Defective mitochondrial metabolism associated with the cancer

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Structure of a mitochondrion
Structure of a mitochondrion Credit: Kelvinsong via Common Wikimedia

Mitochondrial metabolism

Mitochondrial metabolism constitutes central metabolism where end products of the glucose, amino acids, and fats are catabolized through different routes and funneled into the citric acid cycle. Mitochondria are the powerhouse of the cell where most of the ATPs, the energy currency of the cell are produced. Most of the metabolic pathways, such as glucose metabolism through the citric acid cycle, fatty acid catabolism, and metabolism of the carbon skeleton of amino acids all occur inside the mitochondria constituting mitochondrial metabolism.

It is well established that mitochondria evolved from the hydrogen-producing eubacteria that were engulfed by the hydrogen-dependent archaebacteria. Their symbiotic relationship about 2 million years ago led them to be evolved into the eukaryotic cell. During the course of evolution, mitochondria lost most of the control over their self-regulation and transferred their control to the genomic DNA.

Now a day, mitochondria can perform only selected functions directed by their own DNA (mitochondrial DNA) such as the production of enzymes that are required for mitochondrial metabolism and communication with the rest of the parts of the cells and other cells.

Besides the role of the mitochondrion in central metabolism, it acts as a gatekeeper of the cell and regulates the cell viability, and programmed cell death, and also controls the nuclear functions by producing reactive oxygen species, modulating the calcium levels, etc. Therefore, any deviation in the coordination between mitochondria and the rest of the cell may cause different problems in cellular homeostasis and even organismal dysfunction in higher organisms.

Any deregulation in mitochondrial metabolism and its function has been related to a variety of physiological disorders such as muscular degeneration, cardiovascular diseases, neurodegenerative disorders, and even cancer.

The dysfunction of mitochondria has historical relation with cancer that was much focused on defective mitochondrial metabolism. However, the dysfunction of mitochondria in cancer goes beyond the metabolism because mitochondrial dysfunction arises due to different mutations either in the nuclear or in the mitochondrial DNA. These mutations lead to the production of defective key metabolic enzymes that can initiate different cellular reprogramming responsible for the formation and growth of the tumor.

Mitochondrial metabolism; Different enzymes of the TCA cycle are related to various types of cancers
Different enzymes of the TCA cycle are related to various types of cancers. Image: Gaude and Christian, 2014

Defective TCA cycle enzymes related to various cancers

The citric acid (TCA) cycle is the central pathway of mitochondrial metabolism that is a topic of interest in the field of oncology. Enzymes of the TCA cycle are encoded by the nuclear DNA and are located in the mitochondrial matrix (except for the succinate dehydrogenase that is embedded in the inner mitochondrial membrane). It has been reported that several enzymes of the TCA cycles are associated with different types of inherent and sporadic types of cancer.

Citrate synthase has been found overexpressed in pancreatic adenocarcinoma and renal oncocytoma. However, it has also been found deregulated in various cell lines of cervical cancer. Increased expression of citrate synthase leads to the overproduction of citrate that can be utilized for the biosynthesis of fatty acids as in pancreatic cancer while decreased expression of the citrate synthase triggers the glycolysis to support tumor growth.

Aconitate hydrolase or aconitase plays an important role in prostate cancer. In normal prostate cells, aconitase is inhibited by zinc leading to the accumulation of citrate while in prostate cancer cells the activity of aconitase is restored leading that constantly consuming the citrate to produce isocitrate and decrease fatty acid biosynthesis.

Isocitrate dehydrogenase has been found in B-acute lymphoblastic leukemia, prostate cancer, glioblastoma, and NADPH-dependent isoforms of the mitochondrial isocitrate dehydrogenase are mutated. Mutated isocitrate dehydrogenase instead of converting isocitrate to α-ketoglutarate converts α-ketoglutarate to R-enantiomer of 2-hydrooxyglutatate that is accumulated in the cancer cells.

