Understanding the complex-I-ty of metformin action: limiting mitochondrial respiration to improve cancer therapy

Abstract

Metformin has been a first-line treatment for type II diabetes mellitus for decades and is the most widely prescribed antidiabetic drug. Retrospective studies have found that metformin treatment is associated with both reduced cancer diagnoses and cancer-related deaths. Despite the prevalence of metformin use in the clinic, its molecular mechanism of action remains controversial. In a recent issue of Cancer & Metabolism, Andrzejewski et al. present evidence that metformin acts directly on mitochondria to inhibit complex I and limits the ability of cancer cells to cope with energetic stress. Here, we discuss evidence that supports the role of metformin as a cancer therapeutic.

Figure 1

Indirect and direct effects of metformin on tumors. Metformin can suppress tumor progression by modulating metabolic whole body physiology or by acting directly on cancer cells. Metformin diminishes hepatic glucose output leading to lower systemic glucose and insulin levels, which could impair malignant growth indirectly without requiring accumulation of metformin in the tumor. Alternatively, metformin can act on cancer cells directly, inhibiting cancer progression by suppressing mTOR signaling, mitochondrial glucose oxidation, and/or reducing stability of HIF under hypoxic conditions.

Figure 2

Cellular consequences of metformin action at the mitochondria. Metformin enters the cell by organic cation transporter 1 (OCT1), where it then accumulates in the mitochondria. There, metformin inhibits complex I of the electron transport chain and mGDP, resulting in decreased NADH oxidation. Decreased electron chain activity suppresses tricarboxylic acid (TCA) cycle flux and decreases mitochondrial ATP synthesis. These actions result in increased AMPK signaling, decreased cAMP/PKA signaling, decreased gluconeogenesis and increased glycolysis.