How AMPK and PKA Interplay to Regulate Mitochondrial Function and Survival in Models of Ischemia and Diabetes

Figure 2

Model on how AMPK and D-AKAP1/PKA cooperate to regulate mitochondrial structure/function under physiological conditions and during oxidative stress induced by diabetes and ischemia. During homeostasis (indicated in shaded blue), D-AKAP1/PKA and AMPK regulate mitochondrial structure and function to maintain a high ATP/ADP ratio. D-AKAP1/PKA phosphorylates Drp1 at the OMM to inhibit its fission activity and, thereby, promote mitochondrial fusion and maintain oxidative phosphorylation. Concomitantly, AMPK phosphorylates D-AKAP1 leading to stable mitochondrial bioenergetics and structure through an unknown molecular mechanism. These posttranslational events lead to enhanced mitochondrial biogenesis and cell survival. On the other hand, acute or a transient increase in the level of oxidative stress (indicated in shaded red) leads to decreased kinase signaling (uncoupling of PKA from D-AKAP1) and decreased mitochondrial oxidative phosphorylation and mitochondrial dysfunction (decreased transmembrane potential), ensuing mitochondrial damage. AMPK phosphorylates MFF to promote mitochondrial fission, a cellular event that is associated with increased mitophagy. However, is not known whether increased AMPK-mediated fission enhances mitophagy or increased cell survival (conceptual gaps indicated by question marks). On the other hand, conditions that promote ischemia or chronic high levels of oxidative stress, as observed in models of diabetes and CVDs, leads to rapid degradation of endogenous D-AKAP1 through Siah2 (hypoxia), decreased AMPK signaling (diabetes models), increased superoxide levels, and decreased compensatory responses to replenish high quality mitochondria and eventual cell death.