Journal Article

Metformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53

Lee, Byung-Wan, Kang, Eun, Song, Young, Lee, Yong-ho, Lee, Woo, Cha, Bong-Soo

2016

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Animals / Benzothiazoles - pharmacology / Caloric Restriction / Cell Survival - drug effects / Diet / Drug therapy / Endoplasmic Reticulum Stress - drug effects / Endoplasmic Reticulum Stress - genetics / Fatty Liver - drug therapy / Fatty Liver - genetics / Fatty Liver - metabolism / Fatty Liver - pathology / Gene Expression Regulation / Glucose - pharmacology / Hep G2 Cells / Humans / Hypoglycemic Agents - pharmacology / Liver diseases / Metformin - pharmacology / Mice / Mice, Obese / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondria - ultrastructure / Mitochondrial Degradation - drug effects / Palmitic Acid - pharmacology / Phosphates / Signal Transduction / Sirtuin 1 - genetics / Sirtuin 1 - metabolism / Toluene - analogs & derivatives / Toluene - pharmacology / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism