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Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro
Abstract
As a class, the biguanides induce lactic acidosis, a hallmark of mitochondrial impairment. To assess potential mitochondrial impairment, we evaluated the effects of metformin, buformin and phenformin on: 1) viability of HepG2 cells grown in galactose, 2) respiration by isolated mitochondria, 3) metabolic poise of HepG2 and primary human hepatocytes, 4) activities of immunocaptured respiratory complexes, and 5) mitochondrial membrane potential and redox status in primary human hepatocytes. Phenformin was the most cytotoxic of the three with buformin showing moderate toxicity, and metformin toxicity only at mM concentrations. Importantly, HepG2 cells grown in galactose are markedly more susceptible to biguanide toxicity compared to cells grown in glucose, indicating mitochondrial toxicity as a primary mode of action. The same rank order of potency was observed for isolated mitochondrial respiration where preincubation (40 min) exacerbated respiratory impairment, and was required to reveal inhibition by metformin, suggesting intramitochondrial bio-accumulation. Metabolic profiling of intact cells corroborated respiratory inhibition, but also revealed compensatory increases in lactate production from accelerated glycolysis. High (mM) concentrations of the drugs were needed to inhibit immunocaptured respiratory complexes, supporting the contention that bioaccumulation is involved. The same rank order was found when monitoring mitochondrial membrane potential, ROS production, and glutathione levels in primary human hepatocytes. In toto, these data indicate that biguanide-induced lactic acidosis can be attributed to acceleration of glycolysis in response to mitochondrial impairment. Indeed, the desired clinical outcome, viz., decreased blood glucose, could be due to increased glucose uptake and glycolytic flux in response to drug-induced mitochondrial dysfunction.
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“Metformin exerts only weak anti-proliferative effects on an array of cancer cell lines and patient-derived melanoma cells when cells are kept in nutrient-rich conditions (Figure S1A) (Dykens et al., 2008).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Dykens et al., 2008
In the citing paper
“It is also worthy of note that the IC50 for metformin to inhibit mitochondrial complex 1 is 19–66 mM (140, 141).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [140]
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Background
Metadata
- Authors
- Dykens, J. A., Jamieson, J., Marroquin, L., Nadanaciva, S., Billis, P. A., & Will, Y.
- Affiliations
- Pfizer (United Kingdom) (GB)
- Pfizer (United States) (US)
- Corresponding author
- Dykens, James A.
- Venue
- Toxicology and Applied Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 233
- Issue
- 2
- Pages
- 203-210
- ISSN
- 0041-008X (ISSN-L)
- OpenAlex
- W1997224005
- Cited by
- 220
- References
- 35
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 9 · 2023: 7 · 2022: 14 · 2021: 17 · 2020: 13 · 2019: 16 · 2018: 19 · 2017: 11 · 2016: 15 · 2015: 12 · 2014: 17 · 2013: 9 · 2012: 15
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology and Applied Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- biguanides, metformin, buformin, phenformin, mitochondrial dysfunction, lactic acidosis, hepatotoxicity, HepG2 cells, human hepatocytes, galactose metabolism, mitochondrial respiration, mitochondrial membrane potential, reactive oxygen species, glutathione, glycolysis, cytotoxicity, drug-induced liver injury
- MeSH terms
- Acidosis, Lactic, Animals, Blood Glucose, Buformin, Cell Line, Cell Survival, Culture Media, Glutathione, Glycolysis, Humans, Hypoglycemic Agents, Male, Metformin, Mitochondria, Liver, Oxidation-Reduction, Phenformin, Rats, Sprague-Dawley, Reactive Oxygen Species, Cell Respiration, Lactic Acid, Hepatocytes, Rats, Membrane Potential, Mitochondrial
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