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SOD2 and the Mitochondrial UPR: Partners Regulating Cellular Phenotypic Transitions

2016; Elsevier BV; Volume: 41; Issue: 7 Linguagem: Inglês

10.1016/j.tibs.2016.04.004

1362-4326

Chenxia He, Peter C. Hart, Doris Germain, Marcelo G. Bonini,

Adipose Tissue and Metabolism

Reactive oxygen species (ROS) levels are key determinants of cellular plasticity and modulate phenotypic transitions through signaling. Mitochondrial ROS (mtROS) and ATP levels are part of a mitochondrial switch system regulating differentiation/dedifferentiation cycles (cellular phenotypes). The electron flow through mitochondria controls metabolism and signaling, maintaining cellular specialized functions or promoting dedifferentiation. Buffering ROS levels is essential to stabilize cellular states operating at high ROS levels to simultaneously enable redox signaling and mitigate damage that can compromise cell survival. The mitochondrial unfolded protein response (UPRmt) is an indispensable and complex response that allows cells to buffer ROS and exist at high-ROS steady-state levels. High superoxide dismutase 2 (SOD2) and activation of the UPRmt characterize cells with high phenotypic plasticity. ATP and reactive oxygen species (ROS) are signaling molecules that control cellular function and phenotype. Mitochondria produce both ATP and ROS. Since the electrons needed to generate either ATP or ROS originate from NADH/FADH2, the mechanism through which electrons flow towards oxygen determines yields and whether ATP or ROS prevails. Alterations in the electron flow impact cells dramatically, such as by supporting specialization (which requires high ATP) or imposing dedifferentiation. High ROS, facilitated by enzymes such as superoxide dismutase 2 (SOD2) that enhance mitochondrial hydrogen peroxide (mtH2O2), are normally linked to dedifferentiation of somatic cells. Here we propose that combined high mtH2O2 and mitochondrial unfolded protein response (UPRmt) activation are essential for somatic dedifferentiation programs and the acquisition of stem-like properties in reparative processes and disease. ATP and reactive oxygen species (ROS) are signaling molecules that control cellular function and phenotype. Mitochondria produce both ATP and ROS. Since the electrons needed to generate either ATP or ROS originate from NADH/FADH2, the mechanism through which electrons flow towards oxygen determines yields and whether ATP or ROS prevails. Alterations in the electron flow impact cells dramatically, such as by supporting specialization (which requires high ATP) or imposing dedifferentiation. High ROS, facilitated by enzymes such as superoxide dismutase 2 (SOD2) that enhance mitochondrial hydrogen peroxide (mtH2O2), are normally linked to dedifferentiation of somatic cells. Here we propose that combined high mtH2O2 and mitochondrial unfolded protein response (UPRmt) activation are essential for somatic dedifferentiation programs and the acquisition of stem-like properties in reparative processes and disease. a nucleotide capable of storing chemical energy via phosphate anhydride bonds. sequence of electron-donor/electron-accepting complexes that couples electron flow to the formation of the electrochemical potential in mitochondria. The electrochemical potential is used to power ATP synthesis from ADP and inorganic phosphate. transcription factors stabilized under levels of low oxygen availability that activate programs required for cell survival at reduced oxygen availability. electron-storage units in the cell used as cofactors by oxidase and dehydrogenase enzymes. NADH and FADH2 (the reduced forms of NAD+ and FADH2) serve as primary electron donors to the ETC. a regulator of transcription that responds to oxidative stress and is inhibited by Kelch-like ECH-associated protein-1 (Keap-1), a scavenger of Nrf2 that is inhibited by oxidation. a master regulator of transcription activated by inflammatory stimuli recently involved in the acquisition of stemness properties by some cells (e.g., cancer cells). a family of deacetylase enzyme regulators of cell signaling. Sirtuins are implicated in the control of the aging process, longevity, and the metabolism and as tumor suppressors. a mitochondrial, manganese-dependent dismutase of superoxide. SOD2 has been proposed to perform an antioxidant function in mitochondria, but more recent literature indicates that a more accurate role of SOD2 is as a source of H2O2 in mitochondria. In association with enzymes that detoxify H2O2, SOD2 may work as a component of the mitochondrial antioxidant system. used to define a large number of different molecules that are chemically reactive and contain oxygen. Examples include H2O2 (oxidant, soluble in aqueous and lipophilic media), superoxide radicals (reductant, charged, soluble in aqueous media), peroxynitrous acid/peroxynitrite (oxidant, soluble in aqueous media, diffuses through membranes in the peroxynitrous acid form), and HOCl (oxidant, soluble in aqueous media, diffuses through membranes).