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. 2018 Mar 2;122(5):712-729.
doi: 10.1161/CIRCRESAHA.117.312317. Epub 2017 Dec 28.

AMPKα2 Protects Against the Development of Heart Failure by Enhancing Mitophagy via PINK1 Phosphorylation

Bei Wang  1 , Jiali Nie  1 , Lujin Wu  1 , Yangyang Hu  1 , Zheng Wen  1 , Lingli Dong  1 , Ming-Hui Zou  1 , Chen Chen  2 , Dao Wen Wang  2
Affiliations

AMPKα2 Protects Against the Development of Heart Failure by Enhancing Mitophagy via PINK1 Phosphorylation

Bei Wang et al. Circ Res. .

Abstract

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.

Keywords: autophagy; constriction; heart failure; mice; mitochondria.

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Conflict of interest statement

DISCLOSURES

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1. Mitochondrial dysfunction in heart failure (HF) is associated with a switch in AMPKα isoforms
A. Protein extracts of myocardial samples from control (non-HF) hearts (n = 6) and hearts from patients with severe HF (n = 5) were normalized to equal protein levels (GAPDH: glyceraldehyde 3-phosphate dehydrogenase). Representative immunoblots of AMPKα1 expression and quantitative analysis are shown. **P < 0.01 vs. non-HF patients. B. Representative immunoblots of AMPKα2 expression and quantitative analysis. *P < 0.05 vs. non-HF patients. C. Relative AMPKα activities are shown. D. Atrial natriuretic peptide (ANP) and β-myosin heavy chain (MHC) were upregulated in the failing human heart; *P < 0.05 vs. non-HF patients; **P < 0.01 vs. non-HF patients. E. C57BL/6J mice were subjected to either sham operation (n = 20) or transverse aortic constriction (TAC) and observed after 3, 5, 7, 14, 21, 28, or 56 days (n = 9, 10, 12, 10, 9, 11, or 12, respectively). Gross morphologies of adult hearts in wild-type (WT) mice after TAC at different days are shown. F. Heart weight:body weight ratios of adult WT mice after TAC. *P < 0.05 vs. sham group. G. Representative images of echocardiograms. H. Heart rate, left ventricular ejection fraction (LVEF), fractional shortening (LVFS), and left ventricular internal diameter at end-systole (LVIDs) are presented. *P < 0.05 vs. sham group. I. Peak systolic pressure (Pmax), peak instantaneous rate of left ventricular pressure increase (dP/dtmax), peak instantaneous rate of decline in left ventricular pressure increase (dP/dtmin), and left ventricular end-diastolic pressure (LVEDP) were detected by the Millar catheter system in mouse hearts after TAC. *P < 0.05 vs. sham group. J. Representative immunoblots show expression levels of AMPKα1, AMPKα2, ANP, and β-MHC in mouse hearts after TAC. K. Expression levels of AMPKα1 and AMPKα2 were quantified and shown as relative protein expression after normalization to GAPDH. For AMPKα1: *P < 0.05 vs. sham group; For AMPKα2: #P < 0.05 vs. sham group. L. AMPKα1 and AMPKα2 activities were measured by detecting their substrate, SAMS peptide. For AMPKα1: *P < 0.05 vs. sham group; For AMPKα2: #P < 0.05 vs. sham group. All data represent mean ± SEM from at least four independent experiments.
Figure 2
Figure 2. Cardiac general autophagy and mitophagy are transiently increased during the early phase of TAC-induced HF but are downregulated during the chronic phase
