Chemical genetics unveils a key role of mitochondrial dynamics, cytochrome c release and ip3r activity in muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused bymutations in the dystrophin gene.The subcellular mechanisms of DMD remain poorly understood and there is currently no curative treatmentavailable. Using a Caenorhabditis elegans model for DMD as a pharmacologic and genetic tool, we found thatcyclosporineA(CsA) reducesmuscledegeneration atlowdoseandacts, at least in part, through amitochondrialcyclophilin D, CYN-1. We thus hypothesized that CsA acts on mitochondrial permeability modulation throughcyclophilin D inhibition. Mitochondrial patterns and dynamics were analyzed, which revealed dramatic mitochondrialfragmentation not only in dystrophic nematodes, but also in a zebrafish model forDMD.This abnormalmitochondrial fragmentation occurs before any obvious sign of degeneration can be detected. Moreover, wedemonstrate that blocking/delaying mitochondrial fragmentation by knocking down the fission-promotinggene drp-1 reduces muscle degeneration and improves locomotion abilities of dystrophic nematodes.Further experiments revealed that cytochrome c is involved in muscle degeneration in C. elegans and seemsto act, at least in part, through an interaction with the inositol trisphosphate receptor calcium channel, ITR-1.Altogether, our findings reveal that mitochondria play a key role in the early process of muscle degenerationand may be a target of choice for the design of novel therapeutics for DMD. In addition, our results providethe first indication in the nematode that (i) mitochondrial permeability transition can occur and (ii) cytochromec can act in cell death. © The Author 2013. Published by Oxford University Press. All rights reserved.