The Role of SIRT3 in Energy Metabolism of the Normal and Diabetic Heart

• Applicant: Professor Dr. Heiko Bugger
• Subject Area: Cardiology, Angiology
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 187374421

Lysine acetylation of proteins regulates fundamental cellular pathways in mammalian cells. The mitochondrially localized sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase that decreases lysine acetylation of mitochondrial energy metabolic proteins. Absence of SIRT3 increases global mitochondrial lysine acetylation, which is associated with impaired mitochondrial respiration rates. SIRT3 is highly expressed in the heart, but its role in the normal heart is largely unknown. In diabetic cardiomyopathy, mitochondrial energetics are impaired, but the underlying mechanisms are incompletely understood. Whether SIRT3 plays a role in the diabetic heart is unknown. We found increased mitochondrial protein lysine acetylation in murine diabetic hearts, suggesting reduced SIRT3 activity. Hyperactivation of PARP-1 in HEK 293 cells impairs SIRT3 activity by decreasing mitochondrial NAD+ levels, and PARP-1 expression is increased in diabetic hearts. This research proposal aims at (1) investigating the function of SIRT3 in normal cardiac energy metabolism, and (2) testing the hypothesis if increased expression of PARP-1 in diabetic hearts impairs mitochondrial energetics by depleting mitochondrial NAD+ and thereby decreasing SIRT3-dependent mitochondrial protein deacetylation. The resulting data will provide new insights into the role of sirtuins in the regulation of cardiac metabolism and may lead to a novel therapeutic approach to modulate cardiac energy metabolism in order to delay or prevent cardiac complications in diabetics.

• DFG Programme: Research Grants