Mitochondrial Dysfunction Promotes Diabetes via A Previously Unrecognized Mechanism: Protein Succinylation

Abstract

Mitochondrial dysfunction is a central contributor to the development of β‐cell failure and Type 2 Diabetes (T2D). Succinate dehydrogenase subunit B (SDHB) is a key component of the Succinate Dehydrogenase (SDH) protein complex that strongly impacts mitochondrial function via 1) oxidation of succinate to fumarate in the TCA cycle and 2) electron transfer in the electron transport chain as Complex II. Loss of SDH activity has been observed in diabetic β‐cells (humans and rodents); however, the relevance of this observation to diabetes pathogenesis remains poorly understood. Consistent with prior work, we found reduced SDHB expression in the pancreatic islets of human diabetics. To investigate the links between mitochondrial dysfunction, β‐cell failure and diabetes, we generated mice with a β‐cell‐specific knockout of SDHB (SDHBβKO). We found that SDHBβKO mice develop early onset diabetes. At 5 weeks, prediabetic SDHBβKO mice demonstrate mildly elevated glucose levels with low insulin levels and normal insulin sensitivity. These in vivo findings were confirmed by a reduction in glucose‐stimulated insulin secretion in SDHBβKO islets. Furthermore, glucose‐induced β‐cell replication was impaired in SDHBβKO mice; consistent with impaired adaptive β‐cell expansion. Given the prominent role of glucose metabolism in controlling β‐cell insulin secretion and replication, we assessed the mitochondrial bioenergetics by Seahorse Assay and found that basal and glucose‐stimulated respiration were significantly reduced in SDHBβKO islets. Notably, loss of SDH is expected to increase succinate accumulation and promote protein succinylation, a recently described bulky post‐translational modification. Indeed, SDHBβKO islets demonstrated a dramatic increase in succinate levels (16‐fold) and protein succinylation (6‐fold), providing a potential mechanism for global mitochondrial dysfunction. Accordingly, expression of the desuccinylation enzyme, Sirt5, was increased in SDHBβKO islets. Metabolomics by mass spectrometry and transcriptomics by high‐throughput RNA sequencing revealed significantly altered mitochondrial metabolism. Finally, protein succinylation levels were increased in islets of diabetic db/db mice indicating lysine‐succinylation may be characteristic of diabetes. Taken together, these results demonstrate a surprisingly necessary role for the SDH complex in β‐cell function and introduce a pathogenic mechanism of diabetes based upon β‐cell metabolic dysfunction.Support or Funding InformationStanford Diabetes Research Center (SRDC) Pilot & Feasibility Grants Program (P30DK116074), Endocrinology Training grant (T32DK007217) and Child Health Research Institute at Stanford (UL1TR001085)