Abstract
Mitochondrion, a maternally hereditary, subcellular organelle, is the site of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS)—the basic processes of ATP production. Mitochondrial function plays a pivotal role in the development and pathology of different cancers. Disruption in its activity, like mutations in its TCA cycle enzymes, leads to physiological imbalances and metabolic shifts of the cell, which contributes to the progression of cancer. In this review, we explored the different significant mutations in the mitochondrial enzymes participating in the TCA cycle and the diseases, especially cancer types, that these malfunctions are closely associated with. In addition, this paper also discussed the different therapeutic approaches which are currently being developed to address these diseases caused by mitochondrial enzyme malfunction.
Highlights
Mitochondrion is a maternally hereditary, subcellular organelle which plays a role in bioenergetics, biosynthesis, and cell signaling [1]
Carbon sources entering the tricarboxylic acid (TCA) cycle in the mitochondrial matrix produce NADH and FADH2, which transfer their electrons to the electron transport chain (ETC) located in the inner mitochondrial membrane (IMM) [5]
R-2HG produced by mutant isocitrate dehydrogenase (IDH) in low-grade glioma was shown to activate the mammalian target of rapamycin signaling pathway, which is important for cell growth and metabolism [36]
Summary
Mitochondrion is a maternally hereditary, subcellular organelle which plays a role in bioenergetics, biosynthesis, and cell signaling [1]. The human mitochondrial proteome is composed of a subset of ~20,000 distinct mammalian proteins which are localized in the said organelle Thirteen of these proteins are encoded by mitochondrial DNA (mtDNA) and the rest are encoded by nuclear DNA (nDNA) [2]. Carbon sources entering the tricarboxylic acid (TCA) cycle in the mitochondrial matrix produce NADH and FADH2, which transfer their electrons to the electron transport chain (ETC) located in the IMM [5]. In the ETC system, the electrons transferred from NADH/FADH2 to oxygen induce an oxidation-reduction reaction at each step, and energy from the oxidized electron is utilized to pump protons from the mitochondrial matrix into the intermembrane space through complex I (NADH dehydrogenase), complex III (CoQH2-cytochrome c reductase), and complex IV (cytochrome c oxidase) [6].
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