SOD2 and the Mitochondrial UPR: Partners Regulating Cellular Phenotypic Transitions

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 (UPR^mt) activation are essential for somatic dedifferentiation programs and the acquisition of stem-like properties in reparative processes and disease.