Activation of mitochondrial energy metabolism protects against cardiac failure.

Abstract

Cardiac failure is the most prevalent cause of death at higher age, and is commonly associated with impaired energy homeostasis in the heart. Mitochondrial metabolism appears critical to sustain cardiac function to counteract aging. In this study, we generated mice transgenically over-expressing the mitochondrial protein frataxin, which promotes mitochondrial energy conversion by controlling iron-sulfur-cluster biogenesis and hereby mitochondrial electron flux. Hearts of transgenic mice displayed increased mitochondrial energy metabolism and induced stress defense mechanisms, while overall oxidative stress was decreased. Following standardized exposure to doxorubicin to induce experimental cardiomyopathy, cardiac function and survival was significantly improved in the transgenic mice. The insulin/IGF-1 signaling cascade is an important pathway that regulates survival following cytotoxic stress through the downstream targets protein kinase B, Akt, and glycogen synthase kinase 3. Activation of this cascade is markedly inhibited in the hearts of wild-type mice following induction of cardiomyopathy. By contrast, transgenic overexpression of frataxin rescues impaired insulin/IGF-1 signaling and provides a mechanism to explain enhanced cardiac stress resistance in transgenic mice. Taken together, these findings suggest that increased mitochondrial metabolism elicits an adaptive response due to mildly increased oxidative stress as a consequence of increased oxidative energy conversion, previously named mitohormesis. This in turn activates protective mechanisms which counteract cardiotoxic stress and promote survival in states of experimental cardiomyopathy. Thus, induction of mitochondrial metabolism may be considered part of a generally protective mechanism to prevent cardiomyopathy and cardiac failure.

• Authors: Tim J Schulz, Dirk Westermann, Frank Isken, Anja Voigt, Beate Laube, René Thierbach, Doreen Kuhlow, Kim Zarse, Lutz Schomburg, Andreas F H Pfeiffer, Carsten Tschöpe, Michael Ristow
• Journal: Aging (Aging (Albany NY)) Vol. 2 Issue 11 Pg. 843-53 (Nov 2010) ISSN: 1945-4589 [Electronic] United States
• PMID: 21084725 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Insulin
• Iron-Binding Proteins
• frataxin
• Doxorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (adverse effects)
• Disease Models, Animal
• Doxorubicin (adverse effects)
• Energy Metabolism
• Heart Failure (chemically induced, metabolism, prevention & control)
• Hemodynamics
• Humans
• Insulin (metabolism)
• Iron-Binding Proteins (metabolism)
• Mice
• Mice, Transgenic
• Mitochondria (metabolism)
• Signal Transduction (physiology)