Metformin promotes mitophagy in mononuclear cells: a potential in vitro model for unraveling metformin's mechanism of action

Abstract

Increased oxidative stress in patients with type 2 diabetes mellitus (T2DM) results in abnormalities in cell repair processes, such as mitophagy, which compromises mitochondrial function and contributes to insulin resistance and β cell failure. Metformin, widely recommended in the management of T2DM, exerts its pleiotropic effects via 5ʹ‐AMP–activated protein kinase (AMPK); however, its effect on mitophagy remains elusive. Recent evidence demonstrates that peripheral blood mononuclear cells (PBMCs) express insulin receptors and the human organic cation transporter protein, and they are extensively being used as a surrogate for examining mitochondrial function in T2DM. Metformin treatment increased the formation of acidic vesicles and mitophagosomes, upregulated mitophagy markers, and enhanced mitophagic flux, as indicated by increased LC3‐II expression and reduced p62 protein levels. In addition, pretreatment with compound C (an AMPK inhibitor) significantly decreased the expression of mitophagy markers in metformin‐treated cells, indicating that metformin induces mitophagy via the AMPK pathway. In conclusion, metformin‐induced mitophagy may improve cellular function, including in β cells, by restoring normal mitochondrial phenotype, which may prove beneficial in patients with T2DM and other mitochondrial‐related diseases. Moreover, PBMCs may be used as a novel diagnostic biomarker for identifying mitochondrial disorders.

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

“…These findings suggest that metformin significantly influenced the process of mitophagy de novo, and this propitious effect was observed to be independent of its efficacy on glycaemic control, in contrast to voglibose. In line with our findings, our previous in vitro study revealed that there was an increased formation of mitophagosomes as well as enhanced mitophagic flux in mononuclear cells following metformin exposure …”

“…Our findings highlight that metformin caused a significant increase in p‐AMPKα (T172) levels, whereas voglibose did not display any effect on the same. Therefore, it is conceivable that metformin regulates mitophagy, which is mediated via the activation of the AMPK as also supported by our previous in vitro observations …”

“…11,21,22 Further, documentation of the presence of metformin transporter, that is human organic cation transporter 1 (hOCT1; also known as SLC22A1) on mononuclear cells, uncovers new vistas in elucidating the novel mechanistic insights into metformin's action in these cells. 23 Therefore, the present study aimed to assess the role of metformin in the modulation of mitophagy and NLRP3 in the mononuclear cells of drug-naïve patients with newly diagnosed T2DM (NDT2DM).…”

Diabetes Mellitus and Periodontitis Share Intracellular Disorders as the Main Meeting Point

“…Autophagy has different stages that are regulated directly by AMPK, where in its early stages it acts by activating Beclin-1 [85] and in parallel inactivating mTOR and phos-phorylating ULK1, a key autophagic initiator [82,85,97], and in the final stages stimulating the conversion from LC3-I to LC3-II [85]. The early stages of autophagy have been related to an enhancement of osteogenic differentiation of PDL stem cells, however in late stages this mechanism seems to be reduced, which may indicate a suppression of autophagic activity [85].…”

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

“…Metformin is a widely used antidiabetic drug that has been shown to extend lifespan in animal models of aging, and to increase human healthspan (251 -253). Metformin was also reported to activate mitophagy (254). It is known that metformin directly inhibits NADH dehydrogenase, and it was shown that this inhibition leads to inhibition of mPTP and protection from I/R damage (255 -257).…”