Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.

Mitochondrial dysfunction is one of the primary cellular conditions involved in developing Huntington's disease (HD) pathophysiology. The accumulation of mutant huntingtin protein with abnormal PolyQ repeats resulted in the death of striatal neurons with enhanced mitochondrial fragmentation. In search of neuroprotective molecules against HD conditions, we synthesized a set of isoxazole-based small molecules to screen their suitability as beneficial chemicals improving mitochondrial health. Systematic characterization of one of these isoxazole derivatives, C-5, demonstrated improved mitochondrial health with reduced apoptosis via rebalancing fission-fusion dynamics in HD condition. Gene and protein expression analysis confirmed that C-5 treatment enhanced the expression of mitochondrial fusion regulators (MFN1/2) via transcriptional upregulation of PGC-1α, a transcriptional co-activator controlling mitochondrial biogenesis. Collectively, this novel fusion agonist can potentially become a new therapeutic alternative for treating PolyQ-mediated mitochondrial dysfunction, a hallmark of HD pathology.