Calcium and mitochondrial reactive oxygen species generation: how to read the facts

Abstract

A number of recent discoveries indicate that abnormal Ca2+ signaling, oxidative stress, and mitochondrial dysfunction are involved in the neuronal damage in Alzheimer's disease. However, the literature on the interactions between these factors is controversial especially in the interpretation of the cause-effect relationship between mitochondrial damage induced by Ca2+ overload and the production of reactive oxygen species (ROS). In this review, we survey the experimental observations on the Ca2+-induced mitochondrial ROS production, explain the sources of controversy in interpreting these results, and discuss the different molecular mechanisms underlying the effect of Ca2+ on the ROS emission by brain mitochondria.

Fig. 1

Mitochondrial ROS production and scavenging. Abbreviations: mGPDH, mitochondrial alpha-glycerophosphate dehydrogenase located at the outer surface of inner mitochondrial membrane which is pictured as a solid line; C1, CIII, COX, respiratory chain complexe I and III, and cytochrome oxidase, respectively; α-KGDHC, alpha-ketoglutarate dehydrogenase complex; ACO, aconitase, PDHC, pyruvate dehydrogenase complex; MAO, monoamine oxidases located in the outer membrane of mitochondria; GR, glutathione reductase; GPX1, glutathione perodixase I, RDS, other enzymes of mitochondrial ROS defense system including (not pictured) manganese SOD, peroxiredoxins 3 and 5, glutaredoxin 2, thioredoxin 2 and thioredoxin reductase, glutathione S-transferase, catalase, Cu, Zn superoxide dismutase, and phospholipid hydroperoxide glutathione peroxidase 4 (see [68] for a review); GSH and GSSG, reduced and oxidized glutathione; CYPD, cyclophilin D. PTP, mitochondrial permeability transition pore. Stars indicate reactive oxygen species (ROS); enzymes labeled with stars are ROS sources.

Fig. 2

Enhancement of ROS production in mitochondria that underwent Ca²⁺-induced permeability transition. Abbreviations are the same as in Fig. 1. Overloading of mitochondria with Ca²⁺ results in PTP opening, which in turn, results in leakage of pyridine nucleotides (NAD⁺, NADP) and Krebs cycle substrates such as oxaloacetate, alpha-ketoglutarate, and malate from the mitochondrial matrix. This renders both the Krebs cycle and RDS inoperable and results in sever oxidation of mitochondrial glutathione. Leakage of NAD⁺ also stimulates ROS production by α-KGDHC and PDHC. In addition to that, elevated Ca²⁺ inhibits GPX1, and directly stimulates ROS production by MAO and mGPDH. Elevated intramitochondrial ROS may further damage aconitase and complex I thereby turning them into ROS sources. Both the inability of permeabilized mitochondria to efficiently scavenge ROS (due to the damage of the RDS) and the elevated primary ROS production contribute to the enhanced ROS emission from mitochondria.