Huntington’s disease (HD) is an inherited neurodegenerative disease caused by elongation of polyglutamine in mutant huntingtin (Htt) protein. Mutant Htt causes various mitochondrial functional impairments and bioenergetics dysfunctions. Besides, it also causes increase of mitochondrial fragmentation and alteration of mitochondrial morphology as well as distribution. Aggregates of mutant Htt could also impair trafficking and causes mitochondrial or cellular membranes damage. Previous study showed that Htt-HAP40 (Htt-associated protein 40) complex is an effector of Rab5 that regulates dynamics of early endosomes. Moreover, endogenous level of HAP40 is increased in patient’s brain samples, animal and cell models of HD. Hence, up-regulation of HAP40 might involve in the pathogenesis of HD. To date, its function remains unclear. Microtubule is suggested as crucial factor for mitochondria distribution and regulation. Moreover, autophagy pathway that is essential for clearance of aggregates prone proteins required an intact microtubule cytoskeleton. Therefore, it was presumed that microtubule and diversification of mitochondrial morphology as well as autophagy are interrelated.
In present study, it was found that HAP40 is associated with microtubules via microtubule co-sedimentation assay. Besides, results of nocodazole treatment suggested that HAP40 might exert mild impact on microtubule dynamics. Based on images of immunocytochemistry, HAP40 overexpressed cells exhibited imbalance of mitochondrial fusion/fission events where level of fragmented mitochondria is increased. Further, ATP assay showed that overexpression of HAP40 exhibited a trend of low ATP level, suggesting that mitochondria function is affected. Likewise, current study also observed that STHdh Q111/Q111 (striatal cells expressing mutant Htt) demonstrated more fragmented mitochondria as compared to STHdh Q7/Q7 (striatal cells expressing wild-type Htt), which are consistent with previous study. Also, immunocytochemistry images revealed that impairment of mitochondrial fusion/fission dynamics in STHdh Q111/Q111 and HAP40 overexpressed cells is able to be rescued by wild-type Htt rather than Tubastatin A treatment. However, both wild-type Htt and Tubastatin A treatment have high tendency in reverting low ATP level of STHdh Q111/Q111 and HAP40 overexpressed cells, based on results obtained from ATP assay. On the other hand, present study noticed that autophagic activities were greatly activated in both STHdh Q111/Q111 and HAP40 overexpressed cells instead of mitophagy, indicating that inefficient clearance of damaged mitochondria could be the factor that results in accumulation of abnormal or impaired mitochondria in HD.

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