Cardiolipin content is involved in liver mitochondrial energy wasting associated with cancer-induced cachexia without the involvement of adenine nucleotide translocase

Julienne, Cloé Mimsy; Tardieu, M.; Chevalier, Stéphan; Pinault, Michelle; Bougnoux, Philippe; Labarthe, François; Couet, Charles; Servais, Stéphane; Dumas, Jean‐François

doi:10.1016/j.bbadis.2014.02.003

Cited by 32 publications

(30 citation statements)

References 25 publications

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“…In addition, we cannot exclude a role of imeglimin preventing other deleterious effects of oxidative stress, as previously reported (28,29). Cardiolipin content increases in mitochondrial membranes could contribute to the increase in the respiration rate during overfeeding because cardiolipins are known to induce nonphosphorylating energy wasting in mitochondria (16,30). Increases in ATP synthase and ANT content could also amplify mitochondrial respiration.…”

Section: Discussionmentioning

confidence: 79%

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Imeglimin Normalizes Glucose Tolerance and Insulin Sensitivity and Improves Mitochondrial Function in Liver of a High-Fat, High-Sucrose Diet Mice Model

et al. 2014

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Imeglimin is the first in a new class of oral glucose-lowering agents currently in phase 2b development. Although imeglimin improves insulin sensitivity in humans, the molecular mechanisms are unknown. This study used a model of 16-week high-fat, high-sucrose diet (HFHSD) mice to characterize its antidiabetic effects. Six-week imeglimin treatment significantly decreased glycemia, restored normal glucose tolerance, and improved insulin sensitivity without modifying organs, body weights, and food intake. This was associated with an increase in insulin-stimulated protein kinase B phosphorylation in the liver and muscle. In liver mitochondria, imeglimin redirects substrate flows in favor of complex II, as illustrated by increased respiration with succinate and by the restoration of respiration with glutamate/malate back to control levels. In addition, imeglimin inhibits complex I and restores complex III activities, suggesting an increase in fatty acid oxidation, which is supported by an increase in hepatic 3-hydroxyacetyl-CoA dehydrogenase activity and acylcarnitine profile and the reduction of liver steatosis. Imeglimin also reduces reactive oxygen species production and increases mitochondrial DNA. Finally, imeglimin effects on mitochondrial phospholipid composition could participate in the benefit of imeglimin on mitochondrial function. In conclusion, imeglimin normalizes glucose tolerance and insulin sensitivity by preserving mitochondrial function from oxidative stress and favoring lipid oxidation in liver of HFHSD mice.

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Section: Discussionmentioning

confidence: 79%

“…Because mitochondrial phospholipids protect and control the activity of OXPHOS complexes (16)(17)(18)(19), liver mitochondrial membrane lipid composition was analyzed.…”

Section: Effect Of Imeglimin On Mitochondrial Phospholipid Contentmentioning

confidence: 99%

Imeglimin Normalizes Glucose Tolerance and Insulin Sensitivity and Improves Mitochondrial Function in Liver of a High-Fat, High-Sucrose Diet Mice Model

et al. 2014

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“…A decline in cardiolipin content has been reported with age, and this is associated with biochemical and functional alterations in many components of the mitochondrial ETC, resulting in reduced efficiency of electron transport, inhibition of oxidative phosphorylation (OXPHOS), and increased leakage of reactive oxygen species (ROS) 23 , 24 , 25 . Alterations in cardiolipin have also been reported in a variety of pathological conditions, including ischemia–reperfusion injury, heart failure, skeletal muscle weakness, neurodegenerative diseases, traumatic brain injury, diabetes, and cancer cachexia 26 , 27 , 28 , 29 . In many of these disorders, mitochondria have been found to be swollen, with loss of cristae membranes.…”

Section: Cardiolipin As a Drug Targetmentioning

confidence: 99%

Serendipity and the Discovery of Novel Compounds That Restore Mitochondrial Plasticity

Szeto

Birk

2014

Clin Pharmacol Ther

160

144

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The mitochondrial electron transport chain (ETC) plays a central role in energy generation in the cell. Mitochondrial dysfunctions diminish adenosine triphosphate (ATP) production and result in insufficient energy to maintain cell function. As energy output declines, the most energetic tissues are preferentially affected. To satisfy cellular energy demands, the mitochondrial ETC needs to be able to elevate its capacity to produce ATP at times of increased metabolic demand or decreased fuel supply. This mitochondrial plasticity is reduced in many age-associated diseases. In this review, we describe the serendipitous discovery of a novel class of compounds that selectively target cardiolipin on the inner mitochondrial membrane to optimize efficiency of the ETC and thereby restore cellular bioenergetics in aging and diverse disease models, without any effect on the normal healthy organism. The first of these compounds, SS-31, is currently in multiple clinical trials.

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“…However, liver mass increase in colorectal cancer patients has been shown to correlate with increased energy expenditure, 94 increased expression of UCPs. 80 Furthermore, inefficient oxidative phosphorylation, primarily related to an increased mitochondrial cardiolipin accumulation, 96 has been identified ex vivo in liver hepatocytes from a cachectic rat model of peritoneal carcinoma, 97 indicating a direct involvement of liver tissue in cachexia.…”

Section: Introductionmentioning

confidence: 99%

Understanding cachexia as a cancer metabolism syndrome

2016

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Metabolic reprogramming occurs in tumors to foster cancer cell proliferation, survival and metastasis, but as well at a systemic level affecting the whole organism, eventually leading to cancer cachexia. Indeed, as cancer cells rely on external sources of nitrogen and carbon skeleton to grow, systemic metabolic deregulation promoting tissue wasting and metabolites mobilization ultimately supports tumor growth. Cachectic patients experience a wide range of symptoms affecting several organ functions such as muscle, liver, brain, immune system and heart, collectively decreasing patients' quality of life and worsening their prognosis. Moreover, cachexia is estimated to be the direct cause of at least 20% of cancer deaths. The main aspect of cachexia syndrome is the unstoppable skeletal muscle and fat storage wasting, even with an adequate caloric intake, resulting in nutrient mobilization – both directly as lipid and amino acids and indirectly as glucose derived from the exploitation of liver gluconeogenesis – that reaches the tumor through the bloodstream. From a metabolic standpoint, cachectic host develops a wide range of dysfunctions, from increased insulin and IGF-1 resistance to induction of mitochondrial uncoupling proteins and fat tissue browning resulting in an increased energy expenditure and heat generation, even at rest. For a long time, cachexia has been merely considered an epiphenomenon of end-stage tumors. However, in specific tumor types, such as pancreatic cancers, it is now clear that patients present markers of tissue wasting at a stage in which tumor is not yet clinically detectable, and that host amino acid supply is required for tumor growth. Indeed, tumor cells actively promote tissue wasting by secreting specific factors such as parathyroid hormone-related protein and micro RNAs. Understanding the molecular and metabolic mediators of cachexia will not only advance therapeutic approaches against cancer, but also improve patients' quality of life.

show abstract

Cardiolipin content is involved in liver mitochondrial energy wasting associated with cancer-induced cachexia without the involvement of adenine nucleotide translocase

Cited by 32 publications

References 25 publications

Imeglimin Normalizes Glucose Tolerance and Insulin Sensitivity and Improves Mitochondrial Function in Liver of a High-Fat, High-Sucrose Diet Mice Model

Imeglimin Normalizes Glucose Tolerance and Insulin Sensitivity and Improves Mitochondrial Function in Liver of a High-Fat, High-Sucrose Diet Mice Model

Serendipity and the Discovery of Novel Compounds That Restore Mitochondrial Plasticity

Understanding cachexia as a cancer metabolism syndrome

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