MitoNEET-Parkin effects in pancreatic α- and β-cells, cellular survival, and intrainsular cross talk

Christine Kusminski, Shiuhwei Chen, Risheng Ye, Kai Sun, Qiong A. Wang, Stephen B. Spurgin, Phillip E. Sanders, Joseph T. Brozinick, Werner J. Geldenhuys, Wen-Hong Li, Roger H Unger, Philipp E Scherer

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Mitochondrial metabolism plays an integral role in glucose-stimulated insulin secretion (GSIS) in β-cells. In addition, the diabetogenic role of glucagon released from α-cells plays a major role in the etiology of both type 1 and type 2 diabetes because unopposed hyperglucagonemia is a pertinent contributor to diabetic hyperglycemia. Titrating expression levels of the mitochondrial protein mitoNEET is a powerful approach to fine-tune mitochondrial capacity of cells. Mechanistically, β-cell-specific mitoNEET induction causes hyperglycemia and glucose intolerance due to activation of a Parkin-dependent mitophagic pathway, leading to the formation of vacuoles and uniquely structured mitophagosomes. Induction of mitoNEET in α-cells leads to fasting-induced hypoglycemia and hypersecretion of insulin during GSIS. MitoNEET-challenged α-cells exert potent antiapoptotic effects on β-cells and prevent cellular dysfunction associated with mitoNEET overexpression in β-cells. These observations identify that reduced mitochondrial function in α-cells exerts potently protective effects on β-cells, preserving β-cell viability and mass.

Original languageEnglish (US)
Pages (from-to)1534-1555
Number of pages22
JournalDiabetes
Volume65
Issue number6
DOIs
StatePublished - Jun 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Kusminski, C., Chen, S., Ye, R., Sun, K., Wang, Q. A., Spurgin, S. B., Sanders, P. E., Brozinick, J. T., Geldenhuys, W. J., Li, W-H., Unger, R. H., & Scherer, P. E. (2016). MitoNEET-Parkin effects in pancreatic α- and β-cells, cellular survival, and intrainsular cross talk. Diabetes, 65(6), 1534-1555. https://doi.org/10.2337/db15-1323