Full-length PGC-1alpha salvages the phenotype of a mouse model of human neuropathy through mitochondrial proliferation.
Fiche publication
Date publication
décembre 2013
Auteurs
Membres identifiés du Cancéropôle Est :
Dr LOEFFLER Jean-Philippe
Tous les auteurs :
Rona-Voros K, Eschbach J, Vernay A, Wiesner D, Schwalenstocker B, Geniquet P, Mousson De Camaret B, Echaniz-Laguna A, Loeffler JP, Ludolph AC, Weydt P, Dupuis L
Lien Pubmed
Résumé
Increased mitochondrial mass, commonly termed mitochondrial proliferation, is frequently observed in many human diseases directly or indirectly involving mitochondrial dysfunction. Mitochondrial proliferation is thought to counterbalance a compromised energy metabolism, yet it might also be detrimental through alterations of mitochondrial regulatory functions such as apoptosis, calcium metabolism or oxidative stress. Here, we show that prominent mitochondrial proliferation occurs in Cramping mice, a model of hereditary neuropathy caused by a mutation in the dynein heavy chain gene Dync1h1. The mitochondrial proliferation correlates with post-prandial induction of full-length (FL) and N-terminal truncated (NT) isoforms of the transcriptional co-activator PGC-1alpha. The selective knock-out of FL-PGC-1alpha isoform, preserving expression and function of NT-PGC-1alpha, led to a complete reversal of mitochondrial proliferation. Moreover, FL-PGC-1alpha ablation potently exacerbated the mitochondrial dysfunction and led to severe weight loss. Finally, FL-PGC-1alpha ablation triggered pronounced locomotor dysfunction, tremors and inability to rear in Cramping mice. In summary, endogenous FL-PGC-1alpha activates mitochondrial proliferation and salvages neurological and metabolic health upon disease. NT-PGC-1alpha cannot fulfil this protective action. Activation of this endogenous salvage pathway might thus be a valuable therapeutic target for diseases involving mitochondrial dysfunction.
Référence
Hum Mol Genet. 2013 Dec 20;22(25):5096-106