Mitochondrial quality control, promoted by PGC-1 α, is dysregulated by Western diet-induced obesity and partially restored by moderate physical activity in mice
Open accessAbstract
Skeletal muscle mitochondrial degeneration is a hallmark of insulin resistance/obesity marked by lost function, enhanced ROS emission, and altered morphology which may be ameliorated by physical activity (PA). However, no prior report has examined mitochondrial quality control regulation throughout biogenesis, fusion/fission dynamics, autophagy, and mitochondrial permeability transition pore (MPTP) in obesity. Therefore, we determined how each process is impacted by Western diet (WD)-induced obesity and whether voluntary PA may alleviate derangements in mitochondrial quality control mechanisms. Despite greater mitochondrial content following WD (COX-IV and Cytochrome C), induction of biogenesis controllers appears impaired (failed induction of PGC-1α). Mitochondrial fusion seems diminished (reduced MFN2, Opa1 proteins), with no significant changes in fission, suggesting a shift in balance of dynamics regulation favoring fission. Autophagy flux was promoted in WD (reduced p62, increased LC3II:I ratio); however, mitophagy marker BNIP3 is reduced in WD which may indicate reduced mitophagy despite enhanced total autophagy flux. MPTP regulator Ant mRNA is reduced by WD. Few processes were impacted by physical activity. Finally, mitochondrial quality control processes are partially promoted by PGC-1α, as PGC-1α transgenic mice display elevated mitochondrial biogenesis and autophagy flux. Additionally, these mice exhibit elevated Mfn1 and Opa1 mRNA, with no change in protein content suggesting these factors are transcriptionally promoted by PGC-1α overexpression. These data demonstrate dysfunctions across mitochondrial quality control in obesity and that PGC-1α is sufficient to promote multiple, but not necessarily all, aspects of mitochondrial quality control. Mitochondrial quality control may therefore be an opportune target to therapeutically treat metabolic disease.
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There is evidence suggesting a disruption in mitophagy in skeletal muscle in obesity.
“While previous reports remain conflicting, there are evidence suggesting a disruption in mitophagy in the skeletal muscle in obesity [26], long-term high-fat diet consumption [27], and aged skeletal muscle [22, 23].”
From Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds (2024) · cites this paper as [26]
Greene et al. reported decreased mitophagy in obese animals with accumulation of dysfunctional organelles.
“Regarding obesity, for instance, Greene et al. reported decreased mitophagy in obese animals with accumulation of dysfunctional organelles [26].”
From Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds (2024) · cites this paper as [26]
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References 48 · Cited by 89
- Authors
- Greene, N. P., Lee, D. E., Brown, J. L., Rosa, M. E., Brown, L. A., Perry, R. A., Henry, J. N., & Washington, T. A.
- Affiliations
- University of Arkansas at Fayetteville (US)
- Corresponding author
- Greene, Nicholas P.
- ORCID
- Venue
- Physiological Reports
- Publisher
- Wiley
- Published
- 2015-07
- Volume
- 3
- Issue
- 7
- Pages
- e12470
- ISSN
- 2051-817X (ISSN-L)
- PMC
- PMC4552545
- OpenAlex
- W2114664713
- Cited by
- 89
- References
- 48
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 3 · 2022: 10 · 2021: 16 · 2020: 7 · 2019: 13 · 2018: 6 · 2017: 7 · 2016: 8 · 2015: 1
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Physiological Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- University of Arkansas - Fayetteville.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- mitochondrial quality control, PGC-1α, voluntary physical activity, skeletal muscle mitochondria, mitochondrial biogenesis, mitochondrial fusion, mitochondrial fission, mitophagy, autophagic flux, mitochondrial permeability transition pore, Mfn1, OPA1, insulin resistance, metabolic disorders
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