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Mitochondrial metabolism constitutes central metabolism of the 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 is produced. Most of the metabolic pathways, such as glucose metabolism through the citric acid cycle, fatty acid catabolism, metabolism of the carbon skeleton of amino acids all occur inside the mitochondria constituting mitochondrial metabolism.
It is well established that mitochondria are 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 their 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 the 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, 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 rest of the cell may cause different problems in the cellular homeostasis and even organismal dysfunction in higher organisms.
Any deregulation in the mitochondrial metabolism and its function has been related to the varieties of physiological disorders such as muscular degeneration, cardiovascular diseases, neurodegenerative disorders, and even cancer.
Dysfunction of mitochondria has historical relation with cancer that was much focused on defective mitochondrial metabolism. However, dysfunction of mitochondria to cancer goes more 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.
Defective TCA cycle enzymes related to various cancers
The citric acid (TCA) cycle is the central pathway of the 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. Increase 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 consumes the citrate to produce isocitrate and decrease the fatty acid biosynthesis.
Isocitrate dehydrogenase has been found that in B-acute lymphoblastic leukemia, prostate cancer, glioblastoma, NADPH-dependent isoforms of the mitochondrial isocitrate dehydrogenase are mutated. Mutated isocitrate dehydrogenase instead of converting isocitrate to α-ketoglutarate it converts α-ketoglutarate to R-enantiomer of 2-hydrooxyglutatate that is accumulated in the cancer cells.