Lifespan and mitochondrial control of neurodegeneration
Abstract
We examine the allometric (comparative scaling) relationships between rates of neurodegeneration resulting from equivalent mutations in a diverse group of genes from five mammalian species with different maximum lifespan potentials. In both retina and brain, rates of neurodegeneration vary by as much as two orders of magnitude and are strongly correlated with maximum lifespan potential and rates of formation of mitochondrial reactive oxygen and nitrogen species (RONS). Cell death in these disorders is directly or indirectly regulated by the intrinsic mitochondrial cell death pathway. Mitochondria are the main source of RONS production and integrate cellular stress signals to coordinate the intrinsic pathway. We propose that these two functions are intimately related and that steady-state RONS-mediated signaling or damage to the mitochondrial stress-integration machinery is the principal factor setting the probability of cell death in response to a diverse range of cellular stressors. This provides a new and unifying framework for investigating neurodegenerative disorders.
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Aging-associated expression changes in genes associated with mitochondrial function, protein metabolism, and immune response have been identified in several tissues and are consistent with some proposed mechanisms for late-onset neurodegenerative diseases.
“Aging-associated expression changes in genes associated with mitochondrial function, protein metabolism, and immune response have been identified in several tissues (173) and are consistent with some proposed mechanisms for late-onset neurodegenerative diseases (98, 113, 124, 166).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [166]
Numerous studies have demonstrated a central role of mitochondria and energy homeostasis in the pathogenesis of aging-associated neurodegenerative diseases.
“Numerous studies have demonstrated a central role of mitochondria and energy homeostasis in the pathogenesis of aging-associated neurodegenerative diseases (98, 157, 166).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [166]
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- Authors
- Wright, A. F., Jacobson, S. G., Cideciyan, A. V., Roman, A. J., Shu, X., Vlachantoni, D., McInnes, R. R., & Riemersma, R. A.
- Affiliations
- Western General Hospital (GB)
- University of Pennsylvania (US)
- University of Toronto (CA)
- UiT The Arctic University of Norway (NO)
- Corresponding author
- Wright, Alan F
- Venue
- Nature Genetics
- Published
- 2004-10-28
- Volume
- 36
- Issue
- 11
- Pages
- 1153-1158
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2050863429
- Cited by
- 111
- References
- 53
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 8 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 3 · 2015: 5 · 2014: 5 · 2013: 3 · 2012: 3
- FWCI
- 0.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- ResearchOnline (Glasgow Caledonian University) (acceptedVersion)
- Funders
- Macula Vision Research Foundation
- National Institutes of Health
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- neurodegeneration, lifespan, allometric scaling, retina, brain, mammalian species comparison, genetic mutations
- MeSH terms
- Animals, Brain, Humans, Life Expectancy, Mitochondria, Nerve Degeneration, Retina, Species Specificity, Cell Death, Reactive Oxygen Species, Oxidative Stress, Neurodegenerative Diseases, Reactive Nitrogen Species
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