Muscle choline kinase beta defect causes mitochondrial dysfunction and increased mitophagy
Open accessAbstract
Choline kinase is the first step enzyme for phosphatidylcholine (PC) de novo biosynthesis. Loss of choline kinase activity in muscle causes rostrocaudal muscular dystrophy (rmd) in mouse and congenital muscular dystrophy in human, characterized by distinct mitochondrial morphological abnormalities. We performed biochemical and pathological analyses on skeletal muscle mitochondria from rmd mice. No mitochondria were found in the center of muscle fibers, while those located at the periphery of the fibers were significantly enlarged. Muscle mitochondria in rmd mice exhibited significantly decreased PC levels, impaired respiratory chain enzyme activities, decreased mitochondrial ATP synthesis, decreased coenzyme Q and increased superoxide production. Electron microscopy showed the selective autophagic elimination of mitochondria in rmd muscle. Molecular markers of mitophagy, including Parkin, PINK1, LC3, polyubiquitin and p62, were localized to mitochondria of rmd muscle. Quantitative analysis shows that the number of mitochondria in muscle fibers and mitochondrial DNA copy number were decreased. We demonstrated that the genetic defect in choline kinase in muscle results in mitochondrial dysfunction and subsequent mitochondrial loss through enhanced activation of mitophagy. These findings provide a first evidence for a pathomechanistic link between de novo PC biosynthesis and mitochondrial abnormality.
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These findings suggest that during diet-induced obesity/diabetes etiology, mitochondrial architecture deteriorates, ultimately leading to mitophagy and complete organelle dissolution.
“These findings suggest that at some point in the etiology of diet-induced obesity/diabetes, mitochondrial architecture begins to deteriorate, ultimately leading to mitophagy and the complete dissolution of the organelle (Mitsuhashi et al., 2011).”
From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Mitsuhashi et al., 2011
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- Authors
- Mitsuhashi, S., Hatakeyama, H., Karahashi, M., Koumura, T., Nonaka, I., Hayashi, Y. K., Noguchi, S., Sher, R. B., Nakagawa, Y., Manfredi, G., Goto, Y.-I., Cox, G. A., & Nishino, I.
- Affiliations
- National Center of Neurology and Psychiatry (JP)
- Kitasato University (JP)
- Jackson Laboratory (US)
- Cornell University (US)
- Corresponding author
- Nishino, Ichizo
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-07-12
- Volume
- 20
- Issue
- 19
- Pages
- 3841-3851
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3168292
- OpenAlex
- W2097367553
- Cited by
- 95
- References
- 40
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 9 · 2020: 5 · 2019: 8 · 2018: 2 · 2017: 6 · 2016: 12 · 2015: 8 · 2014: 4 · 2013: 7 · 2012: 8
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- Ministry of Health, Labour and Welfare (20B-13, 20B-12)
- Japan Society for the Promotion of Science (21591104, 20390250, 22791019)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR054170, AR054170)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- congenital muscular dystrophy, skeletal muscle mitochondria, mitochondrial dysfunction, mitophagy, phosphatidylcholine synthesis, mitochondrial DNA copy number, Parkin, PINK1, coenzyme Q10, superoxide, respiratory chain enzyme activity
- MeSH terms
- Adenosine Triphosphate, Animals, Choline Kinase, Disease Models, Animal, Female, Humans, Male, Mitochondria, Muscular Dystrophies, Mice, Knockout, Muscle, Skeletal, Mice
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