Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I*

By M. El-Mir, V. Nogueira, É. Fontaine, N. Avéret, M. Rigoulet, X. Leverve. Journal of Biological Chemistry, 2000

1,410 citations recorded by the source corpus.

We report here a new mitochondrial regulation occurring only in intact cells. We have investigated the effects of dimethylbiguanide on isolated rat hepatocytes, permeabilized hepatocytes, and isolated liver mitochondria. Addition of dimethylbiguanide decreased oxygen consumption and mitochondrial membrane potential only in intact cells but not in permeabilized hepatocytes or isolated mitochondria. Permeabilized hepatocytes after dimethylbiguanide exposure and mitochondria isolated from dimethylbiguanide pretreated livers or animals were characterized by a significant inhibition of oxygen consumption with complex I substrates (glutamate and malate) but not with complex II (succinate) or complex IV (N,N,N′,N′-tetramethyl-1,4-phenylenediamine dihydrochloride (TMPD)/ascorbate) substrates. Studies using functionally isolated complex I obtained from mitochondria isolated from dimethylbiguanide-pretreated livers or rats further confirmed that dimethylbiguanide action was located on the respiratory chain complex I. The dimethylbiguanide effect was temperature-dependent, oxygen consumption decreasing by 50, 20, and 0% at 37, 25, and 15 °C, respectively. This effect was not affected by insulin-signaling pathway inhibitors, nitric oxide precursor or inhibitors, oxygen radical scavengers, ceramide synthesis inhibitors, or chelation of intra- or extracellular Ca2+. Because it is established that dimethylbiguanide is not metabolized, these results suggest the existence of a new cell-signaling pathway targeted to the respiratory chain complex I with a persistent effect after cessation of the signaling process.

Subfields: Endocrine and Autonomic Systems, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/65ff25f7f79cf6c88f5e96fb5ca1631f2fd4d890

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Citations in the corpus

Cellular and molecular mechanisms of metformin: an overview. (2012, background): “In addition, it seems that mitochondrial action of metformin requires intact cells [22, 29, 30] and is prevented, at least in hepatocytes, neither by inhibition of nitric oxide synthase nor by various reactive oxygen species (ROS)”
Metformin: from mechanisms of action to therapies. (2014, background): “It was also shown that the inhibitory effect of metformin on complex 1was not prevented by nitric oxide (NO) synthase inhibitors or reactive oxygen species (ROS) scavengers (El-Mir et al., 2000) and was independent of AMPK, at least in primary mouse hepatocytes (Stephenne et al., 2011).”
AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. (2005, background): “Both metformin (El-Mir et al., 2000) and thiazolidinediones (Brunmair et al.”
The mechanisms of action of metformin (2017, background): “The most intensively studied mitochondrial action of metformin is the inhibition of Complex I of the respiratory chain [14, 16], which suppresses ATP production.”
Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. (2007, background): “Because treatment with metformin has been reported to inhibit respiratory chain complex I in hepatocytes (31, 32), the rate of oxygen consumption in intact cells after treatment with metformin was measured.”
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).”
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).”
Targeting cancer metabolism: a therapeutic window opens (2011, background): “Metformin is widely used for the treatment of type 2 diabetes and acts by inhibiting mitochondrial complex I in the liver to interfere with ATP productio”
Role of AMP-activated protein kinase in mechanism of metformin action. (2001, background): “Although some have reported that very high metformin concentrations (10 mM) can suppress total cellular ATP levels (25, 33), Owen et al.”
Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status (2016, neutral): “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.”
Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity (2017, neutral): “…from ARC neurons to the PVN not only play a role in the regulation of food intake, but also in energy expenditure: POMC neurons increase (Enriori et al., 2011) while AgRP/NPY neurons decrease (Shi et al., 2013) metabolic activity in BAT (for reviews, see Waterson and Horvath, 2015;…”
The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level (2008, background): “, 2002), but instead appear to inhibit complex I of the respiratory chain leading to an increase in AMP:ATP ratio (El-Mir et al., 2000).”