Wang Wenzhang, Ma Xiaopin, Zhou Leping, Liu Jun, Zhu Xiongwei
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200020, People's Republic of China.
Hum Mol Genet. 2017 Feb 15;26(4):781-789. doi: 10.1093/hmg/ddw430.
Impaired mitochondria dynamics and quality control are involved in mitochondrial dysfunction and pathogenesis of Parkinson's disease (PD). VPS35 mutations cause autosomal dominant PD and we recently demonstrated that fPD-associated VPS35 mutants can cause mitochondrial fragmentation through enhanced VPS35-DLP1 interaction. In this study, we focused on the specific sites on DLP1 responsible for the VPS35-DLP1 interaction. A highly conserved FLV motif was identified in the C-terminus of DLP1, mutation of which significantly reduced VPS35-DLP1 interaction. A decoy peptide design based on this FLV motif could block the VPS35-DLP1 interaction and inhibit the recycling of mitochondrial DLP1 complexes. Importantly, VPS35 D620N mutant-induced mitochondrial fragmentation and respiratory deficits could be rescued by the treatment of this decoy peptide in both M17 cells overexpressing D620N or PD fibroblasts bearing this mutation. Overall, our results lend further support to the notion that VPS35-DLP1 interaction is key to the retromer-dependent recycling of mitochondrial DLP1 complex during mitochondrial fission and provide a novel therapeutic target to control excessive fission and associated mitochondrial deficits.
线粒体动力学和质量控制受损与帕金森病（PD）的线粒体功能障碍和发病机制有关。VPS35突变导致常染色体显性PD，我们最近证明，与家族性PD相关的VPS35突变体可通过增强VPS35与动力蛋白1（DLP1）的相互作用导致线粒体碎片化。在本研究中，我们聚焦于DLP1上负责VPS35-DLP1相互作用的特定位点。在DLP1的C末端鉴定出一个高度保守的FLV基序，该基序的突变显著降低了VPS35-DLP1的相互作用。基于该FLV基序设计的诱饵肽可阻断VPS35-DLP1的相互作用，并抑制线粒体DLP1复合物的循环利用。重要的是，在过表达D620N的M17细胞或携带该突变的PD成纤维细胞中，用这种诱饵肽处理可挽救VPS35 D620N突变体诱导的线粒体碎片化和呼吸功能缺陷。总体而言，我们的结果进一步支持了这样一种观点，即VPS35-DLP1相互作用是线粒体分裂过程中retromer依赖的线粒体DLP1复合物循环利用的关键，并为控制过度分裂和相关线粒体缺陷提供了一个新的治疗靶点。
