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Lifespan and mitochondrial control of neurodegeneration

Nature Genetics volume 36, pages 1153–1158 (2004)Cite this article

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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Figure 1: Inherited neurodegeneration rates in the retina and brain in different species.
Figure 2: Rates of mitochondrial superoxide and hydrogen peroxide (H2O2) formation as a function of maximum LSP.
Figure 3: Species differences in rates of neurodegeneration suggest that constitutive RONS production has a profound influence on the mitochondrial regulation of apoptosis.

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Acknowledgements

We thank M. Murphy and N. Hastie for critical reading and advice on the manuscript and S. B. Schwartz and E. A. M. Windsor for help with data analyses. We acknowledge the financial support of the British Retinitis Pigmentosa Society, Foundation Fighting Blindness, the US National Institutes of Health (National Eye Institute) and the Macula Vision Research Foundation.

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Authors and Affiliations

  1. MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK

    Alan F Wright, Xinhua Shu & Dafni Vlachantoni

  2. Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, USA

    Samuel G Jacobson, Artur V Cideciyan & Alejandro J Roman

  3. Program in Genetics and Developmental Biology, Hospital for Sick Children, and Departments of Pediatrics and Molecular and Medical Genetics, University of Toronto, Toronto, Canada

    Roderick R McInnes

  4. Department of Biochemistry, Cardiovascular Research Unit, University of Edinburgh, Edinburgh, UK

    Rudolph A Riemersma

  5. Department of Medical Physiology, University of Tromso, Norway

    Rudolph A Riemersma

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  1. Alan F Wright
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Correspondence to Alan F Wright.

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Wright, A., Jacobson, S., Cideciyan, A. et al. Lifespan and mitochondrial control of neurodegeneration. Nat Genet 36, 1153–1158 (2004). https://doi.org/10.1038/ng1448

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