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 steadystate 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.Cell death in inherited neurodegenerative disorders most commonly occurs by apoptosis 1-4 . The evidence is often indirect and inferred on the basis of characteristic morphological changes, such as chromatin compaction and cell shrinkage, or evidence of caspase activation, but in many cases it is more reliably based on multiple lines of evidence [1][2][3][4] . Caspase-independent cell death also occurs, although the precise mechanisms are less well understood and evidence that this occurs in inherited neurodegenerations is sparse. In these disorders, cell death occurs with a probability that is constant through part or all of the adult lifespan, consistent with a steady-state (one-hit or exponential kinetics) rather than a cumulative damage model 5,6 . The retina is a particularly well understood model of neurodegeneration. Mutations in more than 100 genes are known to cause neurodegeneration of retinal photoreceptors (RetNet; see URL below); these affect virtually all areas of metabolism and all parts of the cell 7-9 .Two main pathways lead to the activation of cysteine proteases or caspases that execute the apoptotic death program [10][11][12] . The extrinsic pathway involves cell-surface signaling complexes (e.g., Fas or FasL), which trigger the cell death cascade by activating caspase 8 and downstream caspases. The intrinsic, or mitochondrial, pathway controls activation of caspase 9, through the adaptor molecule Apaf-1, by regulating release of cytochrome c from mitochondria. Proapoptotic and antiapoptotic members of the Bcl-2 family and various stress and survival signals regulate the release of cytochrome c. Proapoptotic signals can also release proteins such as Smac and Omi, which antagonize IAP (inhibitor of apoptosis) proteins to activate cell death caspases, from the mitochondrial intermembrane space.Evidence from animal models of human photoreceptor degeneration suggests that the mitochondrial, rather than the extrinsic, cell death pa...

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

“…Control oligo is THF control (Table 2) Tables 1 and 4 FIC analysis in many instances. Nonetheless, this negative correlation is consistent with four related observations from multi-species comparisons: (1) cellular respiration rates (e.g., liver hepatocytes, Porter and Brand 1995) and the corresponding proportion of cell volume occupied by mitochondria (multiple cell types, Else and Hulbert 1985;Porter and Brand 1995) are greater in smaller species; (2) ROS production per mitochondrion (multiple tissues; Sohal et al 1989;Sohal et al 1990;Ku et al 1993;Barja 1998;Wright et al 2004;Lambert et al 2007) is generally greater in smaller, shorter-lived species (Fig. 5a); (3) steady-state levels of nuclear DNA oxidative damage are greater in some tissues of smaller species (see Fig.…”

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

“…Under the simplifying assumptions of a delayed exponential progression of disease (56) and a relationship between the square of ONL thickness and light sensitivity (57), the rate of ONL thickness change in human RPGR-XLRP can be estimated to fall in the range of −0.03 to −0.05 log 10 /y. Using allometric scaling based on maximum lifespan (26), the human progression estimate corresponds to −0.18 to −0.31 log 10 per canine-equivalent years, which is similar to the rate of −0.33 log 10 /y estimated in the superior retina of XLPRA2 dogs but slower than the −0.45 log 10 /y estimated in the inferior retina. Thus, the current studies were performed to place the treatment injections in the superior retinal locations whenever possible.…”

“…The natural course of RPGR-XLRP disease is severe, with males showing loss of night vision in the first decade of life (23). The disease onset in the naturally occurring or Rpgr KO mouse models is very late (23)(24)(25) as it corresponds to 35 human years (26), whereas the disease onset in two naturally occurring canine models of RPGR-XLRP (27)(28)(29) are earlier and correspond better to the human disease time course. Gene augmentation delivered by means of an adeno-associated viral (AAV) vector has been shown to be efficient in both the dog and mouse models (30,31).…”

Cerebral Formation of Free Radicals during Hypoxia Does Not Cause Structural Damage and is Associated with a Reduction in Mitochondrial PO2; Evidence of O2-Sensing in Humans?

“…Emerging evidence suggests that the mitochondrion may function as the primary O 2 'sensor', given its capacity to increase free radical and associated reactive oxygen-nitrogen species formation during hypoxia (Chandel et al, 1998). Although thermodynamically capable of causing structural damage when in excess, these oxidant signals can act as secondary messengers (Wright et al, 2004), which activate O 2 salvage genes through stabilization of the transcription factor hypoxia-inducible factor-1a (Guzy and Schumacker, 2006) in physiologically controlled, although as of yet undefined, amounts.…”