Oxidative metabolism and mitochondrial calcium handling in mouse models of Huntington's Disease

Abstract

Huntington’s disease (HD) is an autosomal dominantly inherited, fatal neurodegenerative disorder for which there is no cure. HD is clinically characterized by progressively worsening motor, cognitive, and psychiatric disturbances. Currently available therapeutics for HD only treat symptoms, but do not address underlying disease pathology. HD pathogenesis is linked to a mutation in the huntingtin gene, which encodes a protein called huntingtin (Htt) that is normally involved in a variety of cellular processes. In healthy individuals, the N-terminus of huntingtin possesses a polyglutamine stretch containing less than 35 glutamines, however, the mutated huntingtin protein (mHtt) has an elongated polyglutamine tract that correlates with the development of HD. The mechanism of deleterious action by mHtt is unknown, but a major hypothesis postulates that mHtt may cause mitochondrial dysfunction. However, the data regarding involvement of mitochondrial impairment in HD pathology are contradictory. Some investigators previously reported, for example, that mHtt suppresses mitochondrial respiratory activity and decreases mitochondrial Ca2+ uptake capacity. However, other investigators found increased respiratory activity and augmented mitochondrial Ca2+ uptake capacity. We used transgenic mouse models of HD to investigate the effect of full-length and fragments of mHtt on oxidative metabolism and Ca2+ handling using a combination of isolated mitochondria, primary neurons, and whole-animal metabolic measurements. We evaluated the effect of full-length mHtt on isolated mitochondria and primary neurons from YAC128 mice. We found no alteration in respiratory activity or Ca2+ uptake capacity, indicative of mitochondrial damage, between mitochondria or neurons from YAC128 mice compared to wild-type (WT) mice. Furthermore, we measured whole animal oxidative metabolism and physical activity level and found that YAC128 mice do not display any decline in metabolic and physical activity. Although full-length mHtt expressing YAC128 mice may be a more faithful genetic recapitulation of HD, data suggests mHtt fragments may be more toxic. To assess the effect of mHtt fragments, we used isolated brain mitochondria and primary striatal neurons from the R6/2 mouse model and found no significant impairment in respiration or Ca2+ handling. Thus, our data strongly support the hypothesis that mHtt does not alter mitochondrial functions assessed either with isolated mitochondria, primary neurons, or whole animals.