title: Metformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53.
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.
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 03722 Seoul, Korea. ymsong1225@gmail.com.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Song
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 03722 Seoul, Korea. lewoky7@yuhs.ac.
authors.forename: Woo Kyung
authors.initials: WK
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 03722 Seoul, Korea. yholee@yuhs.ac.
authors.forename: Yong-Ho
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 03722 Seoul, Korea. edgo@yuhs.ac.
authors.forename: Eun Seok
authors.initials: ES
authors.lastname: Kang
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 03722 Seoul, Korea. bscha@yuhs.ac.
authors.forename: Bong-Soo
authors.initials: BS
authors.lastname: Cha
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 03722 Seoul, Korea. bwanlee@yuhs.ac.
authors.forename: Byung-Wan
authors.initials: BW
authors.lastname: Lee
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D031204:Caloric Restriction; D002470:Cell Survival / Q000187:drug effects; D004032:Diet; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D005234:Fatty Liver / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D063306:Mitophagy / Q000187:drug effects; D019308:Palmitic Acid / Q000494:pharmacology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D007004:Hypoglycemic Agents; D016159:Tumor Suppressor Protein p53; D019308:Palmitic Acid; D014050:Toluene; D008687:Metformin; C121565:pifithrin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose
keywords: Parkin; metformin; mitochondrial spheroid; mitophagy; p53