Titration of mitochondrial fusion rescues Mff -deficient cardiomyopathy
Open accessAbstract
Defects in mitochondrial fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the mitochondrial fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of mitochondrial fusion and fission can restore tissue integrity and mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of fusion and fission is cell type specific.
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In mice, MFF deletion leads to smaller animals that display neuromuscular defects, kyphosis, and premature death at 13 weeks due to dilated cardiomyopathy.
“In mice, MFF deletion leads to smaller animals that display neuromuscular defects, kyphosis, and premature death at 13 weeks due to dilated cardiomyopathy [207].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [207]
Simultaneous deletion of MFN1 and MFF in mice rescues mitochondrial function, heart dysfunction, and lifespan of both lethal MFN1 and MFF knockout mice.
“Similarly, the simultaneous deletion of MFN1 and MFF in mice rescues mitochondrial function, heart dysfunction, and lifespan of both lethal MFN1 and MFF knockout mice [207].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [207]
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- Authors
- Chen, H., Ren, S., Clish, C., Jain, M., Mootha, V., McCaffery, J. M., & Chan, D. C.
- Affiliations
- California Institute of Technology (US)
- University of California, Los Angeles (US)
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Corresponding author
- Chan, David C.
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2015-11-23
- Volume
- 211
- Issue
- 4
- Pages
- 795-805
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC4657172
- OpenAlex
- W2177679111
- Cited by
- 168
- References
- 32
- Citations by year
- 2026: 6 · 2025: 18 · 2024: 12 · 2023: 21 · 2022: 14 · 2021: 20 · 2020: 24 · 2019: 18 · 2018: 13 · 2017: 14 · 2016: 6 · 2015: 1
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- Alfaisal University
- National Institute of General Medical Sciences (R01GM062967)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- mitochondrial fusion, mitochondrial fission, Mff, Mfn1, dilated cardiomyopathy, heart failure, mitophagy, mitochondrial dynamics
- MeSH terms
- Animals, Cardiomyopathy, Dilated, Cells, Cultured, Female, Male, Membrane Proteins, Mice, Inbred C57BL, Mitochondria, Heart, Titrimetry, Mice, Knockout, Mitochondrial Proteins, Mice, 129 Strain, Genetic Pleiotropy, Mitochondrial Dynamics
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