Over-Reduced State of Mitochondria as a Trigger of "β-Oxidation Shuttle" in Cancer Cells.

Zhivko Zhelev,Ichio Aoki,Tatyana Vlaykova,Tatsuya Higashi,Dessislava Lazarova,Rumiana Bakalova,Akira Sumiyoshi

doi:10.3390/cancers14040871

Abstract

Simple SummaryThis review proposes the idea that many peculiarities of the cancer cell metabolism are easier to explain considering the incomplete combustion of fatty acids in the cancerous mitochondria due to their over-reduced redox state. Recent studies indicate that overactivated mitochondrial β-oxidation may significantly alter the mitochondrial redox state and vice versa. Thus, the impaired redox state of cancerous mitochondria can ensure the continuous operation of β-oxidation by disconnecting it from the Krebs cycle and connecting it to the citrate–malate shuttle. This could create a new metabolic state/pathway in cancer cells, which we have called the “β-oxidation shuttle”. This artificial pathway is inefficient as an energy source. However, when combined with acetyl-CoA consuming pathways, such as fatty acid synthesis and mevalonate pathways, it is a source of cataplerosis, leading to biomass accumulation, accelerated oxygen consumption, and, ultimately, a source of proliferation.A considerable amount of data have accumulated in the last decade on the pronounced mitochondrial fatty acid oxidation (mFAO) in many types of cancer cells. As a result, mFAO was found to coexist with abnormally activated fatty acid synthesis (FAS) and the mevalonate pathway. Recent studies have demonstrated that overactivated mitochondrial β-oxidation may aggravate the impaired mitochondrial redox state and vice versa. Furthermore, the impaired redox state of cancerous mitochondria can ensure the continuous operation of β-oxidation by disconnecting it from the Krebs cycle and connecting it to the citrate–malate shuttle. This could create a new metabolic state/pathway in cancer cells, which we have called the “β-oxidation-citrate–malate shuttle”, or “β-oxidation shuttle” for short, which forces them to proliferate. The calculation of the phosphate/oxygen ratio indicates that it is inefficient as an energy source and must consume significantly more oxygen per mole of ATP produced when combined with acetyl-CoA consuming pathways, such as the FAS and mevalonate pathways. The “β-oxidation shuttle” is an unconventional mFAO, a separate metabolic pathway that has not yet been explored as a source of energy, as well as a source of cataplerosis, leading to biomass accumulation, accelerated oxygen consumption, and, ultimately, a source of proliferation. The role of the “β-oxidation shuttle” and its contribution to redox-altered cancer metabolism provides a new direction for the development of future anticancer strategies. This may represent the metabolic “secret” of cancer underlying hypoxia and genomic instability.

Highlights

Over the last decade, mitochondrial fatty acid oxidation (mFAO) has been found to be activated under conditions common to solid tumors and cancer cells
This review proposes the idea that many “mysteries” about the peculiarities of cancer cell metabolism, including respiration and even hypoxia, seem easier to explain in the light of the incomplete combustion of fatty acids in cancerous mitochondria
This study showed that mitochondrial function is important for the survival of cancer cells, this does not mean that the production of mitochondrial ATP is the only vital factor

Summary

Mitochondrial β-Oxidation

May Inhibit Pyruvate Combustion and Complex I via Acetylation of Mitochondrial Proteins. In 2015, Lantier et al demonstrated that muscles in SIRT3-deficient mice exhibit profound mitochondrial dysfunction with decreased reliance on glycolytic substrates and increased reliance on fatty acid substrates [36]. The authors observed that respiration decreases in the muscle fibers of SIRT3-deficient mice when malate-glutamate substrate is used, while oxygen consumption is significantly higher with malate palmitoyl-carnitine substrate These studies are consistent with the idea that fatty acid catabolism could antagonize glucose catabolism by acetylating mitochondrial proteins. It has been reported that the antagonism between fatty acid catabolism and glucose catabolism in a high-fat diet does not depend only on decreased SIRT3 expression and/or activity [37–39]. CrAT-deficiency increases tissue acetyl-CoA levels and susceptibility to diet-induced lysine acetylation of broad-spectrum mitochondrial proteins, which is accompanied by decreased whole-body glucose control [39]. CrAT was found to be responsible for the export of excess acetyl-CoA from the mitochondrial matrix, and CrAT-knockout mice (CrAT−/−) showed a similar over-acetylated phenotype as SIRT3-knockout mice (SIRT3−/−)

Over-Reduced State of Mitochondria Can Inhibit the Krebs Cycle but

Reductive Carboxylation, Over-Reduced State of Mitochondrial Matrix, and Krebs Cycle Impairments

Definition of the “β-Oxidation Shuttle” and Its Components

Findings

Conclusions