Over-Reduced State of Mitochondria as a Trigger of “β-Oxidation Shuttle” in Cancer Cells

Author:

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

Abstract

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.

Funder

Japanese Agency for Medical Research and Development

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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