| Summary: | Rationale/statement of the problem : High blood glucose levels increase individuals’ susceptibility to age-related diseases and mortality. However, the molecular mechanisms by which hyperglycemia impairs cellular function is unclear. Emerging research suggests that mitochondrial dysfunction may be a potential allostatic mechanism that mediates the deleterious effects of hyperglycemia via dynamic pathways. Mitochondria are ubiquitous organelles that are the primary producer of cellular energy and, therefore, central to health and disease. In addition, mitochondria contain their own genetic material – the mitochondrial DNA (mtDNA). Importantly, mutations in mtDNA cause human neurological diseases, and hyperglycemia can impair mitochondrial DNA and function. Here, we hypothesized that in patients with inherited mtDNA mutations, those with poor glucose homeostasis or with diabetes would present with more severe neurological symptoms than those with normal glucose balance. Methods : A literature review and retrospective study of 86 patients with the mtDNA 3243A > G mutation was conducted. We assessed glucose homeostasis and neurological symptoms using the Newcastle Mitochondrial Disease Assessment Scale (NMDAS), and Chi-squared statistics were used to compare the incidence of neurological symptoms in patients with or without glucose intolerance. Results : In patients with pre-existing mitochondrial disease, the incidence of neurological symptoms, including cerebellar ataxia (OR: 9.52; 95% CI: 2.03-44.52) and peripheral neuropathy (OR: 3.91; 95% CI: 1.43-10.76) were greater in those with glucose intolerance than in those with no diagnosed glucose intolerance. In addition, a dose–response relationship linked the severity of glucose intolerance and incidence of cerebellar ataxia. Conclusions : These preliminary results suggest that mtDNA mutations may render brain tissue more susceptible to glucose toxicity. Given that the accumulation of mtDNA damage occurs with senescence, our findings may have implications for resilience in the elderly. In addition to metabolic stress (i.e., hyperglycemia), mitochondrial functions are modulated by mediators of stress (i.e., cortisol), suggesting that integration of psychoneuroendocrine mediators can occur within mitochondria, thus contributing to the “wear and tear” of allostatic load. In this presentation, we introduce mitochondrial allostatic load (MAL) as a biological mechanism that might contribute to explain how metabolic and psychosocial stresses synergistically influence health and disease susceptibility.
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