LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes

Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but it is unknown whether impaired proteostasis in T2D is generalized or has special features. Here, we report a robust accumulation of misfolded proteins within the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability. Quantitative proteomics studies of protein aggregates surprisingly reveal that islets from donors with T2D have a signature more closely resembling mitochondrial rather than ER protein misfolding. Loss of the matrix protease LONP1, a vital component of the mitochondrial proteostatic machinery whose expression is reduced in β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, ultimately leading to β cell apoptosis and hyperglycemia. Intriguingly, LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival following glucolipotoxicity via a protease-independent effect requiring LONP1-mtHSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycemia by facilitating mitochondrial protein folding. These observations open novel insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D that could be considered as future therapeutic targets.