Uncoupling to survive? The role of mitochondrial inefficiency in ageing
Abstract
Mitochondria are incompletely coupled, and during oxidative phosphorylation some of the redox energy in substrates is lost as heat. Incomplete coupling is mostly due to a natural leak of protons across the mitochondrial inner membrane. In rat hepatocytes the futile cycle of proton pumping and proton leak is responsible for 20-25% of respiration; in perfused rat muscle the value is 35-50%. Mitochondrial proton cycling is estimated to cause 20-25% of basal metabolic rate in rats. Proton cycling is equally prominent in hepatocytes from several different mammalian and ectotherm species, so it may be a general pathway of ecologically significant energy loss in all aerobes. Because it occurs in ectotherms, thermogenesis cannot be its primary function. Instead, an attractive candidate for the function of the universal and expensive energy-dissipating proton cycle is to decrease the production of superoxide and other reactive oxygen species (ROS). This could be important in helping to minimise oxidative damage to DNA and in slowing ageing. Mitochondria are the major source of cellular ROS, and increased mitochondrial proton conductance leads to oxidation of ubiquinone and decreased ROS production in isolated mitochondria. However, to date there is no direct evidence in cells or organisms that mitochondrial proton cycling lowers ROS production or oxidative damage or that it increases lifespan.
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Decreased mitochondrial reactive oxygen species production and macromolecular oxidative damage due partly to mitochondrial uncoupling may explain the benefits of calorie restriction.
“Decreased mitochondrial ROS production and macromolecular oxidative damage due, in part, to mitochondrial uncoupling might also explain the benefits of calorie restriction219,220.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [219]
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- Authors
- Brand, M. D.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- Corresponding author
- Brand, M.D
- ORCID
- Brand, M.D
- Venue
- Experimental Gerontology
- Publisher
- Elsevier BV
- Published
- 2000-09
- Volume
- 35
- Issue
- 6-7
- Pages
- 811-820
- ISSN
- 0531-5565 (ISSN-L)
- OpenAlex
- W1979048203
- Cited by
- 789
- References
- 30
- Citations by year
- 2026: 18 · 2025: 29 · 2024: 27 · 2023: 36 · 2022: 31 · 2021: 38 · 2020: 34 · 2019: 38 · 2018: 26 · 2017: 32 · 2016: 35 · 2015: 53 · 2014: 41 · 2013: 37 · 2012: 33
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Gerontology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial proton leak, mitochondrial uncoupling, reactive oxygen species, superoxide, aging, lifespan, energy dissipation, basal metabolic rate, hepatocytes, muscle mitochondria, oxidative damage, thermogenesis
- MeSH terms
- Aging, Animals, Biological Evolution, Humans, Mitochondria, Oxidative Phosphorylation, Reactive Oxygen Species, Proton-Motive Force, Rats
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