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Int. J. Mol. Sci. 2016, 17(1), 122; doi:10.3390/ijms17010122

Metformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53

1
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 03722 Seoul, Korea
2
Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 03722 Seoul, Korea
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Masato Matsuoka
Received: 9 November 2015 / Revised: 13 January 2016 / Accepted: 13 January 2016 / Published: 16 January 2016
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress)
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Abstract

Metformin is known to alleviate hepatosteatosis by inducing 5’ adenosine monophosphate (AMP)-kinase-independent, sirtuin 1 (SIRT1)-mediated autophagy. Dysfunctional mitophagy in response to glucolipotoxicities might play an important role in hepatosteatosis. Here, we investigated the mechanism by which metformin induces mitophagy through restoration of the suppressed Parkin-mediated mitophagy. To this end, our ob/ob mice were divided into three groups: (1) ad libitum feeding of a standard chow diet; (2) intraperitoneal injections of metformin 300 mg/kg; and (3) 3 g/day caloric restriction (CR). HepG2 cells were treated with palmitate (PA) plus high glucose in the absence or presence of metformin. We detected enhanced mitophagy in ob/ob mice treated with metformin or CR, whereas mitochondrial spheroids were observed in mice fed ad libitum. Metabolically stressed ob/ob mice and PA-treated HepG2 cells showed an increase in expression of endoplasmic reticulum (ER) stress markers and cytosolic p53. Cytosolic p53 inhibited mitophagy by disturbing the mitochondrial translocation of Parkin, as demonstrated by immunoprecipitation. However, metformin decreased ER stress and p53 expression, resulting in induction of Parkin-mediated mitophagy. Furthermore, pifithrin-α, a specific inhibitor of p53, increased mitochondrial incorporation into autophagosomes. Taken together, these results indicate that metformin treatment facilitates Parkin-mediated mitophagy rather than mitochondrial spheroid formation by decreasing the inhibitory interaction with cytosolic p53 and increasing degradation of mitofusins. View Full-Text
Keywords: mitophagy; p53; Parkin; mitochondrial spheroid; metformin mitophagy; p53; Parkin; mitochondrial spheroid; metformin
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Song, Y.M.; Lee, W.K.; Lee, Y.-H.; Kang, E.S.; Cha, B.-S.; Lee, B.-W. Metformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53. Int. J. Mol. Sci. 2016, 17, 122.

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