Miquel 2012 PLoS One

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Miquel E, Cassina A, Martinez-Palma L, Bolatto C, Trias E, Gandelman M, Radi R, Barbeito L, Cassina P (2012) Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inherited amyotrophic lateral sclerosis. PLoS One 7:e34776.

» PMID: 22509356 Open Access

Miquel E, Cassina AM, Martinez-Palma L, Bolatto C, Trias E, Gandelman M, Radi R, Barbeito L, Cassina P (2012) PLoS One

Abstract: Mitochondrial dysfunction is one of the pathogenic mechanisms that lead to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). Astrocytes expressing the ALS-linked SOD1(G93A) mutation display a decreased mitochondrial respiratory capacity associated to phenotypic changes that cause them to induce motor neuron death. Astrocyte-mediated toxicity can be prevented by mitochondria-targeted antioxidants, indicating a critical role of mitochondria in the neurotoxic phenotype. However, it is presently unknown whether drugs currently used to stimulate mitochondrial metabolism can also modulate ALS progression. Here, we tested the disease-modifying effect of dichloroacetate (DCA), an orphan drug that improves the functional status of mitochondria through the stimulation of the pyruvate dehydrogenase complex activity (PDH). Applied to astrocyte cultures isolated from rats expressing the SOD1(G93A) mutation, DCA reduced phosphorylation of PDH and improved mitochondrial coupling as expressed by the respiratory control ratio (RCR). Notably, DCA completely prevented the toxicity of SOD1(G93A) astrocytes to motor neurons in coculture conditions. Chronic administration of DCA (500 mg/L) in the drinking water of mice expressing the SOD1(G93A) mutation increased survival by 2 weeks compared to untreated mice. Systemic DCA also normalized the reduced RCR value measured in lumbar spinal cord tissue of diseased SOD1(G93A) mice. A remarkable effect of DCA was the improvement of grip strength performance at the end stage of the disease, which correlated with a recovery of the neuromuscular junction area in extensor digitorum longus muscles. Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss in SOD1(G93A) mice. Taken together, our results indicate that improvement of the mitochondrial redox status by DCA leads to a disease-modifying effect, further supporting the therapeutic potential of mitochondria-targeted drugs in ALS.

Keywords: Amyotrophic lateral sclerosis, Astrocyte cultures, SOD1(G93A) mice, Dichloroacetate, Lumbar spinal cord

O2k-Network Lab: UY Montevideo Radi R


Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology  Pathology: Inherited, Other 

Organism: Mouse  Tissue;cell: Nervous system  Preparation: Intact cells 


Coupling state: OXPHOS 

HRR: Oxygraph-2k