Schematic summary of mitochondrial stress signaling and cellular adaptations. ATP (a), NAD+ (b), and ROS (c) are outputs of the electron transport chain and oxidative phosphorylation that may function as stress signals. NAD+ can activate sirtuins (SIRT) and increased AMP/ATP ration can activate AMPK, which activate transcription of antioxidant defences, mitochondrial DNA repair enzymes, and other target genes important in mitochondrial biogenesis and metabolism through transcription factors FOXO3a, NRF2, and the transcriptional coactivator PGC1α. ROS can also directly activate these transcriptional regulators. Mitochondrial DNA (mtDNA) damage can potentiate oxphos dysfunction (e) and hence lead to the above responses. Loss of innermitochondrial membrane potential (d) can lead to PMTP opening or parkin recruitment and hence mitophagy. Through peptide export, unfolded protein stress (f) can activate a transcriptional complex which acts on the MURE1, MURE2, and CHOP elements to induce the transcription of mitochondrial protein folding chaperones.
