Elevated Cytosolic Na + Increases Mitochondrial Formation of Reactive Oxygen Species in Failing Cardiac Myocytes
- 13 April 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 121 (14), 1606-1613
- https://doi.org/10.1161/circulationaha.109.914911
Abstract
Background— Oxidative stress is causally linked to the progression of heart failure, and mitochondria are critical sources of reactive oxygen species in failing myocardium. We previously observed that in heart failure, elevated cytosolic Na + ([Na + ] i ) reduces mitochondrial Ca 2+ ([Ca 2+ ] m ) by accelerating Ca 2+ efflux via the mitochondrial Na + /Ca 2+ exchanger. Because the regeneration of antioxidative enzymes requires NADPH, which is indirectly regenerated by the Krebs cycle, and Krebs cycle dehydrogenases are activated by [Ca 2+ ] m , we speculated that in failing myocytes, elevated [Na + ] i promotes oxidative stress. Methods and Results— We used a patch-clamp–based approach to simultaneously monitor cytosolic and mitochondrial Ca 2+ and, alternatively, mitochondrial H 2 O 2 together with NAD(P)H in guinea pig cardiac myocytes. Cells were depolarized in a voltage-clamp mode (3 Hz), and a transition of workload was induced by β-adrenergic stimulation. During this transition, NAD(P)H initially oxidized but recovered when [Ca 2+ ] m increased. The transient oxidation of NAD(P)H was closely associated with an increase in mitochondrial H 2 O 2 formation. This reactive oxygen species formation was potentiated when mitochondrial Ca 2+ uptake was blocked (by Ru360) or Ca 2+ efflux was accelerated (by elevation of [Na + ] i ). In failing myocytes, H 2 O 2 formation was increased, which was prevented by reducing mitochondrial Ca 2+ efflux via the mitochondrial Na + /Ca 2+ exchanger. Conclusions— Besides matching energy supply and demand, mitochondrial Ca 2+ uptake critically regulates mitochondrial reactive oxygen species production. In heart failure, elevated [Na + ] i promotes reactive oxygen species formation by reducing mitochondrial Ca 2+ uptake. This novel mechanism, by which defects in ion homeostasis induce oxidative stress, represents a potential drug target to reduce reactive oxygen species production in the failing heart.Keywords
This publication has 46 references indexed in Scilit:
- Domestication of the cardiac mitochondrion for energy conversionJournal of Molecular and Cellular Cardiology, 2009
- Regulation of Intracellular and Mitochondrial Sodium in Health and DiseaseCirculation Research, 2009
- Enhancing Mitochondrial Ca 2+ Uptake in Myocytes From Failing Hearts Restores Energy Supply and Demand MatchingCirculation Research, 2008
- A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine OxidationCell, 2008
- Excitation-contraction coupling and mitochondrial energeticsBasic Research in Cardiology, 2007
- Sequential Opening of Mitochondrial Ion Channels as a Function of Glutathione Redox Thiol StatusJournal of Biological Chemistry, 2007
- Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channelsJCI Insight, 2006
- Elevated Cytosolic Na + Decreases Mitochondrial Ca 2+ Uptake During Excitation-Contraction Coupling and Impairs Energetic Adaptation in Cardiac MyocytesCirculation Research, 2006
- The mitochondrial calcium uniporter is a highly selective ion channelNature, 2004
- Statins as antioxidant therapy for preventing cardiac myocyte hypertrophyJCI Insight, 2001