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Metabolic Decisions in Development and Disease | EK27


Role of Ketoacids, Peroxinsomes, and Mitochondrial Dynamics In Carcinogenesis (Revisiting The Intermediary Matabolism)


Mar 27, 2021 12:00am ‐ Mar 27, 2021 12:00am

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Role of Ketoacids, Peroxinsomes, and Mitochondrial Dynamics In Carcinogenesis (Revisiting The Intermediary Matabolism) Lakshmipathi Vadlakonda. Professor (Retd.) Cell biology, Kakatiya University, Warangal -506609. E-Mail: lvadlakonda@gmail.com. Mobile No. +91 9866574751 (Present Residential address: DD colony, Hyderabad) Two recent articles published in JCI insight reported the role of ketone bodies in controlling the glycaemia and carcinogenesis. Fletcher et al (2019) reported that diminished ketogenic diets promoted hyperglycaemia (https://doi.org/10.1172/jci.insight.127737), and Ferrere et al. (2021) reported that ketogenic diets inhibited carcinogenesis in melanoma model (https://doi.org/10.1172/jci.insight.145207),. Besides, Fletcher et al. reported that impaired ketogenesis increased acetyl-CoA oxidation in the tricarboxylic acid (TCA) cycle but promoted gluconeogenesis, fatty liver, and hyperglycaemia. It opens a century-old debate between ketone bodies, ATP production, and mitochondrial respiration. We recently presented evidence that there are two models of citrate synthesis and two mitochondrial pyruvate carriers, which contradict the present model of TCA cycle (https://doi.org/10.1007/s40200-020-00566-5). We review the original model of TCA cycle proposed by Krebs and Johnson, and subsequent developments on citrate synthesis. A model is proposed that dietary LDL cholesterol (LDLc) activate cholesterol synthesis. Lanosterol, an intermediate of cholesterol biosynthesis pathway, ubiquitinates HMG-CoA reductase (HMGCR), activate the cholesterol synthesis upstream of mitochondrial metabolism. Phosphoglycerate kinase (PGK1) produces ATP in the cytoplasm, which activates the coenzyme A synthesis. Metabolism of the phytol derivatives, very long-chain fatty acids enhance the ketogenesis isoprenoid synthesis, which activates the mitochondrial respiratory chain assembly. HMGCoA reductase inhibitors activate the non-mevalonate pathway, cause the inflammation and insulin resistance. High fat and high sterol (HFHS) diets activate Stearoyl Coenzyme A desaturases (SCD1/SCD2) and bypass the mitochondrial metabolism, de novo fatty acid synthesis, and cause pathology. Citrate synthesis and mitochondrial metabolism is temporally regulated by fusion/fission dynamics of peroxisomes and mitochondria during G1 and G2 phase of the cell cycle progression in proliferating cells.

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