Editors' ChoiceMetabolism

A New Target in Diabetes

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Science Signaling  04 Mar 2014:
Vol. 7, Issue 315, pp. ec65
DOI: 10.1126/scisignal.2005235

Mitochondrial dysfunction in insulin-secreting β cells is a pathological feature of type 1 and type 2 diabetes. The transcription factor p53 promotes mitochondrial genomic integrity, but the accumulation of cytosolic p53, which can occur in response to metabolic stress, disrupts the clearance of dysfunctional mitochondria (mitophagy) mediated by Parkin. Hoshino et al. investigated the role of p53 in mitochondrial dysfunction in two animal models of diabetes using mice lacking p53 in islet β cells. Compared with wild-type counterparts, p53-deficient mice treated with streptozocin (STZ, which induces experimental type 1 diabetes) showed decreased hyperglycemia, preserved serum insulin concentrations, and improved glucose tolerance, as well as increased oxygen consumption in islet cells and insulin secretion in response to glucose injections. Electron microscopy showed that p53-deficient β cells from STZ-treated mice had increased incorporation of mitochondria into autophagosomes and decreased numbers of abnormal mitochondria compared with wild-type counterparts. Inhibition of p53 with injections of pifithrin-α (PFT-α) increased insulin secretion, oxygen consumption, and autophagic clearance of dysfunctional mitochondria in wild-type db/db mice (a model of type 2 diabetes) similar to the extent seen in p53-deficient STZ-treated mice. Knocking down Parkin in islet β cells in either p53-deficient or PFT-α–treated mice did not improve mitochondrial integrity or glucose-induced insulin secretion. Knocking down p53 in MIN6 β cells overexpressing GFP-tagged light chain 3 (LC3), a marker of autophagy, preserved the colocalization between LC3 and mitochondria and the fusion between lysosomes and mitochondria compared with wild-type cells in response to glucose. Furthermore, p53 knockdown preserved insulin secretion and increased adenosine triphosphate (ATP) production in MIN6 cells in response to glucose. Parkin knockdown or genetic or pharmacological inhibition of mitophagy abolished the protective effects of p53 knockdown in MIN6 cells. These findings suggest that p53 disrupts Parkin-mediated mitophagy and insulin secretion in β cells. The abundance of p53 in islets from STZ-treated or db/db mice was unchanged in total but was increased in the cytosol and decreased in the nucleus compared with controls. In MIN6 β cells, endogenous p53 and Parkin interacted, and this interaction was increased in the cytosolic fraction in response to glucose. Treating cells with LiCl, an inhibitor of glycogen synthase kinase 3β (which is implicated in diabetes), decreased the cytosolic translocation of p53 and improved insulin secretion. The findings suggest that preventing the translocation of p53 in β cells may be therapeutic in diabetes.

A. Hoshino, M. Ariyoshi, Y. Okawa, S. Kaimoto, M. Uchihashi, K. Fukai, E. Iwai-Kanai, K. Ikeda, T. Uemaya, T. Ogata, S. Matoba, Inhibition of p53 preserves Parkin-mediated mitophagy and pancreatic β-cell function in diabetes. Proc. Nat. Acad. Sci. USA 111, 3116–3121 (2014). [Abstract] [Full Text]

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