Role of Glucose Metabolism and ATP in Maintaining PINK1 Levels During Parkin-mediated Mitochondrial Damage Responses [Protein Synthesis and Degradation]

November 17th, 2014 by Lee, S., Zhang, C., Liu, X.

Mutations in several genes, including PINK1 and Parkin, are known to cause autosomal recessive cases of Parkinsons disease in humans. These genes operate in the same pathway and play a crucial role in mitochondrial dynamics and maintenance. PINK1 is required to recruit Parkin to mitochondria and initiate mitophagy upon mitochondrial depolarization. In this study, we show that PINK1-dependent Parkin mitochondrial recruitment in response to global mitochondrial damage by carbonyl cyanide m-chlorophenyl hydrazine (CCCP) requires active glucose metabolism. Parkin accumulation on mitochondria and subsequent Parkin-dependent mitophagy is abrogated in glucose-free media or in the presence of 2-deoxyglucose upon CCCP treatment. The defects in Parkin recruitment correlate with intracellular ATP levels and can be attributed to suppression of PINK1 up-regulation in response to mitochondria depolarization. Low levels of ATP appear to prevent PINK1 translation instead of affecting PINK1 mRNA expression or reducing its stability. Consistent with a requirement of ATP for elevated PINK1 levels and Parkin mitochondrial recruitment, local or individual mitochondrial damage via photoirradiation does not affect Parkin recruitment to damaged mitochondria as long as a pool of functional mitochondria is present in the photoirradiated cells even in glucose-free or 2-DG-treated conditions. Thus, our data identifies ATP as a key regulator for Parkin mitochondrial translocation and sustaining elevated PINK1 levels during mitophagy. PINK1 functions as an AND-gate and a metabolic sensor coupling biogenetics of cells and stress signals to mitochondria dynamics.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Role of Glucose Metabolism and ATP in Maintaining PINK1 Levels During Parkin-mediated Mitochondrial Damage Responses [Protein Synthesis and Degradation]