Mutant Huntingtin and Elusive Defects in Oxidative Metabolism and Mitochondrial Calcium Handling.
Elongation of a polyglutamine (polyQ) stretch in huntingtin protein (Htt) is linked to Huntington's disease (HD) pathogenesis. The mutation in Htt correlates with neuronal dysfunction in the striatum and cerebral cortex and eventually leads to neuronal cell death. The exact mechanisms of the injurious effect of mutant Htt (mHtt) on neurons are not completely understood but might include aberrant gene transcription, defective autophagy, abnormal mitochondrial biogenesis, anomalous mitochondrial dynamics, and trafficking. In addition, deficiency in oxidative metabolism and defects in mitochondrial Ca(2+) handling are considered essential contributing factors to neuronal dysfunction in HD and, consequently, in HD pathogenesis. Since the discovery of the mutation in Htt, the questions whether mHtt affects oxidative metabolism and mitochondrial Ca(2+) handling and, if it does, what mechanisms could be involved were in focus of numerous investigations. However, despite significant research efforts, the detrimental effect of mHtt and the mechanisms by which mHtt might impair oxidative metabolism and mitochondrial Ca(2+) handling remain elusive. In this paper, I will briefly review studies aimed at clarifying the consequences of mHtt interaction with mitochondria and discuss experimental results supporting or arguing against the mHtt effects on oxidative metabolism and mitochondrial Ca(2+) handling.
Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Dr., Medical Science Bldg 547, Indianapolis, IN, 46202, USA. nbrous@iu.edu.|Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. nbrous@iu.edu.
Nickolay
N
Brustovetsky
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction
D000071058:Huntingtin Protein; D050505:Mutant Proteins; D002118:Calcium
Calcium uptake; Mitochondria; Mutant huntingtin; Permeability transition pore; Respiration