Mitochondria-ros crosstalk in the control of cell death and aging

Abstract

Reactive oxygen species (ROS) are highly reactive molecules, mainly generated inside mitochondria that can oxidize DNA, proteins, and lipids. At physiological levels, ROS function as "redox messengers" in intracellular signalling and regulation, whereas excess ROS induce cell death by promoting the intrinsic apoptotic pathway. Recent work has pointed to a further role of ROS in activation of autophagy and their importance in the regulation of aging. This review will focus on mitochondria as producers and targets of ROS and will summarize different proteins that modulate the redox state of the cell. Moreover, the involvement of ROS and mitochondria in different molecular pathways controlling lifespan will be reported, pointing out the role of ROS as a "balance of power," directing the cell towards life or death.

Figure 1

Mitochondrial sources of ROS and mitochondrial ROS targets. ROS generators (red) and ROS targets (yellow) are shown in their precise localizations inside mitochondria. Dotted yellow trace encloses the permeability transition pore components. See text, in particular sections 2 and 3, for further details. Abbreviations: OMM: outer mitochondrial membrane; IMS: intermembrane space; IMM: inner mitochondrial membrane; MAO A/B: monoamine oxidases A and B; Cyt. b5 reduct.: cytochrome b5 reductase; DHOH: dihydroorotate dehydrogenase; mGPDH: glycerol-3-phosphate dehydrogenase; I, II, III, and IV: Complex I to IV of the respiratory chain; Q: coenzyme Q; Cyt. c: cytochrome c; KGDHC: α-ketoglutarate dehydrogenase complex; PGDH: pyruvate dehydrogenase complex; e⁻: electrons; VDAC, voltage-dependent anion channel, Cycl. D: cyclophilin D; ANT: adenine nucleotide translocase; Pol. Γ: polymerase γ; mtDNA: mitochondrial DNA.

Figure 2

ROS levels control cell fate. Low production of ROS works as trigger of autophagic/mitophagic process, with consequent removal of damaged mitochondria and in turn cellular survival (upper panel). On the other hand, high levels of ROS lead to cell death promoting the apoptotic pathway when prosurvival attempt fails (lower panel).