Dysfunctional mitochondrial respiration in the wobbler mouse brain

The involvement of mitochondrial dysfunction promoting neurodegenerative di seases, including amyotrophic lateral sclerosis (ALS), has been suggested. Histopathological and biochemical mitochondrial abnormalities have been rep orted in both sporadic and familial patients and suggest the contention tha t mitochondria may play a key role promoting ALS. Animal models of ALS prov ide a unique opportunity to study this incurable and fatal human disease. I n the present study we tested the hypothesis that alterations in mitochondr ial physiology occur in the brain of wobbler mice. No significant differenc e was found in the respiratory control index or adenosine diphosphate/oxyge n ratio values between isolated mitochondria of wobbler and control mice. W hen pyruvate and malate were used as substrates, oxygen consumption was dec reased significantly by approximately 33% in mitochondria isolated from wob bler mouse brain com pared to controls. Oxygen consumption in the presence of ascorbate and N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) was decrea sed significantly by approximately 21% in wobbler brain mitochondria compar ed to controls, which suggests impairment in the function of complex IV. Th ese findings are the first demonstration of mitochondrial respiratory chain dysfunction in the brain of the wobbler mouse. (C) 2001 Elsevier Science I reland Ltd. All rights reserved.