Abstract
Cancer metabolism is an extensively studied field since the discovery of the Warburg effect about 100 years ago and continues to be increasingly intriguing and enigmatic so far. It has become clear that glycolysis is not the only abnormally activated metabolic pathway in the cancer cells, but the same is true for the fatty acid synthesis (FAS) and mevalonate pathway. In the last decade, a lot of data have been accumulated on the pronounced mitochondrial fatty acid oxidation (mFAO) in many types of cancer cells. In this article, we discuss how mFAO can escape normal regulation under certain conditions and be overactivated. Such abnormal activation of mitochondrial β-oxidation can also be combined with mutations in certain enzymes of the Krebs cycle that are common in cancer. If overactivated β-oxidation is combined with other common cancer conditions, such as dysfunctions in the electron transport complexes, and/or hypoxia, this may alter the redox state of the mitochondrial matrix. We propose the idea that the altered mitochondrial redox state and/or inhibited Krebs cycle at certain segments may link mitochondrial β-oxidation to the citrate-malate shuttle instead to the Krebs cycle. We call this abnormal metabolic condition “β-oxidation shuttle”. It is unconventional mFAO, a separate metabolic pathway, unexplored so far 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. 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 pathway.
Highlights
The discussion of cancer cell metabolism always begins with Warburg’s first unified theory of cancer about 100 years ago [1, 2]
We propose the idea that many mysteries about the peculiarities of cancer cell metabolism, including respiration and even hypoxia, seem less inexplicable in the light of incomplete “combustion” of fatty acids in mitochondria
We propose the idea that elevated levels of ATP and NADH do not have this power to inhibit mitochondrial fatty acid oxidation (mFAO) itself and the part of mFAO preceding the Krebs cycle—β-oxidation
Summary
The discussion of cancer cell metabolism always begins with Warburg’s first unified theory of cancer about 100 years ago [1, 2]. The main postulate in this theory is the huge consumption of glucose in the tumor tissue, accompanied by the production of lactate, and this characteristic is attributed to the cancer cells themselves Warburg wrote that this distinctive feature is the result of “irreversibly impaired respiration” and lists many respiratory inhibitors that cause cancer [2]. The presumption is that cells do not necessarily have to use the same fatty acids for β-oxidation that they have synthesized This model indicates that the energy stored by NADPH must be utilized primarily for lipid synthesis, to maintain the “β-oxidation shuttle” and mitochondrial function, not so much for ATP synthesis, but for synthesis of aspartate and citrate. Just to clarify that the article is focused only on mitochondrial β-oxidation
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