Lipin1 ameliorates cognitive ability of diabetic encephalopathy via regulating Ca2+ transfer through mitochondria-associated endoplasmic reticulum membranes

Diabetic encephalopathy (DE) is a common central nervous system complication resulting from diabetes mellitus (DM). While the exact pathogenesis remains unclear, a homeostatic imbalance of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) within neurons has been shown to be closely associated with the dysfunctional cognitive pathology of this condition. Our previous work has revealed that phosphatidate phosphatase Lipin1 plays a critical role in the cognitive processes of DE via regulating mitochondrial function. In this study, we reported that the integrity of neuronal MAMs was disrupted in DE mice, which was accompanied by a decrease in the expression of hippocampal Lipin1. With a knock-down of hippocampal Lipin1 in normal mice, ER stress was induced, MAMs structures were impaired and Ca²⁺ transfer was suppressed. Such effects resulted in mitochondrial dysfunction, synaptic plasticity impairments, and finally cognitive dysfunctions. In contrast, an up-regulation of hippocampal Lipin1 in the DE model partially alleviated these dysfunctions. These results suggest that Lipin1 may ameliorate the cognitive dysfunctions associated with DE via regulating Ca²⁺ transfers through MAMs. Therefore, targeting Lipin1 may serve as a therapeutic strategy for the clinical treatment of DE.