Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is a conserved, redox-activated master regulator of cell metabolism. In the presence of oxidative stress, AMPK promotes cytoprotection by enhancing the conservation of energy by suppressing protein translation and by stimulating autophagy. AMPK interplays with protein kinase A (PKA) to regulate oxidative stress, mitochondrial function, and cell survival. AMPK and dual-specificity A-kinase anchoring protein 1 (D-AKAP1), a mitochondrial-directed scaffold of PKA, interact to regulate mitochondrial function and oxidative stress in cardiac and endothelial cells. Ischemia and diabetes, a chronic disease that increases the onset of cardiovascular diseases, suppress the cardioprotective effects of AMPK and PKA. Here, we review the molecular mechanisms by which AMPK and D-AKAP1/PKA interplay to regulate mitochondrial function, oxidative stress, and signaling pathways that prime endothelial cells, cardiac cells, and neurons for cytoprotection against oxidative stress. We discuss recent literature showing how temporal dynamics and localization of activated AMPK and PKA holoenzymes play a crucial role in governing cellular bioenergetics and cell survival in models of ischemia, cardiovascular diseases, and diabetes. Finally, we propose therapeutic strategies that tout localized PKA and AMPK signaling to reverse mitochondrial dysfunction, oxidative stress, and death of neurons and cardiac and endothelial cells during ischemia and diabetes.
Highlights
AMPK is a heterotrimeric holoenzyme that consists of a catalytic subunit (α) bound to two regulatory subunits (β and γ)
We present evidence on the molecular mechanisms by which AMPK and protein kinase A (PKA) coregulate mitochondrial function and structure in cardiac cells and neurons, two cell types targeted in ischemia and in diabetes, a chronic disease that increases the risk for developing cardiovascular diseases (CVDs) and stroke
Other research reports suggest that metformin can inhibit dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in endothelial cells of streptozocin- (STZ-) induced diabetic ApoE−/− mice and in adipose tissue of STZ-induced diabetic WT mice [40, 41]. These studies suggest that AMPK can have opposing effects on mitochondrial fission/fusion, a phenomenon that likely depends on the bioenergetic status and levels of oxidative stress in the cell
Summary
AMPK is a heterotrimeric holoenzyme that consists of a catalytic subunit (α) bound to two regulatory subunits (β and γ). AMPK signaling supports mitochondrial fragmentation (fission) of oxidatively damaged mitochondria by activating the fission modulator dynamin-related protein 1 (Drp). Other research reports suggest that metformin can inhibit Drp1-mediated mitochondrial fission in endothelial cells of streptozocin- (STZ-) induced diabetic ApoE−/− mice and in adipose tissue of STZ-induced diabetic WT mice [40, 41] Overall, these studies suggest that AMPK can have opposing effects on mitochondrial fission/fusion, a phenomenon that likely depends on the bioenergetic status and levels of oxidative stress in the cell. Adipose tissue, another tissue with low levels of MFF, benefits from the inhibition of mitochondrial fission via AMPK activation in hyperglycemic conditions. AMPK activation induces diverse effects on mitochondria dynamics which partly depends on levels of endogenous MFF across different tissues
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