Modulation of the matrix redox signaling by mitochondrial Ca2+

Abstract

Mitochondria sense, shape and integrate signals, and thus function as central players in cellular signal transduction. Ca²⁺ waves and redox reactions are two such intracellular signals modulated by mitochondria. Mitochondrial Ca²⁺ 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 Ca²⁺ transport has been revealed only recently. Mitochondrial Ca²⁺ 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 Ca²⁺ combined with the utilization of the novel redox sensors is shedding light on the complex relation between mitochondrial Ca²⁺ and redox signals and their impact on cell function. In this review, we describe mitochondrial Ca²⁺ handling, focusing on a number of newly identified proteins involved in mitochondrial Ca²⁺ uptake and release. We further discuss our recent findings, revealing how mitochondrial Ca²⁺ influences the matrix redox state. As a result, mitochondrial Ca²⁺ is able to modulate the many mitochondrial redox-regulated processes linked to normal physiology and disease.

Keywords: Calcium transport, Signal transduction, Redox regulation, Mitochondria, Oxidation-reduction, Mitochondrial membrane transport proteins, Mitochondrial Ca²⁺ uniporter, Mitochondrial Na⁺/Ca²⁺ exchanger

Core tip: Deregulated redox signaling in mitochondria leads to mitochondrial dysfunction, associated with several disorders and disease states. Matrix Ca²⁺ rising can be linked through multiple pathways to the mitochondrial redox state. Here we describe recent progress in the field of mitochondrial Ca²⁺ handling. We further summarize how mitochondrial Ca²⁺ signals are influencing the mitochondrial redox state. This link between Ca²⁺ and redox signals is likely of central importance in the regulation of mitochondrial function in health and disease.