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 5'-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.
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