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1864 (4 Pt A), 1115-1128

Apr 2018

Metformin Regulates Mitochondrial Biogenesis and Senescence Through AMPK Mediated H3K79 Methylation: Relevance in Age-Associated Vascular Dysfunction

Santosh Karnewar 1Praveen Kumar Neeli 1Devayani Panuganti 2Sasikumar Kotagiri 2Sreevidya Mallappa 1Nishant Jain 1Mahesh Kumar Jerald 3Srigiridhar Kotamraju 4

Abstract

Endothelial senescence in conjunction with mitochondrial dysfunction orchestrates age-associated cardiovascular disorders. In this study we investigated the causal link between these two processes and studied the molecular mechanisms by which metformin acts to coordinate the delay of endothelial senescence via enhancing mitochondrial biogenesis/function. AMPK activators metformin and AICAR delayed endothelial senescence via SIRT1-mediated upregulation of DOT1L, leading to increased trimethylation of H3K79 (H3K79me3). Treatment of cells with either siAMPK or siSIRT1 repressed DOT1L-mediated enhancement of H3K79me3. Moreover, the increase in SIRT3 expression and mitochondrial biogenesis/function by AMPK activators was H3K79me-dependent as H3K79N mutant or siDOT1L abrogated these effects. This was confirmed by the enrichment of H3K79me3 in the SIRT3 promoter with AMPK activation. Intriguingly, enhanced PGC-1α expression by SIRT3 via AMPK activation was responsible for increased hTERT expression and delayed endothelial senescence. In contrast, SIRT3 knockdown caused increased oxidative stress and premature senescence, possibly by depleting hTERT expression. Furthermore, a chronic low dose administration of metformin significantly attenuated vascular aging and inhibited age-associated atherosclerotic plaque formation in ApoE-/- mice. Overall, the results of this study show a novel regulation of mitochondrial biogenesis/function, and cellular senescence by H3K79me acting through SIRT3, thus providing a molecular basis for metformin-mediated age-delaying effects.

Keywords: Aging; Atherosclerosis; Cardiovascular diseases; Endothelial dysfunction; Metformin; Mitochondrial function.

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