C57BL/6J mice were subjected to either sham operation (n = 20) or TAC and observed after 3, 5, 7, 14, 21, 28, or 56 days (n = 9, 10, 12, 10, 9, 11, or 12, respectively). A–B. Representative immunoblots and quantitative analysis of whole-cell heart homogenates for light chain 3 (LC3) and sequestosome-1 (SQSTM1) are shown. For LC3-II: *P < 0.05 vs. sham-operated mice. For SQSTM1: #P < 0.05 vs. sham-operated mice. C–D. Representative immunoblots and quantitative analysis of whole-cell heart homogenates for LC3 and GAPDH in the presence of chloroquine (chl). E. C57BL/6J mice were subjected to either sham operation (n = 8) or 5 days post-TAC (n = 6) in the presence or absence of intraperitoneally injected chl (10 mg/kg). Representative confocal images of mRFP-GFP-LC3 puncta in primary isolated adult mouse cardiomyocytes (CMs) are shown. Scale bar, 50 μm. F. Bar graph shows the mean number of autophagosomes (yellow dots) and autolysosomes (red dots) per cell. *1P < 0.05, *2P < 0.05, *3P < 0.05 vs. sham-operated mice; #P < 0.05 vs. 5-day TAC-operated mice without chl. G. Representative images from transmission electron microscopy (TEM) and showing fluorescence staining of LC3 and SQSTM1 after sham operation (n = 5) or TAC for 5, 28, or 56 days (n = 5, 6, or 5, respectively). H. Bar graphs indicate the number of autophagosomes containing mitochondria per total number of mitochondria from a cross-sectional assessment of the heart tissues in TEM. *P < 0.05 vs. sham group. I. Autophagy was quantified by counting the green LC3 puncta in CMs. *P < 0.05 vs. sham group. J. Number of SQSTM1-positive CMs is shown. *P < 0.05 vs. sham group. K-L. Representative immunoblots and quantitative analysis of MT-ND1, MT-CYB, MT-CO2, and electron transport chain (ETC) complexes in whole-cell heart homogenates. *P < 0.05 vs. sham group. M. Top, representative immunoblots of PINK1 and Parkin in the cytosolic fraction prepared from heart homogenates; Bottom, representative immunoblots of PINK1, p-Parkin S65, and Parkin in the mitochondrial fraction prepared from heart homogenates. N. Quantitative analysis of PINK1 and Parkin in the cytosolic fraction. For PINK1: *P < 0.05 vs. sham group; For Parkin: #P < 0.05 vs. sham group. O. Quantitative analysis of p-Parkin S65/Parkin, PINK1, and Parkin in the mitochondrial fraction. For PINK1: *P < 0.05 vs. sham group; For Parkin: #P < 0.05 vs. sham group. §P < 0.05 vs. sham group. All data represent the mean ± SEM from at least four independent experiments.
Figure 3
Figure 3. Overexpression of AMPKα2 protects mice against TAC-induced HF associated with increasing cardiac mitophagy
C57BL/6J mice were first injected with rAAV9-cTNT-AMPKα2 in the caudal vein; rAAV9-cTNT-GFP was used as a control. After 2 weeks, infected mice were subjected to either sham operation (n = 20 in rAAV9-cTNT-AMPKα2 group; n = 20 in rAAV9-cTNT-GFP group) or TAC for 28 days (n = 25 in rAAV9-cTNT-AMPKα2 group; n = 25 in rAAV9-cTNT-GFP group). A. Gross morphology by Hematoxylin and Eosin (H&E) and Masson’s trichrome staining of adult hearts from WT C57BL/6J mice. Scale bars, 1.0 mm. B. Heart weight:body weight ratios of adult WT mice. *P < 0.05 vs. sham group; #P < 0.05 vs. TAC in the green fluorescent protein (GFP) group. C. Ejection fraction is shown. *P < 0.05 vs. sham group; #P < 0.05 vs. TAC in GFP group. D. Survival curve of mice in sham+rAAV9-cTNT-GFP, TAC+rAAV9-cTNT-GFP, sham+rAAV9-cTNT-AMPKα2, and TAC+ rAAV9-cTNT-AMPKα2 groups (n = 15, 20, 16, or 22, respectively) (P = 0.0249, log-rank test). E. Myocardial ATP levels. *P < 0.05 vs. sham group; #P < 0.05 vs. TAC in GFP group. F–H. Oxygen consumption by each mitochondrial complex was calculated (n = 5–7 per group). *P < 0.05 vs. sham group; #P < 0.05 vs. TAC in GFP group. I. Representative images of SQSTM1 staining, TEM, dihydroethidium (DHE) staining, and the TUNEL assay in mouse heart tissues after sham operation (n = 8) or 28 days after TAC (n = 9). J. Number of SQSTM1-positive CMs. K. Bar graphs indicate the number of autophagosomes containing mitochondria per total number of mitochondria from a cross-sectional assessment of the heart tissues in TEM. L. Myocardial reactive oxygen species (ROS) levels. M. Quantitative analysis of TUNEL-positive CMs. N. Top, representative immunoblots of PINK1, Parkin, and SQSTM1 in the cytosolic fraction prepared from heart homogenates; Bottom, representative immunoblots of PINK1, Parkin, and SQSTM1 in the mitochondrial fraction prepared from heart homogenates (n = 4 for each group). O. Representative immunoblots and quantitative analysis of p-Parkin S65 and Parkin in the mitochondrial fraction prepared from heart homogenates (n = 4 for each group) are shown. All data represent the mean ± SEM from at least four independent experiments.
