MTFP1 preserves β-cell cristae structure and bioenergetics to ensure insulin release and glucose homeostasis

Abstract Pancreatic β-cells are uniquely dependent on mitochondrial metabolism to couple glucose sensing to insulin secretion, a process impaired in diabetes. Mitochondrial fission process 1 (MTFP1) is an inner mitochondrial membrane protein that plays pleiotropic, tissue-specific roles in mitochondrial function and dynamics. Our previous work has identified Mtfp1 mRNA as a target for miR-125b, a microRNA that negatively regulates insulin secretion from β-cells. Nevertheless, the function of MTFP1 in these cells remained unexplored. Here, we show that MTFP1 is essential for normal glucose-stimulated insulin secretion (GSIS) in mouse and human cell lines and islets, and that mice with β-cell-specific elimination of MTFP1 develop glucose intolerance. Whereas β-cell survival and mitochondrial content were unaffected, oxidative phosphorylation and ATP production were sharply lowered. These changes were accompanied by disruption of mitochondrial cristae structure and a reduced contact surface with the endoplasmic reticulum, providing a mechanistic basis for defective stimulus-secretion coupling. Conversely, MTFP1 overexpression in mouse and human islets sufficed to improve mitochondrial respiration and GSIS. Finally, MTFP1 downregulation blocked the positive effects of miR-125b elimination in GSIS and mitochondrial respiration, unveiling MTFP1 as a downstream effector of miR-125b. Together, our findings identify MTFP1 as a critical regulator of β-cell mitochondrial architecture and function, necessary for efficient insulin secretion and glucose homeostasis, and a potential therapeutic target to enhance β-cell bioenergetic resilience in diabetes. Competing Interest Statement GAR has received grant funding from, and is a consultant for, Sun Pharmaceuticals Inc. No other potential conflicts of interest relevant to this article were reported. Footnotes We have increased the number of samples quantified for Mitotracker measurements and edited the figures accordingly. Overall content and conclusions of the manuscript were not affected by the results.