A conserved retromer sorting motif is essential for mitochondrial DLP1 recycling by VPS35 in Parkinson's disease model.

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.