosphorylation was induced within 0.5 h after DPH treatment in primary neurons (Figure 1g) and SH-SY5Y cells (a human neuroblastoma cell line) (Supplementary Figure S1D) Taken together, these data suggest that c-Abl is responsible for the excessive mitochondrial fragmentation in MPTP-induced PD model. GTPase activity of Drp[1], we evaluated the effect of Drp[1] mutants on mitochondrial morphology and neuronal cell death under oxidative stress To this end, we first reduced the levels of endogenous Drp[1] using two individual Drp[1] knockdown plasmids, which target two different coding regions of Drp[1] (Figure 6a). C-Abl-mediated Drp[1] phosphorylation promoted oxidative stress-induced neuronal cell death

Discussion

Findings

Materials and Methods