Figure 4
Figure 4. Deletion of AMPKα2 exacerbates early TAC (5 days)-induced HF in mice by reducing cardiac mitophagy. AMPKα2−/− mice and control littermates were subjected to either sham operation (n = 10 in the control group, n = 12 in the AMPKα2−/− group) or TAC for 5 days (n = 12 in control group, n = 14 in AMPKα2−/− group)
A. Gross morphology by H&E and Masson’s trichrome staining of adult hearts from WT C57BL/6J mice. Scale bars, 1.0 mm. B. Heart weight:body weight ratios of adult WT mice. *P < 0.05 vs. sham group; #P < 0.05 vs. TAC in control group. C. Ejection fraction is shown. *P < 0.05 vs. sham group; #P < 0.05 vs. TAC in control group. D. Representative immunoblots of ANP, β-MHC, p-AMPKα2, and AMPKα2 proteins in lysates prepared from heart homogenates (n = 4 for each group). E. RT-qPCR analyses of the relative expression of nppa and myh7 from the hearts of mice exposed to the indicated conditions (n = 4 for each group). F. Representative images of SQSTM1 staining, TEM, and DHE staining in heart sections from mice after sham operation (n = 5) or TAC for 5 days (n = 6). G. Number of SQSTM1-positive CMs. *P < 0.05 vs. sham group; #P < 0.05 vs. TAC in control group. H. Bar graphs indicate the number of autophagosomes containing mitochondria per total number of mitochondria from a cross-sectional assessment of the heart tissues in TEM. *P < 0.05 vs. sham group; #P < 0.05 vs. TAC in control group. I. Myocardial ROS levels. *P < 0.05 vs. sham group; #P < 0.05 vs. TAC in control group. J. Top, representative immunoblots of PINK1, Parkin, and SQSTM1 in the cytosolic fraction prepared from heart homogenates. Bottom, representative immunoblots of PINK1, Parkin, and SQSTM1 in the mitochondrial fraction prepared from heart homogenates (n = 4 for each group). K. Representative immunoblots and quantitative analysis of p-Parkin S65 and Parkin in the mitochondrial fraction prepared from heart homogenates (n = 4 for each group). All data represent the mean ± SEM from at least four independent experiments.
Figure 5
Figure 5. Overexpression of AMPKα2 prevents the phenylephedrine (PE)-induced impairment of mitophagy in CMs
A. HL-1 mouse CMs were infected with an adenovirus encoding AMPKα2 and then subjected to PE (50 μmol/L) stimulation, followed by the induction of mitophagy. Mitophagy induction was performed by treatment with 20 μmol/L CCCP 24 h after PE stimulation. Representative images of TEM assay are shown. B. Mitophagy levels in CMs. Bar graph indicates the number of autophagosomes containing mitochondria (black arrows in [A]) per total number of mitochondria from a cross-sectional assessment of the CMs in TEM. *P < 0.05 vs. Ad-LacZ group; #P < 0.05 vs. PE+Ad-LacZ group. Blue arrows in (A) indicate prolonged mitochondria. C. Mitochondrial membrane potential (ΔΨm) was examined by flow cytometry with JC-1 probe treatment. The excitation ratio (JC-1 aggregates, red; monomer, green) indicates ΔΨm. Bar graphs indicate the quantification of ΔΨm. *P < 0.05 vs. Ad-LacZ group; #P < 0.05 vs. PE+Ad-LacZ group. D. Representative immunoblots of PINK1, p-Parkin S65, and Parkin in the presence or absence of CCCP in HL-1 CMs are shown. E. Quantitative analysis