337-OR: ADA Presidents' Select Abstract: The LonP1 Protease Maintains Pancreatic ß-Cell Survival by Governing Mitochondrial Protein Folding

Accumulating evidence indicates that type 2 diabetes (T2D) is a protein misfolding disease. LonP1 is an essential mitochondrial protease that mediates mitochondrial proteostasis through clearance of unfolded or misfolded proteins, but its role in β-cells is unknown. We generated mice bearing β-cell specific deletion of LonP1 (β-LonP1^KO) and found that LonP1 deletion led to progressively impaired glucose tolerance with age and decreased glucose-stimulated insulin release (GSIS). LonP1 deficiency also induced β-cell apoptosis resulting in the loss of β-cell mass. In the mitochondria, β-LonP1^KO mice exhibited diminished mitochondrial respiration, abnormal mitochondrial ultrastructure, reduced mitochondrial mass, and elevated ROS levels. An accumulation of misfolded mitochondrial proteins, defect of OXPHOS complex assembly, and/or induction of ROS could be primary triggers driving mitochondrial dysfunction and β-cell apoptosis in β-LonP1^KO islets. Interestingly, β-cell specific overexpression of the antioxidant enzyme catalase targeted to mitochondria exerted only a modest, transient protective effect on glucose tolerance and β-cell mass in β-LonP1^KO mice yet did not relieve accumulation of misfolded mitochondrial proteins, suggesting ROS alone could not account for the phenotype in LonP1-deficient mice. Concordantly, a similar effect of anti-oxidants on β-cell survival and mitochondrial protein misfolding was observed in human islets in the context of LonP1-deficiency. Thus, the LonP1 protease is vital for β-cell survival and mass by governing mitochondrial protein folding, which could be a potential therapeutic target to prevent β-cell failure during the development of T2D.