Proteotoxicity and mitochondrial dynamics in aging diabetic brain.

Impaired neuronal proteostasis is a salient feature of both aging and protein misfolding disorders. Amyloidosis, a consequence of this phenomena is observed in the brains of diabetic patients over the chronic time period. These toxic aggregates not only cause age-related decline in proteostasis, but also dwindle its ability to increase or restore the chaperones in response to any stressful condition. Mitochondria acts as the main source of energy regulation and many metabolic disorders such as diabetes have been associated with altered oxidative phosphorylation (OxPhos) and redox imbalance in the mitochondria. The mitochondrial unfolded protein response (UPR) acts as a mediator for maintaining the mitochondrial protein homeostasis and quality control during such conditions. Over a long time period, these responses start shutting off leading to proteotoxic stress in the neurons. This reduces the buffering capacity of protein network signalling during aging, thereby increasing the risk of neurodegeneration in the brain. In this review, we focus on the proteotoxic stress that occurs as an amalgamation of diabetes and aging, as well as the impact of mitochondrial dysfunction on the neuronal survival affecting the diabetic brain and its long term consequences on the memory changes.