Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Nov 26, 2015; 6(4): 310-323
Published online Nov 26, 2015. doi: 10.4331/wjbc.v6.i4.310
Modulation of the matrix redox signaling by mitochondrial Ca2+
Jaime Santo-Domingo, Andreas Wiederkehr, Umberto De Marchi
Jaime Santo-Domingo, Andreas Wiederkehr, Umberto De Marchi, Mitochondrial Function, Nestlé Institute of Health Sciences, CH-1015 Lausanne, Switzerland
Author contributions: All authors contributed to this manuscript
Conflict-of-interest statement: The authors are employees of NIHS which is part of Nestle Group.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Umberto De Marchi, PhD, Mitochondrial Function, Nestlé Institute of Health Sciences, EPFL Innovation Park, Batiment G, CH-1015 Lausanne, Switzerland. umberto.demarchi@rd.nestle.com
Telephone: +41-21-6326122
Received: July 4, 2015
Peer-review started: July 10, 2015
First decision: July 31, 2015
Revised: September 23, 2015
Accepted: October 12, 2015
Article in press: October 13, 2015
Published online: November 26, 2015
Processing time: 142 Days and 13 Hours
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.