Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice
Data de publicació2010
Kujoth, Gregory C.
Seo, Arnold Y.
Samhan-Arias, Alejandro K.
Barger, Jamie L.
Prolla, Tomas A.
MetadadesMostra el registre d'unitat complet
Background: Aging results in a progressive loss of skeletal muscle, a condition known as sarcopenia. Mitochondrial DNA (mtDNA) mutations accumulate with aging in skeletal muscle and correlate with muscle loss, although no causal relationship has been established. Methodology/Principal Findings: We
investigated the relationship between mtDNA mutations and sarcopenia at the gene expression and biochemical levels using a mouse model that expresses a proofreading-deficient version (D257A) of the mitochondrial DNA Polymerase c, resulting in increased spontaneous mtDNA mutation rates. Gene expression profiling of D257A mice followed by Parametric Analysis of Gene Set Enrichment (PAGE) indicates that the D257A mutation is associated with a profound downregulation of gene sets associated with mitochondrial function. At the biochemical level, sarcopenia in D257A mice is associated with a marked reduction (35–50%) in the content of electron transport chain (ETC) complexes I, III and IV, all of which are partly encoded by mtDNA. D257A mice display impaired mitochondrial bioenergetics associated with compromised state-3 respiration, lower ATP content and a resulting decrease in mitochondrial membrane potential (Dym). Surprisingly, mitochondrial dysfunction was not accompanied by an increase in mitochondrial reactive oxygen species (ROS) production or oxidative damage. Conclusions/Significance: These findings demonstrate that mutations in mtDNA can be causal in sarcopenia by affecting the assembly of functional ETC complexes, the lack of which provokes a decrease in oxidative phosphorylation, without an increase in oxidative stress, and ultimately, skeletal muscle apoptosis and sarcopenia.
És part dePLoS ONE, 2010, vol. 5, núm. 7, e11468
Els fitxers de llicència següents estan associats amb aquest element:
Mostrant elements relacionats per títol, autor i matèria.
Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer Granados Principal, Sergio; El-azem, Nuri; Pamplona Gras, Reinald; Ramirez Tortosa, Cesar; Pulido Moran, Mario; Vera Ramirez, Laura; Quiles, Jose L.; Sánchez Rovira, Pedro; Naudí i Farré, Alba; Portero Otín, Manuel; Pérez López, Patricia; Ramírez Tortosa, MCarmen (Elsevier, 2014)Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant ...
Skeletal muscle uncoupling-induced longevity in mice is linked to increased substrate metabolism and induction of the endogenous antioxidant defense system Keipert, Susanne; Ost, Mario; Chadt, A.; Voigt, A.; Ayala Jové, Ma. Victoria (Maria Victoria); Portero Otín, Manuel; Pamplona Gras, Reinald; Al-Hasani, H.; Klaus, Susanne (American Physiological Society, 2013)Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) mitochondria increases lifespan considerably in high-fat diet-fed UCP1 Tg mice compared with wild types (WT). To clarify the underlying mechanisms, ...
Fourcade, Stéphane; Ruiz, Montserrat; Guilera, Cristina; Hahnen, Eric; Brichta, Lars; Naudí i Farré, Alba; Portero Otín, Manuel; Dacremont, Georges; Cartier, Nathalie; Wanders, Ronald; Kemp, Stephan; Mandel, Jean Louis; Wirth, Brunhilde; Pamplona Gras, Reinald; Aubourg, Patrick; Pujol, Aurora (Oxford University Press, 2010)X-linked adrenoleukodystrophy (X-ALD) is a fatal, axonal demyelinating, neurometabolic disease. It results from the functional loss of a member of the peroxisomal ATP-binding cassette transporter subfamily D (ABCD1), ...