Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.

By Mark R. Owen, E. Doran, A. Halestrap. Biochemical Journal, 2000

2,146 citations recorded by the source corpus.

Subfields: Molecular Biology, Physiology, Surgery

View Paper: https://www.semanticscholar.org/paper/94ca7c91d9ba320c14790626fc1d49898f16c5b0

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Citations in the corpus

Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis (2014, positive): “The positive charge of metformin has been proposed to account for it is accumulation within the matrix of mitochondria that exhibit a robust inner mitochondria membrane potential (Owen et al., 2000).”
AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. (2011, background): “…from reports that some of these compounds inhibit mitochondrial ATP synthesis by inhibiting either complex I of the respiratory chain (e.g., metformin [El-Mir et al. 2000; Owen et al. 2000] or berberine [Turner et al. 2008]) or complex V, the ATP synthase (e.g., resveratrol) (Gledhill et al. 2007).”
AMP‐activated protein kinase – development of the energy sensor concept (2006, background): “Both appear to do this indirectly by inhibiting complex I of the respiratory chain (El-Mir et al. 2000; Owen et al. 2000; Brunmair et al. A green arrow indicates activation, whereas a red line with a bar at the end indicates inhibition.”
Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status (2016, positive): “The most likely cellular effect underlying this response is inhibition of mitochondrial enzymes, including complex I in the electron transport chain.(10,11) More recently, mitochondrial glycerophosphate dehydrogenase has been suggested as an alternative target.”
The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. (2002, background): “The plasma concentrations of metformin in patients treated with the drug are estimated to be 10–20 mol/l, although higher concentrations may be reached in the portal vein (20).”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “Treatment with the antidiabetic drug metformin, an inhibitor of complex 1 of the mitochondrial electron transport chain (El-Mir et al., 2000; Owen et al., 2000), is especially toxic to p53-deficient tumor cells (Buzzai et al., 2007).”
An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis (2015, background): “This lipophilic biguanide inhibits complex I of the ETC (Birsoy et al., 2014; Owen et al., 2000; Wheaton et al., 2014) and only mildly slowed proliferation at the concentration used (Figure 1A).”
Metformin-associated lactic acidosis: Current perspectives on causes and risk. (2016, background): “, reduced lactate clearance) [25,26], and/or in the presence of”
Role of AMP-activated protein kinase in mechanism of metformin action. (2001, background): “(32) pointed out that more subtle changes in the free ATP/ADP ratio might occur with concentrations of metformin that do not suppress total ATP, but do inhibit gluconeogenesis.”
A Comprehensive Review of Drug–Drug Interactions with Metformin (2015, background): “L an so p ra zo le H ea lt h y su b je ct s (2 0 ) ? 1 7 ? 1 5 1 3 3 0 m g si n g le d o se 1 g o n d ay 1 an d 7 5 0 m g o n d ay 2 O C T 2 in h ib it io n [5 4 ]”