β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes

Abstract

Mitochondrial dysfunction plays a central role in Type 2 Diabetes (T2D); however, the pathogenic mechanisms in pancreatic β-cells are incompletely elucidated. Succinate dehydrogenase (SDH) is a key mitochondrial enzyme with dual functions in the TCA cycle and electron transport chain (ETC). Using human diabetic samples and a mouse model of β-cell-specific SDH ablation (SDHBβKO), we define SDH deficiency as a driver of mitochondrial dysfunction in β-cell failure and insulinopenic diabetes. β-Cell SDH deficiency impairs glucose-induced respiratory oxidative phosphorylation and mitochondrial membrane potential (ΔΨm) collapse, thereby compromising glucose-stimulated ATP production, insulin secretion and β-cell growth. Mechanistically, metabolomic and transcriptomic studies reveal that the loss of SDH causes excess succinate accumulation, which inappropriately activates mTORC1-regulated metabolic anabolism, including increased SREBP-regulated lipid synthesis. These alterations, which mirror diabetes-associated human β-cell dysfunction, are partially reversed by acute mTOR inhibition with rapamycin. We propose SDH deficiency as a contributing mechanism to the progressive β-cell failure of diabetes and identify mTORC1 inhibition as a potential mitigation strategy.

Cardiolipin coordinates inflammatory metabolic reprogramming through regulation of Complex II disassembly and degradation

“…Gene-encoding components of Complex II are mutated in several types of cancer, including hereditary paraganglioma due at least in part to increased ROS production and cell proliferation ( 45 – 47 ). In β cells, deficiency in Complex II leads to metabolic dysfunction and diabetes in a mouse model of disease ( 48 ). A substantial body of evidence therefore points to Complex II as a critical regulatory nexus for metabolic reprogramming and accordingly positions it as a target of multiple layers of regulation.…”

IFI27 Integrates Succinate and Fatty Acid Oxidation to Promote Adipocyte Thermogenic Adaption

“…[38,39] Genetic Sdh gene mutation is tumorigenesis, and also implicated in neurodegeneration and diabetes. [40][41][42] Tumor cells associated with Sdh mutations shut down the TCA cycle, but oxidize more glutamine or increase pyruvate carboxylase-dependent pyruvate utilization to replenish TCA intermediates. [43,44] Compared to the SDH-deficient cells, adipocytes with Ifi27 deletion showed relatively minor metabolic remodeling possibly due to some remaining SDH activity.…”

Cardiolipin coordinates inflammatory metabolic reprogramming through regulation of Complex II assembly and stability

“…Genes encoding components of Complex II are mutated in several types of cancer, including hereditary paraganglioma due at least in part to increased ROS production and cell proliferation ( 31 – 33 ). In β-cells, deficiency in Complex II leads to metabolic dysfunction and diabetes in a mouse model of disease ( 34 ). A substantial body of evidence therefore points to Complex II as a critical regulatory nexus for metabolic reprogramming, and accordingly positions it as a target of multiple layers of regulation.…”

“…Our results further establish that cardiolipin, a key architect of homeostatic mitochondrial function, plays a prominent and distinct role in CII regulation, and possibly other respiratory complexes, during LPS-induced mitochondrial reprogramming that leads to inflammation.Metabolic reprogramming is implicated in the pathophysiology of many human diseases, with changes in respiratory chain function evident in many disease states. Genes encoding components of Complex II are mutated in several types of cancer, including hereditary paraganglioma due at least in part to increased ROS production and cell proliferation(31)(32)(33).In β-cells, deficiency in Complex II leads to metabolic dysfunction and diabetes in a mouse model of disease(34). A substantial body of evidence therefore points to Complex II as a critical regulatory nexus for metabolic reprogramming, and accordingly positions it as a target of multiple layers of regulation.…”