Chemical genetics unveils a key role of mitochondrial dynamics, cytochrome c release and IP3R activity in muscular dystrophy
- Authors
- Giacomotto, J., Brouilly, N., Walter, L., Mariol, M.C., Berger, J., Ségalat, L., Becker, T.S., Currie, P.D., and Gieseler, K.
- ID
- ZDB-PUB-130710-81
- Date
- 2013
- Source
- Human molecular genetics 22(22): 4562-78 (Journal)
- Registered Authors
- Becker, Thomas S., Berger, Joachim, Currie, Peter D., Giacomotto, Jean
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Binding Sites
- Caenorhabditis elegans/genetics
- Caenorhabditis elegans/metabolism
- Caenorhabditis elegans Proteins/genetics
- Caenorhabditis elegans Proteins/metabolism
- Cell Death
- Cyclophilins/antagonists & inhibitors
- Cyclophilins/metabolism*
- Cyclosporine/pharmacology*
- Cytochromes c/genetics
- Cytochromes c/metabolism*
- Gene Knockdown Techniques
- Humans
- Inositol 1,4,5-Trisphosphate Receptors/genetics
- Inositol 1,4,5-Trisphosphate Receptors/metabolism*
- Methazolamide/pharmacology
- Mitochondrial Dynamics*/drug effects
- Mitochondrial Dynamics*/genetics
- Mitochondrial Proteins/genetics
- Mitochondrial Proteins/metabolism
- Muscular Dystrophy, Animal/drug therapy*
- Muscular Dystrophy, Animal/pathology
- Muscular Dystrophy, Duchenne/genetics
- Muscular Dystrophy, Duchenne/metabolism*
- Muscular Dystrophy, Duchenne/pathology
- Phylogeny
- Sequence Homology
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 23804750 Full text @ Hum. Mol. Genet.
Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations in the dystrophin gene. The subcellular mechanisms of DMD remain poorly understood and there is currently no curative treatment available. Using a Caenorhabditis elegans model for DMD as a pharmacologic and genetic tool, we found that cyclosporine A (CsA) reduces muscle degeneration at low dose and acts, at least in part, through a mitochondrial cyclophilin D, CYN-1. We thus hypothesized that CsA acts on mitochondrial permeability modulation through cyclophilin D inhibition. Mitochondrial patterns and dynamics were analyzed, which revealed dramatic mitochondrial fragmentation not only in dystrophic nematodes, but also in a zebrafish model for DMD. This abnormal mitochondrial fragmentation occurs before any obvious sign of degeneration can be detected. Moreover, we demonstrate that blocking/delaying mitochondrial fragmentation by knocking down the fission-promoting gene 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 seems to 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 degeneration and may be a target of choice for the design of novel therapeutics for DMD. In addition, our results provide the first indication in the nematode that (i) mitochondrial permeability transition can occur and (ii) cytochrome c can act in cell death.