Endogenous Drp1 Mediates Mitochondrial Autophagy and Protects the Heart Against Energy Stress
Abstract
Rationale: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood. Objective: We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. Methods and Results: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. After Drp1 downregulation, cardiac-specific Drp1 knockout mice developed left ventricular dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in cardiac-specific Drp1 knockout mice. Although left ventricular function in cardiac-specific Drp1 heterozygous knockout mice was normal at 12 weeks of age, left ventricular function decreased more severely after 48 hours of fasting, and the infarct size/area at risk after ischemia/reperfusion was significantly greater in cardiac-specific Drp1 heterozygous knockout than in control mice. Conclusions: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to ischemia/reperfusion.
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Conditional ablation of DRP1 in the heart, brain, and skeletal muscle causes lethality.
“Consistent with this crucial role, conditional ablation of DRP1 in the heart, brain, and skeletal muscle causes lethality [196, 198–200, 208, 209].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [198]
Impairment of fission leads to disruption of selective mitochondrial autophagic degradation, followed by dysfunctional organelle accumulation.
“Impairment of fission leads to the disruption of selective mitochondrial autophagic degradation, followed by dysfunctional organelles accumulation [58, 196–200].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [198]
Disrupted mitochondrial fission obtained with specific ablation of DRP1 in the heart induces accumulation of defective mitochondria due to impaired autophagy/mitophagy, which over time promotes cardiomyocyte death.
“Disrupted mitochondrial fission, obtained with the specific ablation of DRP1 in the heart, induces accumulation of defective mitochondria due to impaired autophagy/mitophagy, that over-time promotes cardiomyocyte death [198–200].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [198]
Energy stress consequent to acute or chronic exercise triggers autophagy in different tissues.
“Energy stress consequent to acute or chronic exercise triggers autophagy in different tissues [197–200].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [198]
Conditional cardiomyocyte-specific deletion of Dnm1l exacerbates size of myocardial infarction/area after inhibition of mitophagy.
“| IRI | Conditional cardiomyocyte‐specific deletion of Dnm1l | Exacerbated size of myocardial infarction/area after inhibition of mitophagy | Cahill et al (2015), Ikeda et al (2015) |”
From Autophagy in major human diseases (2021) · cites this paper as Ikeda et al (2015)
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 [208]
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“(36) have found that inducible down-regulation of Drp1 leads to reduced mitophagy with accumulation of damaged mitochondria.”
Background
- Authors
- Ikeda, Y., Shirakabe, A., Maejima, Y., Zhai, P., Sciarretta, S., Toli, J., Nomura, M., Mihara, K., Egashira, K., Ohishi, M., Abdellatif, M., & Sadoshima, J.
- Affiliations
- Kagoshima University (JP)
- ORCID
- Venue
- Circulation Research
- Published
- 2015-01-16
- Volume
- 116
- Issue
- 2
- Pages
- 264-278
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2171317360
- Cited by
- 571
- References
- 37
- Citations by year
- 2026: 23 · 2025: 51 · 2024: 47 · 2023: 53 · 2022: 57 · 2021: 65 · 2020: 61 · 2019: 46 · 2018: 48 · 2017: 47 · 2016: 36 · 2015: 34 · 2014: 2 · 2013: 1
- FWCI
- 29.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- Rotary Foundation
- Fondation Leducq
- U.S. Public Health Service
- Japan Society for the Promotion of Science (25291046)
- National Institute on Aging (AG23039, R01AG023039)
- National Heart, Lung, and Blood Institute (HL91469, R01HL067724, HL102738, R01HL102738, R01HL112330, HL-67724, R01HL091469, HL112330)
- 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 › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- Drp1, mitochondrial fission, mitophagy, cardiomyocyte apoptosis, mitochondrial elongation, mitochondrial quality control, autophagic flux, glucose deprivation, energy stress, left ventricular dysfunction, myocardial ischemia-reperfusion injury, myocardial energy metabolism
- MeSH terms
- Animals, Autophagy, Energy Metabolism, Mice, Transgenic, Mitochondria, Heart, Rats, Wistar, Mice, Knockout, Oxidative Stress, Myocytes, Cardiac, Dynamins, Mice, Rats
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