## 8 PKA Regulates Mitochondrial Function and Lifespan  
Mitochondrial fusion and fission are important for mitochondrial network morphology, biogenesis, embryonic development, metabolism, and apoptosis. Upon hypoxia or ischemia (low oxygen and glucose-deprived conditions), decreased availability of A-kinase anchoring protein 121 (AKAP121) by Siah2 (seven in absentia homolog (SIAH) family) leads to mitochondrial fission and cell death in mice [92]. Dynamin-related protein 1 (Drp1), a direct target of PKA, encodes a dynamin-like GTPase that controls mitochondrial fission [93]. AKAP121 binding of PKA blocks phosphorylation of Drp1, which prevents the formation of a complex between Drp1 and the outer mitochondrial membrane protein Fis1 (fission, mitochondrial 1) and subsequent mitochondrial fission. In _C. elegans_, inhibition of _siah-1_ or _drp-1_ during larval development shortens lifespan [92], presumably through effects on mitochondrial activity or dynamics. PKA is required for _C. elegans_ lifespan extension in a variety of contexts. For example, _C. elegans_ with defective oxidative phosphorylation due to a mutation in the respiratory complex I subunit, GAS-1, are short lived. Inhibition of insulin/IGF signaling in these animals through loss of DAF-2/IGF1 receptor or AGE-1/PI3K rewires the animal's metabolism and extends lifespan [94]. This effect depends on PKA signaling; _kin-1(RNAi)_ abrogates the lifespan extension of _age-1; gas-1_ double mutants. The purine base xanthine increases when insulin signaling is inhibited. Treatment of animals with xanthine derivatives increases AAK-2/AMPK and KIN-1/PKA activity, enhances mitochondrial network remodeling, and induces the metabolic changes that give rise to the lifespan extension [95]. In addition, DAF-2/IGF1 receptor and AGE-1/PI3K inhibit KIN-1/PKA-C in dauer-stage animals [96]. In mammalian cells and _C. elegans_, PKA phosphorylates and activates SIRT1, a sirtutin protein, which leads to improved mitochondrial function and fatty acid oxidation. Hydralazine, a drug used for hypertension, heart failure, and cancer treatment, improves mitochondrial function and elevates SIRT1 levels in cells [97]. In _C. elegans_, hydralazine extends lifespan through a PKA-dependent mechanism. Hydralazine binds to the catalytic subunit KIN-1/PKA-C, enabling separation from the regulatory subunit and activating PKA. PKA activation contributes to both SIRT1 activation and to the stress regulatory SKN-1/NRF2 signaling pathway, resulting in increased lifespan through glucose-induced mitochondrial dysfunction. Further studies are required to discover the mechanism by which PKA regulates SIRT1 and NRF2 [97]. Figure 3: **Schematic representation of fasting-induced lipolysis model via the cAMP pathway. ** Food deprivation increases cAMP and activates PKA. PKA-C activates the adipose triglyceride lipase ATGL-1, which then forms a liquid droplet with lipid droplet protein LID-1, which leads to lipid hydrolysis. Adapted with permission from [86], 2022, American Society for Microbiology. Created with BioRender.com (accessed on 23 October 2022). PKA is part of a signaling pathway that regulates nucleotide metabolism and reproductive development in response to nucleotide imbalance in the gut of _C. elegans_. During genotoxic stress, Nucleotide (NT) deficiency stimulates the nucleotide-sensing system that mediates mitotic germline proliferation and NT metabolism in the intestine. The poly(U)-specific endoribonuclease, ENDU-2, is a regulator that reacts to NT imbalance and genotoxic stresses. ENDU-2 regulates of CTPS-1, a cytidine triphosphate (CTP) synthase, by both inhibiting KIN-1/PKA-C signaling, possibly by repressing adenylyl cyclase activity, and by regulating histone deacetylase HDA-1 activity. This prevents activation of the cytidine triphosphate (CTP) synthase CTPS-1, which inhibits proliferation under genotoxic stress and increases lifespan [98].