BNIP3: A POTENTIAL TARGET FOR THE TREATMENT OF MITOCHONDRIAL DYSFUNCTION IN HUNTINGTON'S DISEASE.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the IT-15 gene. This disorder is characterized by progressive neuronal death in the basal ganglia and cortex. Although many years have passed since the discovery of the HD mutation, no therapy has shown a neuroprotective effect or has been shown to slow down the disease progression to date. Growing evidence supports a pivotal role for mitochondrial dysfunction in the death of patients’ neurons but the molecular bases for mitochondrial impairment have not yet been elucidated. We provide the first evidence of an abnormal activation of Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNip3) in cells expressing mutant huntingtin. In the present study we show abnormal accumulation and dimerization of BNip3 in mitochondria from human HD muscle cells and brain tissues from HD model mice. Recent results have suggested that cytotoxicity induced by mutant huntingtin is likely mediated by an alteration in normal mitochondrial dynamics, resulting in increased mitochondrial fragmentation. According to the literature, when BNip3 is overexpressed or induced, it localizes to the mitochondria and causes loss of mitochondrial potential, mitochondrial fragmentation and mitophagy. In this context, BNip3 could have a key role in mediating the impairment of mitochondrial dynamics in HD cells, and BNip3 blocking could improve mitochondrial function, representing a new therapeutic strategy for HD. We have characterized the effects of BNip3 blockade in cell culture model of HD by expression of the dominant negative protein BNip3ΔTM. BNip3ΔTM is a mutant protein deleted of the C-terminal domain that is necessary for BNip3 insertion into the outer mitochondrial membrane. Importantly, we have demonstrated that blocking BNip3 expression and dimerization was able to restore normal mitochondrial phenotype in human HD muscle cells. Our data shed light on the molecular mechanisms underlying mitochondrial dysfunction in HD and point to BNip3 as a new potential target for neuroprotective therapy in HD.