Repurposing metformin for cardioprotection: mechanisms and therapeutic potential across cardiovascular pathologies

Figures

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  FIGURE 1. Mechanism by which low-dose Metformin activates AMPK. Clinically relevant concentrations (micromolar) of metformin directly bind to PEN2 on the lysosomal membrane, inducing a conformational change that enables PEN2 to interact with ATP6AP1, an accessory subunit of the lysosomal proton pump v-ATPase, inhibiting its activity. v-ATPase inhibition leads to a conformational change in the v-ATPase-Ragulator complex, facilitating lysosomal translocation of AXIN, which recruits and serves as a scaffold for LKB1. Once recruited to the lysosomal membrane, LKB1 phosphorylates AMPK, leading to its activation.

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  FIGURE 2. Proposed mechanism by which low-dose Metformin reduces hepatic glucose production. Clinically relevant concentrations (micromolar) of metformin inhibit complex IV of the electron transport chain. When complex IV is inhibited, electrons cannot be efficiently transferred to the final electron acceptor, oxygen, causing upstream complexes to become overwhelmed with electrons. The resulting ETC backlog inhibits the activity of GPD2, as GPD2 donates its electrons (from the reduction of FAD to FADH2) to the oxidized form of CoQ10 (ubiquinone, Q) to generate the reduced form (ubiquinol, QH2). Indirect inhibition of GPD2 results in reduced conversion of G3P to DHAP, resulting in reduced glycerol-derived gluconeogenesis. Further, impaired GPD2 function disrupts the glycerol-phosphate shuttle, leading to an increased cytosolic redox state (NADH:NAD), which inhibits the activity of LDH, thereby reducing lactate-derived gluconeogenesis.