Lifespan and mitochondrial control of neurodegeneration.
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.
Wright
Alan F
AF
MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK. alan.wright@hgu.mrc.ac.uk <alan.wright@hgu.mrc.ac.uk>
Jacobson
Samuel G
SG
Cideciyan
Artur V
AV
Roman
Alejandro J
AJ
Shu
Xinhua
X
Vlachantoni
Dafni
D
McInnes
Roderick R
RR
Riemersma
Rudolph A
RA
D000818:Animals; D001921:Brain / Q000378:metabolism; D016923:Cell Death; D006801:Humans; D008017:Life Expectancy; D008928:Mitochondria / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D013045:Species Specificity
D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species