of PINK1/VDAC1, Parkin/VDAC1, and p-AMPKα2/AMPKα2 in the presence of CCCP. F. Isolated mouse adult CMs were infected with an adenovirus encoding AMPKα2 and then subjected to PE (50 μmol/L) stimulation, followed by the induction of mitophagy or treatment with 0.1 μmol/L bafilomycin A1 (Baf A1). Representative contour plots of CMs stained with MitoTracker are shown. G. Mean fluorescence intensity (MFI) of MitoTracker Deep Red. *P < 0.05 vs. Ad-LacZ group; #P < 0.05 vs. corresponding PE+Ad-LacZ group. H. Expression levels of p-AMPKα2 and AMPKα2 in (F). I. Bar graph indicates the mean number of autophagosomes (yellow) and autolysosomes (red) per cell. *1P < 0.05, *3P < 0.05 vs. Ad-LacZ group; #1P < 0.05, #3P < 0.05 vs. corresponding PE+Ad-LacZ group; *2P < 0.05, *4P < 0.05 vs. Baf A1+Ad-LacZ group; #2P < 0.05, #4P < 0.05 vs. Baf A1+PE+Ad-LacZ group. Lines in yellow indicate statistical comparisons for autophagosomes; Lines in red indicate statistical comparisons for autolysosomes; J. Representative immunoblots of p-AMPKα2, AMPKα2, LC3, SQSTM1, Beclin1, autophagy protein 5 (Atg5), and anti-ubiquitin in CMs are shown. All data represent the mean ± SEM from at least four independent experiments.
Figure 6
Figure 6. Overexpression of AMPKα2 attenuates PE-induced mitochondrial dysfunction in CMs
A. Isolated mouse adult CMs were infected with an adenovirus encoding AMPKα2 and then subjected to PE (50 μmol/L) stimulation. Isolated mouse adult CMs from the indicated groups were stained by immunocytochemistry for mitoSOX (red) and nuclei (blue). Scale bar, 50 μm. B. Quantitative analysis of the MFI of mitoSOX. *P < 0.05 vs. Ad-LacZ group; #P < 0.05 vs. PE+Ad-LacZ group. C. ROS levels of CMs from (A) were scored by 2′,7′-dichlorofluorescin diacetate-fluorescence-activated cell sorting (DCFDA-FACS). D. MFI values of DCFDA staining in the indicated groups. E. MitoSOX (red) and nuclei (blue) staining for 28-day, TAC-induced CMs after cardiac overexpression of AMPKα2. *P < 0.05 vs. rAAV9-cTNT GFP group; #P < 0.05 vs. TAC+ rAAV9-cTNT-AMPKα2 group. F. Representative immunoblots and quantitative analysis of p-Parkin S65, Parkin, p-AMPKα2, and AMPKα2 of CMs from (A) are shown. G. ATP levels of CMs from (A). H–K. Oxygen consumption by each mitochondrial complex was calculated in CMs from (A). *P < 0.05 vs. Ad-LacZ group; #P < 0.05 vs. PE+Ad-LacZ group. All data represent the mean ± SEM from at least four independent experiments.
Figure 7
Figure 7. AMPKα2 interacts with PINK1 and enhances the PINK1-Parkin-SQSTM1 pathway
A. Isolated mouse adult CMs were subjected to PE (50 μmol/L, 24 h) stimulation, followed by the induction of mitophagy. Mitophagy induction was performed by treatment with 20 μmol/L CCCP 8 h after PE stimulation. Representative immunoblots of PINK1, Parkin, SQSTM1, AMPKα2, and ETC complex in lysates of cytosolic and mitochondrial fractions in CMs are shown. B. HL-1 CMs were infected with an adenovirus encoding AMPKα2 (ad-AMPKα2) and then subjected to PE (50 μmol/L, 24 h) stimulation, followed by 20 μmol/L CCCP treatment for 8 h. Representative immunoblots of PINK1, p-Parkin S65, Parkin, SQSTM1, p-AMPKα2, AMPKα2, and anti-ubiquitin in lysates of cytosolic and mitochondrial fractions in CMs are shown. C. Representative immunoblots of PINK1, p-Parkin S65, Parkin, SQSTM1, p-AMPKα2, AMPKα2, and anti-ubiquitin in lysates of mitochondrial fractions in CMs are shown. D–E. HL-1 cells were treated with PE (0, 10, or 50 μmol/L) in the presence or absence of CCCP (20 μmol/L) for 8 h and subsequently subjected to immunoprecipitation with the anti-PINK1 antibody to evaluate its interaction with AMPKα1 or AMPKα2. F–G. HL-1 cells were transfected with ad-Flag-PINK1 and ad-myc-AMPKα2 for 36 hours and then treated