Leucine 7 is a key residue for mutant huntingtin-induced mitochondrial pathology and neurotoxicity in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in exon 1 of the HTT gene. Mutant huntingtin (mHTT) associates with mitochondria, resulting in mitochondrial dysfunction and neuronal cell death. However, the underlying molecular mechanisms remain unknown. In this study, we investigate the role of N-terminal first 17 amino acids (N17) of mHTT in regulating its mitochondrial localization. Specifically, we demonstrate that the mutation at leucine 7 of N17 domain suppresses the association of mHTT with mitochondria. Blocking mitochondrial localization of HTT exon 1 with 73 glutamine repeats (HTT-Q73) strongly ameliorates polyglutamine-induced reduction of mitochondrial membrane potential, increase of reactive oxygen species production, and decrease in NAD+/NADH ratio. We observe that HTT-Q73-mediated abnormal mitochondrial morphology, mitochondrial DNA deletion, and cell death are abolished by HTT-Q73-L7A mutation. Finally, overexpression of HTT-Q73-L7A do not cause neurodegeneration and motor dysfunction in vivo. These findings highlight the pivotal role of the L7 residue which contributes to mHTT-caused HD pathology. Targeting the L7 residue of N17 domain may be a novel therapeutic strategy to alleviate mitochondrial dysfunction and neurodegeneration in HD.