Nature Genetics36, 1153 - 1158 (2004)
Published online: 28 October 2004; | doi:10.1038/ng1448
Lifespan and mitochondrial control of neurodegeneration
Alan F Wright1, Samuel G Jacobson2, Artur V Cideciyan2, Alejandro J Roman2, Xinhua Shu1, Dafni Vlachantoni1, Roderick R McInnes3
& Rudolph A Riemersma4
1
MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK.
2
Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, USA.
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.
4
Cardiovascular Research Unit, Department of Biochemistry, University of Edinburgh, Edinburgh, UK; and Department of Medical Physiology, University of Tromso, Norway.
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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