Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression. Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation. The functions of AMPK during health and disease are far from clear. Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity. In this review, we begin with the description of AMPK structure and regulation, and then focus on the recent advances toward understanding how mitochondrial dysfunction controls AMPK and how AMPK, as a central mediator of the cellular response to energetic stress, maintains mitochondrial homeostasis. Finally, we systemically review how dysfunctional AMPK contributes to the initiation and progression of cardiovascular diseases via the impact on mitochondrial function.
Highlights
Cells constantly coordinate their metabolism to satisfy their energy needs and respond to the use of nutrients
Using HEK293 cells expressing AMPKγ2 R531G, an adenosine monophosphate (AMP)-insensitive adenosine monophosphate-activated protein kinase (AMPK) complex, AMPK cannot be activated by hydrogen peroxide [46]. These findings suggest that the target for hydrogen peroxide may not be AMPK itself, but components of the electron transport chain (ETC), leading to a secondary effect on AMPK through changes to adenosine diphosphate (ADP), AMP, and adenosine triphosphate (ATP)
Hypoxia-reoxygenation (H/R) increased both AMPK and acetyl coenzyme A carboxylase (ACC) phosphorylation in cultured bovine aortic endothelial cell (BAEC), which was prevented by either inhibition of nitric oxide synthase (NOS) or overexpression of superoxide dismutase (SOD), suggesting a role of peroxynitrite formed during H/R [56]
Summary
Cells constantly coordinate their metabolism to satisfy their energy needs and respond to the use of nutrients. Eukaryotes have developed a highly adaptive complex, the serine/threonine kinase adenosine monophosphate (AMP)-activated protein kinase (AMPK), to sense low cellular adenosine triphosphate (ATP) levels [1]. Under conditions of insufficient energy, AMPK activates upon its binding with AMP or adenosine diphosphate (ADP) [1]. AMPK can adjust intracellular metabolism in a prolonged way by aiming at transcriptional regulators (e.g., forkhead box O3) [8]. Overall, activated AMPK balances energy levels by raising ATP synthesis and/or reducing ATP consumption. Thanks to its core roles in intracellular metabolism, dysregulation of AMPK is prevalent in obesity, diabetes, cancer, and cardio-metabolic diseases. AMPK is a prospective pharmacological target [9,10,11,12,13,14,15], notably for treating type 2 diabetes [16,17,18]
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