Invited Speakers

Abstract

Since changes in intracellular [Ca 2+ ] ([Ca 2+ ] i ) homeostasis, mitochondrial dysfunction and reactive oxygen species (ROS) are tightly connected. For instance, an increase in [Ca 2+ ] i affects mitochondrial [Ca 2+ ] and in most cases it is associated with an increased mitochondrial ROS formation, leading to the opening of the permeability transition pore (PTP), mitochondrial dysfunction and cell death. On the other hand, ROS modify [Ca 2+ ] I homeostasis by acting at various sites involved in intracellular Ca 2+ fluxes. The changes induced by [Ca 2+ ] I on ROS generation and vice versa are very rapid, making it difficult to elucidate the primary event under both physiological and pathological conditions. An additional matter of complexity is related to available techniques. While various methods are available to induce a primary and direct rise in [Ca 2+ ] I , the existing protocols to trigger ROS production are far from being specific. An increase in ROS is generally obtained as a consequence of the exogenous administration of an oxidant (mostly H 2 O 2 ) or by applying pathological stimuli (i.e., respiratory chain inhibition) that inevitably trigger several other effects, including alterations in [Ca 2+ ] i homeostasis. Here we investigated the effects of a primary increase in mitochondrial ROS levels induced by MitoParaquat (MitoPQ) a paraquat derivative targeted to mitochondria, which causes a dose-dependent selective increase in superoxide levels. In neonatal rat ventricular cardiomyocytes (NRVMs) high doses of MitoPQ (>100 nM) altered [Ca 2+ ] i homeostasis, hampered mitochondrial function due to permeability transition pore opening, eventually leading to cell death. On the other hand, low doses of MitoPQ caused a decreased susceptibility of neonatal rat ventricular myocytes (NRVMs) to anoxia/reoxygenation injury and profound protection in an in vivo mouse model of ischaemia/ reperfusion. Protection was obeserved also when a slight increase in mitochondrial ROS formation resulted from overexpressing the mitochondrial Ca 2+ uniporter (MCU). Demographic development in many countries reveals that the number of elderly has increased and will increase more and more within the next decades. However, while average life expectancy has increased markedly throughout the last century, this has not been accompanied by an equivalent increase in healthy life expectancy. Indeed, chronic, low-grade inflammation also frequently referred to as inflammaging has been acknowledged as a major characteristic of aging also being suggested to be critically involved in aging-associated decline of many organs including adipose tissue and skeletal muscle but also the liver and the gut. Despite intense research efforts molecular mechanisms underlying inflammaging have not yet been fully understood. Results of several epidemiological studies also suggest that age and herein especially older age increases the odds to develop diseases among them many metabolic diseases like non-alcoholic fatty liver dis...