with PE (50 μmol/L) in the presence of CCCP (20 μmol/L) for 8 h, followed by immunoprecipitation with the anti-Flag or anti-myc antibody, respectively. H. HL-1 cells were infected with ad-AMPKα2 and subjected to PE (50 μmol/L, 24 h) stimulation, followed by induction of mitophagy. The mitochondrial fractions were extracted for immunoprecipitation with AMPKα2-specific antibody or a control IgG, followed by probing with antibodies specific for PINK1. I. Relative binding between PINK1 and AMPKα2 in the indicated groups. *P < 0.05 vs Ad-LacZ group; #P < 0.05 vs PE+Ad-LacZ group. J. Endogenous PINK1 mobility was examined by western blotting. K. Isolated mouse adult CMs were infected with ad-AMPKα2 and treated with PE (50 μmol/L, 24 h) and then with 20 μmol/L CCCP for 8 h; subsequently, they were subjected to SDS-PAGE ± phos-tag and immunoblotted using an anti-PINK1 antibody. Red asterisks show phosphorylated PINK1. L–M. Isolated mouse adult CMs were infected with AMPKα2 short interfering RNA (si-AMPKα2), treated with PE (50 μmol/L, 6 h), subsequently subjected to SDS-PAGE ± phos-tag, and then immunoblotted using an anti-PINK1 antibody. Red asterisks show phosphorylated PINK1. All data represent the mean ± SEM from at least four independent experiments.
Figure 8
Figure 8. AMPKα2 phosphorylates PINK1 on Ser495 to enhance mitophagy and attenuate mitochondrial dysfunction
A. Schematic representation of the human PINK1 protein. B. HL-1 cells expressing PINK1-myc with various mutations were infected with an adenovirus encoding AMPKα2 (ad-AMPKα2), subjected to SDS–PAGE ± phos-tag, and immunoblotted using an anti-PINK1 antibody. Red asterisks show phosphorylated PINK1. C. HL-1 cells expressing PINK1-myc with various mutations were infected with ad-AMPKα2 and immunoblotted using an anti-Ser antibody. D. Representative images of base peaks in indicated groups by LC-MS/MS analysis. E. Representative immunoblots of p-AMPKα2 and AMPKα2 after ad-AMPKα2 or si-AMPKα2 stimulations in HL-1 CMs from (D). F. Multiple sequence alignment of PINK1 residues neighboring Ser495 from various organisms. Ser495 appears to have been evolutionarily conserved across most species. G. HL-1 cells expressing GFP-Parkin were infected with ad-PINK1 harboring the Ser284Ala or Ser495Ala mutation, subjected to 20 μmol/L CCCP induction for 8 h, and then immunoblotted with an anti-Parkin antibody. Ub shows ubiquitylation of GFP-Parkin. H. Isolated mouse adult CMs expressing PINK1-myc with Ser284Ala or Ser495Ala mutation were infected with ad-AMPKα2 and subjected to PE (50 μmol/L) stimulation for 24 h. Representative contour plots of CMs stained with MitoTracker are shown, and the MFIs of MitoTracker Deep Red are depicted. *P < 0.05 vs. PINK1-WT in ad-AMPKα2 group; #P < 0.05 vs. PINK1-WT in PE+ad-AMPKα2 group; &P < 0.05 vs. PINK1-WT in PE+ad-AMPKα2 group. I. CMs from (H) were subjected to mitoSOX red staining by FACS. *P < 0.05 vs. PINK1-WT in ad-AMPKα2 group; #P < 0.05 vs. PINK1-WT in PE+ad-AMPKα2 group; &P < 0.05 vs. PINK1-WT in PE+ad-AMPKα2 group. J. Representative immunoblots of p-PINK1 S495, PINK1, p-Parkin S65, Parkin, p-AMPKα2, and AMPKα2 after PINK1-WT, PINK1-S495A, and PINK1-S495D stimulations in HL-1 CMs. K. MFIs of MitoTracker Deep Red after PINK1-WT, PINK1-S495A, and PINK1-S495D stimulations in HL-1 CMs are shown. L. Representative immunoblots for p-PINK1 Ser495 and total levels of PINK1 recombinant proteins with or without AMPKα2β2γ1 co-incubation in a cell-free system are shown. M–N. Representative immunoblots for p-PINK1 Ser495 and PINK1 after gain- and loss-of-function of AMPKα2 in vivo (n=5). All data represent the mean ± SEM from at least four independent experiments.
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