AMPKα2 Protects Against the Development of Heart Failure by Enhancing Mitophagy via PINK1 Phosphorylation
Open accessAbstract
Rationale: Mitochondrial dysfunction plays an important role in heart failure (HF). However, the molecular mechanisms regulating mitochondrial functions via selective mitochondrial autophagy (mitophagy) are poorly understood. Objective: We sought to determine the role of AMPK (AMP-activated protein kinase) in selective mitophagy during HF. Methods and Results: An isoform shift from AMPKα2 to AMPKα1 was observed in failing heart samples from HF patients and transverse aortic constriction–induced mice, accompanied by decreased mitophagy and mitochondrial function. The recombinant adeno-associated virus Serotype 9-mediated overexpression of AMPKα2 in mouse hearts prevented the development of transverse aortic constriction–induced chronic HF by increasing mitophagy and improving mitochondrial function. In contrast, AMPKα2 −/− mutant mice exhibited an exacerbation of the early progression of transverse aortic constriction–induced HF via decreases in cardiac mitophagy. In isolated adult mouse cardiomyocytes, AMPKα2 overexpression mechanistically rescued the impairment of mitophagy after phenylephrine stimulation for 24 hours. Genetic knockdown of AMPKα2, but not AMPKα1, by short interfering RNA suppressed the early phase (6 hours) of phenylephrine-induced compensatory increases in mitophagy. Furthermore, AMPKα2 specifically interacted with phosphorylated PINK1 (PTEN-induced putative kinase 1) at Ser495 after phenylephrine stimulation. Subsequently, phosphorylated PINK1 recruited the E3 ubiquitin ligase, Parkin, to depolarized mitochondria, and then enhanced the role of the PINK1–Parkin–SQSTM1 (sequestosome-1) pathway involved in cardiac mitophagy. This increase in cardiac mitophagy was accompanied by the elimination of damaged mitochondria, improvement in mitochondrial function, decrease in reactive oxygen species production, and apoptosis of cardiomyocytes. Finally, Ala mutation of PINK1 at Ser495 partially suppressed AMPKα2 overexpression-induced mitophagy and improvement of mitochondrial function in phenylephrine-stimulated cardiomyocytes, whereas Asp (phosphorylation mimic) mutation promoted mitophagy after phenylephrine stimulation. Conclusions: In failing hearts, the dominant AMPKα isoform switched from AMPKα2 to AMPKα1, which accelerated HF. The results show that phosphorylation of Ser495 in PINK1 by AMPKα2 was essential for efficient mitophagy to prevent the progression of HF.
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Ser495 in PINK1 underwent phosphorylation by AMPKα2 upon the dissipation of the ΔΨm in cardiomyocytes.
“Further, ser495 in PINK1 underwent phosphorylation by AMPKα2 upon the dissipation of the ΔΨm in cardiomyocytes [117].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [117]
AMPKα2−/− mice showed an exacerbated progression of TAC-induced HF through defected cardiac mitophagy.
“In contrast, AMPKα2−/− mice showed an exacerbated progression of TAC-induced HF through defected cardiac mitophagy [117].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [117]
This phosphorylation proved critical for the efficient recruitment of PARKIN to mitochondria to initiate mitophagy during HF.
“This phosphorylation proved critical for the efficient recruitment of PARKIN to mitochondria to initiate mitophagy during HF [117].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [117]
In failing heart samples from patients or TAC mice, the isoform of AMPKα shifted from α2 to α1, which is associated with reduced mitophagy and dysfunctional mitochondria.
“In failing heart samples from patients or TAC mice, the isoform of AMPKα shifted from α2 to α1, which is associated with reduced mitophagy and dysfunctional mitochondria [117].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [117]
AMPKα2 regulates PINK1-PARKIN-dependent mitophagy in pressure overload-induced cardiac hypertrophy and HF models.
“Recently, studies in pressure overload-induced cardiac hypertrophy and HF models highlight the role of AMPKα2 in the regulation of PINK1–PARKIN-dependent mitophagy [117].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [117]
Adenovirus overexpression of AMPKα2 in hearts blocked TAC-induced chronic HF via promoting mitophagy and mitochondrial function.
“The adenovirus overexpression of AMPKα2 in hearts blocked TAC-induced chronic HF via promoting mitophagy and mitochondrial function [117].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [117]
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- Authors
- Wang, B., Nie, J., Wu, L., Hu, Y., Wen, Z., Dong, L., Zou, M.-H., Chen, C., & Wang, D. W.
- Affiliations
- Georgia State University (US)
- From the Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College (B.W., J.N., L.W., Z.W.,C.C., D.W.W.), Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders (B.W., J.N., L.W., Z.W.,C.C., D.W.W.), and Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College (B.W., Y.H., L.D.), Huazhong University of Science and Technology, Wuhan, China; and Center for Molecular and Translational...
- Venue
- Circulation Research
- Published
- 2018-03-02
- Volume
- 122
- Issue
- 5
- Pages
- 712-729
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC5834386
- OpenAlex
- W2778528862
- Cited by
- 334
- References
- 40
- Citations by year
- 2026: 37 · 2025: 45 · 2024: 45 · 2023: 43 · 2022: 50 · 2021: 39 · 2020: 43 · 2019: 19 · 2018: 13
- FWCI
- 16.06
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG047776)
- National Heart, Lung, and Blood Institute (R01HL079584, R01HL137371, R01HL132500, R01HL074399, R01HL080499, R01HL140954, R01HL110488, R01HL128014, R01HL089920)
- National Cancer Institute (R01CA213022)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- heart failure, AMPKα2, mitophagy, Parkin, p62, mitochondrial dysfunction, transverse aortic constriction, cardiomyocyte apoptosis, reactive oxygen species, AAV9 gene therapy
- MeSH terms
- AMP-Activated Protein Kinase Kinases, PTEN-Induced Putative Kinase, Animals, Cells, Cultured, Heart Failure, Humans, Isoenzymes, Mitochondria, Heart, Phosphorylation, Protein Kinases, Myocytes, Cardiac, Mice, Mitophagy
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