UCP4A protects against mitochondrial dysfunction and degeneration in pink1/parkin models of Parkinson's disease

Kai Wu, Jia Liu, Na Zhuang, Tao Wang
FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 2014, 28 (12): 5111-21
Genetic mutations in parkin or pink1 are the most common causes of familial Parkinson's disease. PINK1 and Parkin are components of a mitochondrial quality control pathway that degrades dysfunctional mitochondria via autophagy. Using a candidate gene approach, we discovered that overexpression of uncoupling protein 4A (ucp4A) suppresses a range of pink1 mutant phenotypes, including male sterility, locomotor defects, and muscle degeneration that result from abnormal mitochondrial morphology and function. Furthermore, UCP4A overexpression in pink1 mutants rescued mitochondria-specific phenotypes associated with mitochondrial membrane potential, production of reactive oxygen species, resistance to oxidative stress, efficiency of the electron transport chain, and mitochondrial morphology. Consistent with its role in protecting mitochondria, UCP4A rescued mitochondrial phenotypes of parkin mutant flies, as well. Finally, the genetic deletion of ucp4A resulted in increased sensitivity to oxidative stress, a phenotype that was enhanced by the loss of PINK1. Taken together, these results indicate that UCP4A prevents mitochondrial dysfunction and that modulation of UCP activity protects cells in a situation relevant for human Parkinson's disease.

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