Fusion can help mutated mitochondria to recover the loss of function by utilizing the genetic material of fusion partner
Fusion can help mutated mitochondria to recover the loss of function by utilizing the genetic material of fusion partner. observed. A stylish alternative way to target the mitochondria in cancer cells is the induction of an adaptive immune response against mutated mitochondrial proteins. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all actions of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial DNA mutations or Tumor Associated Mitochondria Antigens using the immune system. (Translational Research 2018; 202:3551) MITOCHONDRIA: THE POWERHOUSE OF THE CELL Mitochondria are essential organelles derived from endosymbiotic bacteria, necessary for cellular activity. They are an exceptional example of natural selection, as the host allowed their coevolution since most of the mitochondrial proteins are encoded by the nuclear genome. Mitochondria, however, retain a small 16 Kb DNA genome that encodes tRNAs, rRNAs, and proteins essential for respiration.1 Indeed, they are the powerhouse of the cell. These organelles are maternally inherited with 1 cell made up of hundreds of mitochondria that can be wild-type (a state referred to as homoplasmy) or exist in mixtures of wild-type and mutant Methylprednisolone forms (heteroplasmy) dependently around the mtDNA.2 The system regulating turnover of mitochondria is known as mitophagy, a mechanism by which damaged Methylprednisolone or excess mitochondria are selectively eliminated. Mitophagy is accompanied by the balance of fission (the separation of long, tubular mitochondria into 2 or more smaller parts) and fusion (the combination of two mitochondria into a single organelle).3 As the powerhouse of the cell, mitochondria are essential bioenergetic and biosynthetic factories critical for normal cell function. They use substrates from cytoplasm to drive fatty acid oxidation (FAO), the tricarboxylic acid cycle or the Krebs cycle, the electron transport chain (ETC), and respiration, to synthesize the molecules essential for the construction of macromolecules including amino acids, lipids, nucleotides, heme, and iron-sulfur clusters, and to regenerate reduced nicotinamide adenine dinucleotide phosphate for antioxidant defense.2 Reducing agents NADH and hydroquinone form of flavin adenine dinucleotide (FADH2), produced by Krebs cycle, are indispensable Methylprednisolone and allow, by the ETC, generation of a proton gradient throughout the mitochondrial inner membrane (cristae) that generates adenosine triphosphate (ATP) by way of the H+-ATP synthase enzyme. This enzyme allows protons to cross the membrane in a single direction, according to the process of chemiosmosis.4 This metabolic pathway is called oxidative Methylprednisolone phosphorylation (OXPHOS), in which cells oxidize nutrients to produce ATP. During this mechanism, electrons are transferred from electron donors to electron acceptors, such as molecular oxygen, in the redox reaction. The reduction of oxygen can potentially produce harmful intermediates called reactive oxygen species (ROS), like superoxide or peroxide anions. Cytochrome c oxidase, complex IV, can, however, ameliorate these by-products by reducing oxygen to water.5 The OXPHOS mechanism is highly efficient with 36 ATP molecules as the maximum yield from an initial glucose molecule.6 MITOCHONDRIA AND Malignancy Tumor cell phenotypes are characterized by genetic alterations driving the expression of 10 main characteristics: genetic instability, sustaining proliferative signaling, evading growth suppressors, avoiding immune destruction, sustain promoting inflammation resisting cell death, enabling replicative immortality, inducing angiogenesis, deregulating cellular energetics, activating invasion, and metastasis.7 Warburg observed that cancer cells can reprogram their metabolism by switching from oxidative phosphorylation to glycolysis and consequently to lactic acid fermentation, even in the presence of oxygen, leading to a state that has been termed aerobic glycolysis.8 Unlike the high energy yield of OXPHOS, the conversion of a glucose molecule Rabbit Polyclonal to CDC40 into lactate leads to the low-energy yield with the formation of only 2.