Metformin Affects Heme Function as a Possible Mechanism of Action

Abstract

Metformin elicits pleiotropic effects that are beneficial for treating diabetes, as well as particular cancers and aging. In spite of its importance, a convincing and unifying mechanism to explain how metformin operates is lacking. Here we describe investigations into the mechanism of metformin action through heme and hemoprotein(s). Metformin suppresses heme production by 50% in yeast, and this suppression requires mitochondria function, which is necessary for heme synthesis. At high concentrations comparable to those in the clinic, metformin also suppresses heme production in human erythrocytes, erythropoietic cells and hepatocytes by 30–50%; the heme-targeting drug artemisinin operates at a greater potency. Significantly, metformin prevents oxidation of heme in three protein scaffolds, cytochrome c, myoglobin and hemoglobin, with Kd values < 3 mM suggesting a dual oxidation and reduction role in the regulation of heme redox transition. Since heme- and porphyrin-like groups operate in diverse enzymes that control important metabolic processes, we suggest that metformin acts, at least in part, through stabilizing appropriate redox states in heme and other porphyrin-containing groups to control cellular metabolism.

A Cytoplasmic Heme Sensor Illuminates the Impacts of Mitochondrial and Vacuolar Functions and Oxidative Stress on Heme-Iron Homeostasis in Cryptococcus neoformans

“…The effects of the drug include positive influences on mitochondrial respiration and activation of the 5= AMP-activated protein kinase. Recent work also indicates that MET suppresses heme production in yeast, erythrocytes, erythropoietic cells, and hepatocytes and that the drug acts to influence the redox states of heme (66). The same study and earlier work (88) indicated that ART had an even greater activity in suppressing heme levels.…”

“…For example, metformin (MET) (1,1-dimethylbiguanide hydrochloride) is an FDA-approved drug for the treatment of type 2 diabetes mellitus, and MET also has antifungal activity ( 63 – 65 ). MET suppresses the production of heme in yeast cells, and the suppression involves functional mitochondria ( 66 , 67 ). The activity of the antimalarial drug artemisinin (ART) may involve an antimitochondrial influence as well as the generation of ROS in a heme-dependent manner ( 68 – 70 ).…”

“…Given the reported influence of MET on heme production ( 66 ), we examined the effects of the drug on the heme sensor response and heme levels in more detail. By microscopy, we observed a reduction in the cytosolic heme pool when WT hs cells were grown in 40 or 100 mM MET for 16 h, with the ratio of eGFP/mKATE2 increased by nearly 25% at the highest concentration of metformin compared to that under the control condition ( Fig.…”

“…We therefore employed the heme sensor in C. neoformans to obtain additional evidence that the FDA-approved drugs MET and ART have heme-related activities and could potentially be repurposed as antifungal agents. The mode of action of MET is somewhat controversial, but the drug is known to suppress hepatic glucose production and improve hyperglycemia in diabetics ( 66 , 87 , 88 ). The effects of the drug include positive influences on mitochondrial respiration and activation of the 5′ AMP-activated protein kinase.…”

Commentary: Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration—A Mass Spectrometry Imaging Study of the Perfused Rat Liver

“…Alshawi and Agius (2018) report that metformin (0.1-5 mM) does not inhibit mGPD in permeabilized rodent hepatocytes. Li et al (2018) discovered that cytochrome C reduction, used as the activity reporter for mGPD in one of the assays by Madiraju et al (2014), is inhibited by metformin in a concentration-dependent (0.2-2.5 mM) manner.…”