title: Modulation of the matrix redox signaling by mitochondrial Ca(2.).
abstract: Mitochondria sense, shape and integrate signals, and thus function as central players in cellular signal transduction. Ca(2+) waves and redox reactions are two such intracellular signals modulated by mitochondria. Mitochondrial Ca(2+) transport is of utmost physio-pathological relevance with a strong impact on metabolism and cell fate. Despite its importance, the molecular nature of the proteins involved in mitochondrial Ca(2+) transport has been revealed only recently. Mitochondrial Ca(2+) promotes energy metabolism through the activation of matrix dehydrogenases and down-stream stimulation of the respiratory chain. These changes also alter the mitochondrial NAD(P)H/NAD(P)(+) ratio, but at the same time will increase reactive oxygen species (ROS) production. Reducing equivalents and ROS are having opposite effects on the mitochondrial redox state, which are hard to dissect. With the recent development of genetically encoded mitochondrial-targeted redox-sensitive sensors, real-time monitoring of matrix thiol redox dynamics has become possible. The discoveries of the molecular nature of mitochondrial transporters of Ca(2+) combined with the utilization of the novel redox sensors is shedding light on the complex relation between mitochondrial Ca(2+) and redox signals and their impact on cell function. In this review, we describe mitochondrial Ca(2+) handling, focusing on a number of newly identified proteins involved in mitochondrial Ca(2+) uptake and release. We further discuss our recent findings, revealing how mitochondrial Ca(2+) influences the matrix redox state. As a result, mitochondrial Ca(2+) is able to modulate the many mitochondrial redox-regulated processes linked to normal physiology and disease.
authors.affiliation: Jaime Santo-Domingo, Andreas Wiederkehr, Umberto De Marchi, Mitochondrial Function, Nestlé Institute of Health Sciences, CH-1015 Lausanne, Switzerland.
authors.forename: Jaime
authors.initials: J
authors.lastname: Santo-Domingo
authors.affiliation: Jaime Santo-Domingo, Andreas Wiederkehr, Umberto De Marchi, Mitochondrial Function, Nestlé Institute of Health Sciences, CH-1015 Lausanne, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wiederkehr
authors.affiliation: Jaime Santo-Domingo, Andreas Wiederkehr, Umberto De Marchi, Mitochondrial Function, Nestlé Institute of Health Sciences, CH-1015 Lausanne, Switzerland.
authors.forename: Umberto
authors.initials: U
authors.lastname: De Marchi
keywords: Calcium transport; Mitochondria; Mitochondrial Ca2+ uniporter; Mitochondrial Na+/Ca2+ exchanger; Mitochondrial membrane transport proteins; Oxidation-reduction; Redox regulation; Signal transduction