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.
Highlights
A thorough understanding of the molecular machineries involved in the underlying pathophysiology and pharmacodynamics are crucial to the treatment of metabolic disorders including fatty liver disease
These results indicate the involvement of p53 in the significant decrease in Parkin-dependent mitophagy observed under diabetic conditions
We studied the interplay of metformin in mitophagy and p53 abundance
Summary
A thorough understanding of the molecular machineries involved in the underlying pathophysiology and pharmacodynamics are crucial to the treatment of metabolic disorders including fatty liver disease. Of the intracellular organelles involved in this underlying pathophysiologic mechanism, the degradation of dysfunctional mitochondria and the reciprocal biogenesis of mitochondria, i.e., mitophagy, are areas of debate and investigation [2,3]. AedlthinouHghetphGer2e wcealslslitsttleabcoly-lotcraalnizsafteiocnted with between mitochondria and autophagosomes in the 0.25 mM palmitate-treated HepG2 cells, LC3-. Scpalaelbmarit=a2te0-μtrme.ated HepG2 cells, LC3-labeled structures were seen surrounding the fragmented mitochondria in cells treated with 0.5 mM metformin and 0.25 mM palmitate. HepG2 cells ectopically expressing GFP-LC3 exhibited an increase in the number of punctate GFP-LC3 structures upon exposure to 0.5 mM metformin. LC3-labeled structures were found surrounding the fragmented mitochondria in cells treated with metformin and palmitate, there was little co-localization between mitochondria and autophagosomes in cells treated with 0.25 mM palmitate alone (Figure 1B)
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