Rates of retinal degeneration across species and allometric scaling of metabolic rates suggest a major role for oxidative stress.

Abstract

Abstract: : Purpose: Rates of photoreceptor degeneration resulting from equivalent mutations in the same genes vary between species with markedly different maximum life span potentials (MLSP). The major reasons for differences in MLSP are thought to relate to differing rates of oxidative stress resulting from steady state levels of mitochondrial reactive oxygen species (ROS). Few of the wide variety of genetic abnormalities leading to photoreceptor degeneration directly implicate oxidative stress so that this is generally thought to play a late or minor role in cell death. The aim was to examine the relationship between rates of photoreceptor degeneration across species showing similar phototransduction mechanisms in order to elucidate the role of oxidative stress in retinal degeneration. Methods: Rates of photoreceptor degeneration resulting from broadly equivalent mutations within specific genes were compared using available data from humans, pig, dog, rat and mouse. These were compared with allometric scaling laws and basal metabolic rates, oxygen utilisation and mitochondrial free radical formation in the different species. Results: Rates of photoreceptor degeneration resulting from functionally equivalent genetic mutations in different species increase in proportion to cellular metabolic rates and rates of mitochondrial ROS formation. This relationship was examined in relation to allometric scaling laws, which relate metabolic rates to mass over 27 orders of magnitude, implying fundamental, highly conserved biological mechanisms. Conclusions: Clarke G et al. (2000) proposed that differences in the steady state levels of unspecified homeostatic factor(s) lead to different rates of photoreceptor apoptosis in different retinal degeneration mutants, most of which follow exponential decay kinetics. We propose that in normal mammalian photoreceptors, the apoptotic threshold is relatively constant between species but that differences in steady state levels of mitochondrial ROS production account for the species differences in rates of retinal degeneration. This suggests that oxidative stress is a major factor influencing apoptotic mechanisms in many forms of photoreceptor degeneration and possibly other types of neurodegeneration.

Keywords: retinal degenerations: cell biology • retina • photoreceptors