Fig. 1.

Mitochondria-to-nuclear retrograde signaling pathways in mammals. Mitochondrial respiration produces intrinsic ROS, which is eliminated by endogenous antioxidants. Various stresses produce deleterious excess ROS and cause mitochondrial dysfunction that results in the declined synthesis of ATP and mitochondrial metabolites, loss of mitochondrial membrane potential and Ca²⁺ release, accumulation of unfolded protein and further production of ROS. Energetic stress activates AMPK and induces expression of PGC1α- and FOXO-regulated genes that are involved in mitochondrial biogenesis and mtDNA replication.^(107,108) Increased cytoplasmic Ca²⁺ stimulates glycolysis and Ca²⁺ uptake by activating CaMK and Cn. CaMK activates gene expression by CREB phosphorylation and by the activation of the AMPK-regulated pathway, whereas Cn activates NF-κB- and NFAT-dependent gene expression. Additionally, mtDNA depletion, mitochondrial chaperone inhibition, or mitochondrial protease inhibition induce the expression of mitochondrial chaperonins, known as UPR^MT, in nematodes, although the molecular mechanism is not fully clarified in mammals. ATF4 is activated in response to mitochondrial ROS production via PERK and/or GCN2 to upregulate chaperone expression, amino acid synthesis and antioxidant synthesis. Increased cytoplasmic ROS activates Nrf2 and induces antioxidant gene expression. AMPK, AMP-activated protein kinase; ATF4, activating transcription factor 4; CaMK, calmodulin kinase; Cn, calcineurin; CREB, cAMP response element-binding protein; FOXO, forkhead box O; NFAT, nuclear factor of activated T-cells; NF-κB, nuclear factor-κB; PGC1α, PPARγ coactivator 1α; ROS, reactive oxygen species.