The potassium channel Kv1.3 is highly expressed in the mitochondria of various cancerous cells. Here we show that direct inhibition of Kv1.3 using two mitochondria-targeted inhibitors alters mitochondrial function and leads to reactive oxygen species (ROS)-mediated death of even chemoresistant cells independently of p53 status. These inhibitors killed 98% of ex vivo primary chronic B-lymphocytic leukemia tumor cells while sparing healthy B cells. In orthotopic mouse models of melanoma and pancreatic ductal adenocarcinoma, the compounds reduced tumor size by more than 90% and 60%, respectively, while sparing immune and cardiac functions. Our work provides direct evidence that specific pharmacological targeting of a mitochondrial potassium channel can lead to ROS-mediated selective apoptosis of cancer cells in vivo, without causing significant side effects.

Over the past 30years the mitochondrial permeability transition - the permeabilization of the inner mitochondrial membrane due to the opening of a wide pore - has progressed from being considered a curious artifact induced in isolated mitochondria by Ca(2+) and phosphate to a key cell-death-inducing process in several major pathologies. Its relevance is by now universally acknowledged and a pharmacology targeting the phenomenon is being developed. The molecular nature of the pore remains to this day uncertain, but progress has recently been made with the identification of the FOF1 ATP synthase as the probable proteic substrate. Researchers sharing this conviction are however divided into two camps: these believing that only the ATP synthase dimers or oligomers can form the pore, presumably in the contact region between monomers, and those who consider that the ring-forming c subunits in the FO sector actually constitute the walls of the pore. The latest development is the emergence of a new candidate: Spastic Paraplegia 7 (SPG7), a mitochondrial AAA-type membrane protease which forms a 6-stave barrel. This review summarizes recent developments of research on the pathophysiological relevance and on the molecular nature of the mitochondrial permeability transition pore. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Tryptophan catabolism through the kynurenine pathway generates a variety of bioactive metabolites. Physical exercise can modulate kynurenine pathway metabolism in skeletal muscle and thus change the concentrations of select compounds in peripheral tissues and in the central nervous system. Here we review recent advances in our understanding of how exercise alters tryptophan-kynurenine metabolism in muscle and its subsequent local and distal effects. We propose that the effects of kynurenine pathway metabolites on skeletal muscle, adipose tissue, immune system, and the brain suggest that some of these compounds could qualify as exercise-induced myokines. Indeed, some of the more recently discovered biological activities for kynurenines include many of the best-known benefits of exercise: improved energy homeostasis, promotion of an anti-inflammatory environment, and neuroprotection. Finally, by considering the tissue expression of the different membrane and cytosolic receptors for kynurenines, we discuss known and potential biological activities for these tryptophan metabolites.

Objective— Galectin-3 (Gal-3) can affect atherogenesis by multiple mechanisms, but it remains scarcely known whether plasma Gal-3 levels predict cardiovascular events in patients with coronary artery disease. Therefore, we investigated if Gal-3 predicts cardiovascular death in patients with coronary artery disease of the Genetic and ENvironmental factors In Coronary Artery disease study. Approach and Results— In a prospective cohort study, we measured the plasma levels of Gal-3 in 1013 randomly selected patients who underwent coronary angiography and long-term follow-up to assess incident cardiovascular events. The primary end points were (1) cardiovascular death and (2) a composite of cardiovascular death, acute coronary syndrome, and stroke. Secondary end points entailed (1) acute myocardial infarction, (2) stroke, and (3) a composite fatal ischemic event including fatal myocardial infarction and stroke. The effect of Gal-3 on prognosis was assessed using Kaplan–Meier analysis and multivariate Cox’s regression. During long-term follow-up (median, 7.2 years), 115 cardiovascular deaths occurred (15.2%), more commonly in the high Gal-3 tertile (25.2%) than in the intermediate and the low tertiles (13.6% versus 7.5%, respectively; P <0.001). The adverse prognostic effect of high Gal-3 was confirmed in subgroup analysis of the patients with angiographically documented coronary artery disease and also of those with a normal left ventricular ejection fraction. At multivariate analysis, Gal-3 was a predictor of cardiovascular mortality (hazard ratio, 1.79; 95% confidence interval, 1.10–2.93; P =0.020) along with age, left ventricular ejection fraction, and coronary atherosclerotic burden. Conclusions— In high cardiovascular risk patients referred for coronary angiography Gal-3 is a strong independent predictor of cardiovascular death.