Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.

The current therapy for patients with stable systolic heart failure is largely limited to treatments that interfere with neurohormonal activation. Critical pathophysiological hallmarks of heart failure are an energetic deficit and oxidative stress, and both may be the result of mitochondrial dysfunction. This dysfunction is not (only) the result of defect within mitochondria per se, but is in particular traced to defects in intermediary metabolism and of the regulatory interplay between excitation-contraction coupling and mitochondrial energetics, where defects of cytosolic calcium and sodium handling in failing hearts may play important roles. In the past years, several therapies targeting mitochondria have emerged with promising results in preclinical models. Here, we discuss the mechanisms and results of these mitochondria-targeted therapies, but also of interventions that were not primarily thought to target mitochondria but may have important impact on mitochondrial biology as well, such as iron and exercise. Future research should be directed at further delineating the details of mitochondrial dysfunction in patients with heart failure to further optimize these treatments.

depolarization of mitochondria may be altered by extracellular glucose. Oxidative phosphorylation requires the large aJmito and when the mitochondria are depolarized, oxidative phosphorylation becomes uncoupled and ATP production falls. Here we investigate the effect of hyperglycemia (30 mM versus the physiological glucose of 5 mM) on mitochondrial aJmito under photoninduced oxidative stress in rat ventricular myocytes. Using a buffered physiologic salt solution on quiescent ventricular myocytes, changing the [glucose] has dramatic effect on the rate of aJmito depolarization. The rate of depolarization was significantly decreased in the presence of high glucose (the time-to-50% depolarization was increased from 250 s to 500s). These results were carried out in the absence of insulin. We conclude that hyperglycemia appears to protect mitochondrial function in quiescent heart cells from photon-induced oxidative stress. It is not yet clear how this apparent protection may change as metabolic load and muscle work increases, nor is it clear whether the absence of fatty acid substrates will increase or decrease this seemingly protective effect.

Mitochondrial production of reactive oxygen species (ROS) contributes to the progression of heart failure, but the mechanisms of ROS generation are incompletely resolved. Superoxide (. O 2 À

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