Abstract
Mitochondrial biogenesis occurs under basal conditions and is an adaptive response initiated by cells to maintain energetic demands and metabolic homeostasis following injuries targeting mitochondrial function. Identifying pharmacological agents that stimulate mitochondrial biogenesis is a critical step in the development of new therapeutics for the treatment of these injuries and to test the hypothesis that these agents will expedite recovery of cell and organ function following acute organ injuries. In this study, we examined the effects of SRT1720 on mitochondrial biogenesis and function in primary cultures of renal proximal tubule cells (RPTC). We also tested the ability of this compound to restore mitochondrial functions following oxidant-induced RPTC injury. SRT1720 (3-10 μM) induced mitochondrial biogenesis in RPTC within 24 hrs as determined by elevations in mitochondrial DNA copy number, increased expression of the mitochondrial proteins NDUFB8 and ATP synthase β, and elevated mitochondrial respiration rates and ATP levels. Induction of mitochondrial biogenesis was dependent on SIRT1 deacetylase activity, correlated with deacetylated nuclear PGC-1α, and occurred in the absence of AMP-dependent kinase (AMPK) activation. Finally, SRT1720 treatment accelerated recovery of mitochondrial functions following acute oxidant injury. This study demonstrates that SRT1720 can induce mitochondrial biogenesis through SIRT1 activity and deacetylated PGC-1α, but not AMPK, in RPTC within 24 hrs following oxidant injury. The results support further study of mitochondrial biogenesis as a repair process and a pharmacological target in acute organ injuries and disorders plagued by mitochondrial impairment.
Footnotes
- Received September 24, 2009.
- Revision received January 22, 2010.
- Accepted January 25, 2010.
- The American Society for Pharmacology and Experimental Therapeutics