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Cited by 498Autophagy in Disease and TherapyCardiovascular Function and Risk FactorsMitochondrial Function and Pathology

Mitophagy is essential for maintaining cardiac function during high fat diet-induced diabetic cardiomyopathy

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Tong, Mingming, Saito, Toshiro, Zhai, Peiyong, Oka, Shin-ichi, Mizushima, Wataru, Nakamura, Michinari, Ikeda, Shohei, Shirakabe, Akihiro +1 more·2019·Circulation Research
DOI 10.1161/circresaha.118.314607PMC PMC6483841
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Abstract

RATIONALE: Diabetic patients develop cardiomyopathy characterized by hypertrophy, diastolic dysfunction, and intracellular lipid accumulation, termed lipotoxicity. Diabetic hearts utilize fatty acids as a major energy source, which produces high levels of oxidative stress, thereby inducing mitochondrial dysfunction. OBJECTIVE: To elucidate how mitochondrial function is regulated in diabetic cardiomyopathy. METHODS AND RESULTS: Mice were fed either a normal diet or high-fat diet (HFD, 60 kcal % fat). Although autophagic flux was activated by HFD consumption, peaking at 6 weeks ( P<0.05), it was attenuated thereafter. Mitophagy, evaluated with Mito-Keima, was increased after 3 weeks of HFD feeding (mitophagy area: 8.3% per cell with normal diet and 12.4% with HFD) and continued to increase even after 2 months ( P<0.05). By isolating adult cardiomyocytes from GFP-LC3 mice fed HFD, we confirmed that mitochondria were sequestrated by LC3-positive autophagosomes during mitophagy. In wild-type mice, cardiac hypertrophy, diastolic dysfunction (end diastolic pressure-volume relationship =0.051±0.009 in normal diet and 0.11±0.004 in HFD) and lipid accumulation occurred within 2 months of HFD feeding ( P<0.05). Deletion of atg7 impaired mitophagy, increased lipid accumulation, exacerbated diastolic dysfunction (end diastolic pressure-volume relationship =0.11±0.004 in wild type and 0.152±0.019 in atg7 cKO; P<0.05) and induced systolic dysfunction (end systolic pressure-volume relationship =24.86±2.46 in wild type and 15.93±1.76 in atg7 cKO; P<0.05) during HFD feeding. Deletion of Parkin partially inhibited mitophagy, increased lipid accumulation and exacerbated diastolic dysfunction (end diastolic pressure-volume relationship =0.124±0.005 in wild type and 0.176±0.018 in Parkin KO, P<0.05) in response to HFD feeding. Injection of TB1 (Tat-Beclin1) activated mitophagy, attenuated mitochondrial dysfunction, decreased lipid accumulation, and protected against cardiac diastolic dysfunction (end diastolic pressure-volume relationship =0.110±0.009 in Control peptide and 0.078±0.015 in TB1, P<0.05) during HFD feeding. CONCLUSIONS: Mitophagy serves as an essential quality control mechanism for mitochondria in the heart during HFD consumption. Impairment of mitophagy induces mitochondrial dysfunction and lipid accumulation, thereby exacerbating diabetic cardiomyopathy. Conversely, activation of mitophagy protects against HFD-induced diabetic cardiomyopathy.

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  • Mitophagy impairment can induce cardiomyocyte death and HF.

    “Accumulating evidence suggests that mitophagy impairment can induce cardiomyocyte death and HF [206,207,208,209].”

    From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [206]

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Authors
Tong, M., Saito, T., Zhai, P., Oka, S.-I., Mizushima, W., Nakamura, M., Ikeda, S., Shirakabe, A., & Sadoshima, J.
Affiliations
  • Rutgers New Jersey Medical School (US)
  • From the Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School.
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-04-26
Volume
124
Issue
9
Pages
1360-1371
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.118.314607
PMC
PMC6483841
OpenAlex
W2915285292
Cited by
498
References
33
Citations by year
2026: 57 · 2025: 63 · 2024: 106 · 2023: 60 · 2022: 76 · 2021: 71 · 2020: 50 · 2019: 13
FWCI
39.96
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Fondation Leducq
  • U.S. Public Health Service
  • Japan Society for the Promotion of Science (19K17601)
  • National Institute on Aging (R01AG023039)
  • National Heart, Lung, and Blood Institute (R01HL067724, R01HL102738, R01HL138720, R01HL112330, R01HL091469)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
mitophagy, diabetic cardiomyopathy, high-fat diet, autophagy, ATG7, Parkin, Beclin-1, TB1, lipotoxicity, myocardial lipid accumulation, diastolic dysfunction, systolic dysfunction, cardiac hypertrophy, mitochondrial dysfunction, oxidative stress, LC3, autophagosomes, myocardial energy metabolism, fatty acid utilization
MeSH terms
Autophagy-Related Protein 7, Animals, Female, Heart, Cardiomegaly, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Mice, Knockout, Myocytes, Cardiac, Diabetic Cardiomyopathies, Diet, High-Fat, Mitophagy

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