A theoretical model for the influence of age, race and ethnicity on retinal mitochondria dysfunction

Glaucoma is a group of diseases characterized by a degeneration of retinal ganglion cells (RGC) and is the second major cause of blindness worldwide. RGC vulnerability is thought to be the result of the interaction among mechanical, vascular, metabolic and neurodegenerative processes which progressively lead to RGC and optic nerve axon death. Clinical data show that glaucoma risk increases with age (A) and is higher in subjects with African-American (AA) than White-European (WE) descent. However, no quantitative mechanistic framework currently explains how A, race and ethnicity (χ) interact with cellular metabolism to influence RGC vulnerability, limiting our ability to predict which individuals are at highest risk or to identify metabolic pathways to be targeted therapeutically. To fill this gap, we propose a differential model of how the concentration of RGC mitochondria (MITO) metabolism products vary with time, A and χ. We represent the MITO synthase rate of adenosine triphosphate (ATP) as an exponentially decaying function of A and define the metabolic efficiency η_MITO as the ratio of the stationary ATP concentration and its reference value. Simulation results indicate that η_MITO decreases with A, with a maximum decrease of 37.84% and 32.4% for AA and WE subjects, respectively. Model predictions are consistent with clinical observations indicating higher glaucoma prevalence and severity in older individuals and in specific population groups, and strengthen the view of glaucoma as a multifactorial neurodegenerative disease in which metabolic vulnerability may represent one contributing pathway.