AMPK, Mitochondrial Function, and Cardiovascular Disease

Shengnan Wu; Ming-Hui Zou

doi:10.3390/ijms21144987

journal article Open Access Jul 15, 2020

AMPK, Mitochondrial Function, and Cardiovascular Disease

Shengnan Wu

Ming-Hui Zou

International Journal of Molecular Sciences Vol. 21 No. 14 pp. 4987 · MDPI AG

View at Publisher Save 10.3390/ijms21144987

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.

Topics

No keywords indexed for this article. Browse by subject →

References

271

[1]

AMPK: a nutrient and energy sensor that maintains energy homeostasis

D. Grahame Hardie, Fiona A. Ross, Simon A. Hawley

Nature Reviews Molecular Cell Biology 2012 10.1038/nrm3311

[2]

Gwinn "AMPK phosphorylation of raptor mediates a metabolic checkpoint" Mol. Cell (2008) 10.1016/j.molcel.2008.03.003

[3]

Inoki "TSC2 mediates cellular energy response to control cell growth and survival" Cell (2003) 10.1016/s0092-8674(03)00929-2

[4]

Carling "A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis" FEBS Lett. (1987) 10.1016/0014-5793(87)80292-2

[5]

Munday "Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase" Eur. J. Biochem. (1988) 10.1111/j.1432-1033.1988.tb14201.x

[6]

Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia

A-S. Marsin, L. Bertrand†, M.H. Rider et al.

Current Biology 2000 10.1016/s0960-9822(00)00742-9

[7]

Jager "AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha" Proc. Natl. Acad. Sci. USA (2007) 10.1073/pnas.0705070104

[8]

The Energy Sensor AMP-activated Protein Kinase Directly Regulates the Mammalian FOXO3 Transcription Factor

Eric L. Greer, Philip R. Oskoui, Max R. Banko et al.

Journal of Biological Chemistry 2007 10.1074/jbc.m705325200

[9]

Yuan "Nutrient sensing, metabolism, and cell growth control" Mol. Cell (2013) 10.1016/j.molcel.2013.01.019

[10]

AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance

Daniel García, Reuben J. Shaw

Molecular Cell 2017 10.1016/j.molcel.2017.05.032

[11]

Steinberg "AMPK in health and disease" Physiol. Rev. (2009) 10.1152/physrev.00011.2008

[12]

Hardie "AMPK: A target for drugs and natural products with effects on both diabetes and cancer" Diabetes (2013) 10.2337/db13-0368

[13]

Hardie "Targeting an energy sensor to treat diabetes" Science (2017) 10.1126/science.aao1913

[14]

Hardie "AMP-activated protein kinase: A target for drugs both ancient and modern" Chem. Biol. (2012) 10.1016/j.chembiol.2012.08.019

[15]

Guigas "Targeting AMPK: From ancient drugs to new small-molecule activators" Exp. Suppl. (2016)

[16]

Cokorinos "Activation of skeletal muscle ampk promotes glucose disposal and glucose lowering in non-human primates and mice" Cell Metab. (2017) 10.1016/j.cmet.2017.04.010

[17]

Myers "Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy" Science (2017) 10.1126/science.aah5582

[18]

Steneberg "PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients" JCI Insight (2018) 10.1172/jci.insight.99114

[19]

Yan, Y., Zhou, X.E., Xu, H.E., and Melcher, K. (2018). Structure and physiological regulation of AMPK. Int. J. Mol. Sci., 19. 10.3390/ijms19113534

[20]

Stapleton "Mammalian AMP-activated protein kinase subfamily" J. Biol. Chem. (1996) 10.1074/jbc.271.2.611

[21]

Thornton "Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle" J. Biol. Chem. (1998) 10.1074/jbc.273.20.12443

[22]

Cheung "Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding" Biochem. J. (2000) 10.1042/bj3460659

[23]

Ross "AMP-activated protein kinase: A cellular energy sensor that comes in 12 flavours" FEBS J. (2016) 10.1111/febs.13698

[24]

Viollet "AMPK: Lessons from transgenic and knockout animals" Front. Biosci. (Landmark Ed.) (2009) 10.2741/3229

[25]

Hudson "A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias" Curr. Biol. (2003) 10.1016/s0960-9822(03)00249-5

[26]

Xiao "Structural basis for AMP binding to mammalian AMP-activated protein kinase" Nature (2007) 10.1038/nature06161

[27]

Hardie "AMP-activated protein kinase: Also regulated by ADP?" Trends Biochem. Sci. (2011) 10.1016/j.tibs.2011.06.004

[28]

AMP Is a True Physiological Regulator of AMP-Activated Protein Kinase by Both Allosteric Activation and Enhancing Net Phosphorylation

Graeme J. Gowans, Simon A. Hawley, Fiona A. Ross et al.