Succinate dehydrogenase (complex II) is the only enzyme that is a part of the TCA cycle, as well as the respiratory chain, and it is fully encoded by nuclear DNA. It is found to be mutated in different types of cancers such as gastrointestinal stromal tumors, breast cancer, renal carcinoma, etc. Succinate dehydrogenase-deficient cells accumulate succinate that inhibits the pyruvate dehydrogenase complex as well as DNA and histone demethylases leading to epigenetic changes in the cancerous cell.

Fumarate hydratase is found to be mutated in hereditary leiomyomatosis and renal cell cancer (HLRCC). It is also found to be downregulated in glioblastoma and sporadic clear-cell carcinoma. Fumarate in the same way as succinate inhibits several enzymes such as pyruvate dehydrogenase complex, histone, and DNA demethylases.

Different enzyme complexes of the electron transport chain associated with various cancers
Different enzyme complexes of the electron transport chain are associated with various cancers. Image: Gaude and Christian, 2014

Defective enzymes of the electron transport chain

Mitochondrial DNA is circular double-stranded DNA with 16596 base pairs. It contains 37 genes that can be translated into 13 subunits of the enzymes of the electron transport chain and ATP complex, 22 tRNAs, and 12S and 16S ribosomal RNAs. Mitochondrial DNA mutation can coexist with normal mitochondrial DNA in a heterogeneous form called heteroplasmy. Mitochondrial mutations can lead to several defects related to bioenergetics from mild mitochondrial dysfunction to several impairments and even cell death. Mitochondrial mutations are associated with a wide range of cancers such as colon cancer, breast cancer, lung cancer liver, and pancreatic cancer.

Complex I or NADH: ubiquinone oxidoreductase catalyzes the transfer of two electrons from NADH to ubiquinone via FMN and it also promotes the transfer of 4 protons from the matrix to the intermembrane space. It is the first electron carrier in the electron transport chain that produces reactive oxygen species.

Therefore, mutations in the mitochondrial gene encoding the complex I are associated with the development of colon cancer, thyroid, and pancreatic cancer, and many more types of cancers. Mutant complex-I is also associated with the increase in ROS-dependent metastasis of lung carcinoma, breast cancer, etc. The main contribution of the mutant complex-I depends on the corresponding dysfunctional bioenergetics.

Complex III or coenzyme Q: cytochrome c oxidoreductase of cytochrome bc1 is the third enzyme of the electron transport chain that reduces the ubiquinone to cytochrome c and pumps out 4 protons from the matrix to the intermembrane space. Mutant complex III is also associated with different cancers such as colorectal cancer, ovarian cancer, thyroid cancer, bladder cancer, etc. where it exerts its effect by lactate secretion, increased production of ROS, and resistance to the NF-ĸB2 pathway-activated apoptosis.

Complex IV or cytochrome c oxidase is the terminal complex of the electron transport chain that is composed of 12 subunits. Subunits I, II, and III are encoded by the mitochondrial DAN while the rest are encoded by nuclear DNA. Complex IV catalyzes the conversion of molecular oxygen into water while pumping 4 protons from the matrix to the intermembrane space. It is also associated with cancers such as mutant subunit I (COX1) of complex IV is linked with ovarian cancer and prostate cancer while nuclear DNA-encoded subunits are normally upregulated in cancers.

Complex V or ATP synthase is the end enzyme of oxidative phosphorylation, but it is not part of the electron transport chain. It catalyzes the phosphorylation of the ADP to ATP. During the pumping out of the protons from the matrix to the intermembrane space, an electrochemical gradient is created. To maintain the electrochemical gradient, protons are transported back into the matrix through the complex V during which ATPs are synthesized from the ADP.

It has been found that mutations in the complex V subunits are associated with various cancers such as thyroid cancer, pancreatic cancer, and prostate cancer. Mutant ATP synthase (complex v) is also associated with reduced programmed cell death (reduced apoptosis). Though ATP synthase is not related to the transport of electrons, its inhibition can lead to the leakage of electrons from the electron transport chain.

Reference: Cancer and Metabolism (Defects in mitochondrial metabolism and cancer)

Article DOI: 10.1186/2049-3002-2-10

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