Parkin‐independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain
Open accessAbstract
Mitochondrial dynamics and mitophagy have been linked to cardiovascular and neurodegenerative diseases. Here, we demonstrate that the mitochondrial division dynamin Drp1 and the Parkinson's disease-associated E3 ubiquitin ligase parkin synergistically maintain the integrity of mitochondrial structure and function in mouse heart and brain. Mice lacking cardiac Drp1 exhibited lethal heart defects. In Drp1KO cardiomyocytes, mitochondria increased their connectivity, accumulated ubiquitinated proteins, and decreased their respiration. In contrast to the current views of the role of parkin in ubiquitination of mitochondrial proteins, mitochondrial ubiquitination was independent of parkin in Drp1KO hearts, and simultaneous loss of Drp1 and parkin worsened cardiac defects. Drp1 and parkin also play synergistic roles in neuronal mitochondrial homeostasis and survival. Mitochondrial degradation was further decreased by combination of Drp1 and parkin deficiency, compared with their single loss. Thus, the physiological importance of parkin in mitochondrial homeostasis is revealed in the absence of mitochondrial division in mammals.
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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 [199]
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 [199]
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 [199]
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 [199]
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Background
- Authors
- Kageyama, Y., Hoshijima, M., Seo, K., Bedja, D., Sysa‐Shah, P., Andrabi, S. A., Chen, W., Höke, A., Dawson, V. L., Dawson, T. M., Gabrielson, K., Kass, D. A., Iijima, M., & Sesaki, H.
- Affiliations
- Johns Hopkins University (US)
- University of California San Diego (US)
- Corresponding author
- Sesaki, Hiromi
- ORCID
- Venue
- The EMBO Journal
- Published
- 2014-10-27
- Volume
- 33
- Issue
- 23
- Pages
- 2798-2813
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC4282557
- OpenAlex
- W2170457695
- Cited by
- 420
- References
- 40
- Citations by year
- 2026: 6 · 2025: 18 · 2024: 34 · 2023: 38 · 2022: 40 · 2021: 52 · 2020: 51 · 2019: 26 · 2018: 41 · 2017: 37 · 2016: 42 · 2015: 33 · 2014: 2
- FWCI
- 28.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH (GM084015, GM089853, NS084154, HL107153, HL59480, HL077180, NS38377)
- AHA (0840013N, 12GRANT1173006)
- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- Parkin, Drp1, mitophagy, mitochondrial division, mitochondrial dynamics, mitochondrial ubiquitination, mitochondrial homeostasis, cardiomyocytes, neuronal survival, cardiac anomalies, brain, Parkinson's disease, mitochondrial respiration
- MeSH terms
- Animals, Brain, Microscopy, Fluorescence, Mitochondria, Mice, Knockout, Myosin Heavy Chains, Myocytes, Cardiac, Dynamins, Ubiquitin-Protein Ligases, Mice, Ubiquitination, Electron Microscope Tomography, Mitophagy
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