New Research Finds Mitochondrial Protein Misfolding Contributes to Type 2 Diabetes Progression

Recent scientific studies have uncovered that misfolded proteins tend to accumulate within the mitochondria of individuals suffering from type 2 diabetes, shedding light on a potential cellular mechanism behind the disease. Aging-related conditions such as cancer, cardiovascular issues, and diabetes are often linked to defects in how proteins are synthesized and folded within cells. Previous research had highlighted protein misfolding primarily occurring in insulin-producing beta cells located in the pancreatic islets, particularly within the endoplasmic reticulum, leading to cell death and pancreatic dysfunction.

However, a groundbreaking study published in Nature Metabolism by researchers from the University of Michigan reveals that mitochondria—the cell's energy producers—also build up misfolded proteins, which directly contribute to the destruction of beta cells. This discovery opens new avenues for understanding the molecular underpinnings of type 2 diabetes and highlights potential targets for therapy.

The proteins insulin and amylin, both synthesized by pancreatic beta cells, are known to misfold in diabetic patients. Amylin, which promotes satiety after meals, can form amyloid aggregates similar to plaques in Alzheimer’s disease. Researchers, led by Dr. Scott Soleimanpour, sought to identify all misfolded proteins in pancreatic cells and found that the body’s defense systems, particularly the protein LONP1 responsible for clearing damaged proteins, are less active in diabetic conditions.

This reduced activity impairs the cell's ability to eliminate faulty proteins, leading to an accumulation that damages mitochondria and causes beta cell death. Experiments with mice lacking LONP1 showed higher blood glucose levels and fewer functional beta cells, but these issues were reversed when LONP1 was restored, indicating promising therapeutic potential.

The findings suggest that enhancing mitochondrial protein quality control systems could be a strategy to prevent or treat type 2 diabetes. Future research aims to develop drugs that can help refold or break down misfolded proteins, potentially protecting beta cell health over time. Understanding how these mitochondrial failures progress could also provide insights into early intervention and disease prevention.

This study underscores the importance of mitochondrial health in metabolic diseases and opens new directions for targeted therapies to combat diabetes at the cellular level. For more details, see the original publication: Jin Li et al, LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes, Nature Metabolism (2025).