Cell Metabolism 2013 10.1016/j.cmet.2013.08.019

[29]

Ross "Differential regulation by AMP and ADP of AMPK complexes containing different gamma subunit isoforms" Biochem. J. (2016) 10.1042/bj20150910

[30]

Hawley "Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade" J. Biol. (2003) 10.1186/1475-4924-2-28

[31]

Shaw "The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress" Proc. Natl. Acad. Sci. USA (2004) 10.1073/pnas.0308061100

[32]

LKB1 Is the Upstream Kinase in the AMP-Activated Protein Kinase Cascade

Angela Woods, Stephen R. Johnstone, Kristina Dickerson et al.

Current Biology 2003 10.1016/j.cub.2003.10.031

[33]

Fujiwara "Differential AMP-activated Protein Kinase (AMPK) Recognition mechanism of Ca2+/calmodulin-dependent protein kinase kinase isoforms" J. Biol. Chem. (2016) 10.1074/jbc.m116.727867

[34]

Hawley "Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase" Cell Metab. (2005) 10.1016/j.cmet.2005.05.009

[35]

Xiao "Structure of mammalian AMPK and its regulation by ADP" Nature (2011) 10.1038/nature09932

[36]

Neumann "The PP1-R6 protein phosphatase holoenzyme is involved in the glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, in MIN6 beta cells" FASEB J. (2010)

[37]

Joseph "Inhibition of AMP kinase by the protein phosphatase 2a heterotrimer, PP2APpp2r2d" J. Biol. Chem. (2015) 10.1074/jbc.m114.626259

[38]

Sanders "Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family" J. Biol. Chem. (2007) 10.1074/jbc.m706543200

[39]

Davies "5’-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC" FEBS Lett. (1995) 10.1016/0014-5793(95)01368-7

[40]

Willows "Phosphorylation of AMPK by upstream kinases is required for activity in mammalian cells" Biochem. J. (2017) 10.1042/bcj20170458

[41]

Alfadda "Reactive oxygen species in health and disease" J. Biomed. Biotechnol. (2012) 10.1155/2012/936486

[42]

Liangpunsakul "Effect of ethanol on hydrogen peroxide-induced AMPK phosphorylation" Am. J. Physiol. Gastrointest. Liver Physiol. (2008) 10.1152/ajpgi.90349.2008

[43]

Han, Y., Wang, Q., Song, P., Zhu, Y., and Zou, M.H. (2010). Redox regulation of the AMP-activated protein kinase. PLoS ONE, 5. 10.1371/journal.pone.0015420

[44]

Hinchy "Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly" J. Biol. Chem. (2018) 10.1074/jbc.ra118.002579

[45]

Choi "The regulation of AMP-activated protein kinase by H(2)O(2)" Biochem. Biophys. Res. Commun. (2001) 10.1006/bbrc.2001.5544

[46]

Hawley "Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation" Cell Metab. (2010) 10.1016/j.cmet.2010.04.001

[47]

McCullough "Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke" J. Biol. Chem. (2005) 10.1074/jbc.m409985200

[48]

Zmijewski "Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase" J. Biol. Chem. (2010) 10.1074/jbc.m110.143685

[49]

Xie "Activation of protein kinase C zeta by peroxynitrite regulates LKB1-dependent AMP-activated protein kinase in cultured endothelial cells" J. Biol. Chem. (2006) 10.1074/jbc.m511178200

[50]

Wu "Activation of AMPKalpha2 in adipocytes is essential for nicotine-induced insulin resistance in vivo" Nat. Med. (2015) 10.1038/nm.3826

Showing 50 of 271 references

Cited By

215

α-KG alleviates mitochondrial dysfunction and attenuates HPDLSCs senescence in periodontitis through LKB1-AMPK activation

Xin Zhang, Lingshuang Li · 2026

Cellular Signalling

Acupuncture modulates the AMPK/PGC-1 signaling pathway to facilitate mitochondrial biogenesis and neural recovery in ischemic stroke rats

Kaixin Guo, Yan Lu · 2024

Frontiers in Molecular Neuroscience

Nrf2/Keap1/ARE regulation by plant secondary metabolites: a new horizon in brain tumor management

Saikat Dewanjee, Hiranmoy Bhattacharya · 2024

Cell Communication and Signaling

Why is endothelial resilience key to maintain cardiac health?

Lukas S. Tombor, Stefanie Dimmeler · 2022

Basic Research in Cardiology

Metrics

215

Citations

271

References

Details

Published: Jul 15, 2020
Vol/Issue: 21(14)
Pages: 4987
License: View

Authors

S

Shengnan Wu

Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA

M

Ming-Hui Zou

Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA

Cite This Article

Shengnan Wu, Ming-Hui Zou (2020). AMPK, Mitochondrial Function, and Cardiovascular Disease. International Journal of Molecular Sciences, 21(14), 4987. https://doi.org/10.3390/ijms21144987

AMPK, Mitochondrial Function, and Cardiovascular Disease

You May Also Like