Mitochondrial dysfunction in cancer

Abstract

Mitochondria are semi-autonomous organelles of eukaryotic cells. They perform crucial functions such as generating most of the cellular energy through the oxidative phosphorylation (OXPHOS) system and some other metabolic processes. In addition, mitochondria are involved in regulation of cell death and reactive oxygen species (ROS) generation. Also, mitochondria play important roles in carcinogenesis via altering energy metabolism, resistance to apoptosis, increase of production of ROS and mtDNA (mitochondrial genome) changes. Studies have suggested that aerobic glycolysis is high in malignant tumors. Probably, it correlates with high glucose intake of cancerous tissues. This observation is contrary to Warburg's theory that the main way of energy generation in cancer cells is non-oxidative glycolysis. Further studies have suggested that in tumor cells both oxidative phosphorylation and glycolysis were active at various rates.An increase of intracellular oxidative stress induces damage of cellular structure and somatic mutations. Further studies confirmed that permanent activity of oxidative stress and the influence of chronic inflammation damage the healthy neighboring epithelium and may lead to carcinogenesis. For instance, chronic inflammatory bowel disease could be related to high risk of colon adenocarcinoma.The data have shown a role of ROS generation, mtDNA or nDNA alterations and abnormal apoptotic machinery in endometrial cancer progress. Recent studies suggest that mtDNA mutations might play a potential role in endometrial cancer progress and indicate an increase of mitochondrial biogenesis in this cancer. The investigators suggested that MtCOI and MtND6 alteration has an influence on assembly of respiratory complexes in endometrial cancer.In many human cancers, there is a deregulation of the balance between cell growth and death. The tumor cells can avoid apoptosis through a loss of balance between anti- and pro-apoptotic proteins, reduced caspase function and impaired death receptor signaling. Over-expression of the anti-apoptotic BCL-2 gene has also been identified in numerous cancers including colon, thyroid, breast and endometrial cancer. Most studies have found low BCL-2 family gene expression, which could be a sign of blocking apoptosis in breast and endometrial cancer. Moreover, BCL-2 gene expression is correlated with the degree of aggressiveness and differentiation in endometrial cancer. As a result, it could be a valuable predictor of disease progression.

Cytochrome c1 in ductal carcinoma in situ of breast associated with proliferation and comedo necrosis

“…It is known that proliferating carcinoma cells preferentially use anaerobic glycolysis rather than OXPHOS for energy production, and the metabolic alteration is commonly referred to as the Warburg effect . Although efficiency of ATP synthesis in aerobic glycolysis is much lower compared to OXPHOS, the glycolytic pathway can provide precursors for biomolecules necessary for proliferation . Indeed, Sato‐Tadano et al .…”

“…In our present in vitro study, MCF10DCIS.com cells transfected with siRNA against CYC1 significantly decreased pro‐apoptotic caspase 3 activity under anaerobic conditions compared to normoxia. Mitochondrial OXPHOS also regulates apoptosis and enhanced OXPHOS function increased intracellular oxidative stress and apoptosis . Ducts in DCIS are frequently enlarged beyond 200 μm in diameter, although diffusion of oxygen from periductal vessels into ducts is limited to 100 μm, suggesting that the center of DCIS becomes poorly oxygenated .…”

“…(34) Although efficiency of ATP synthesis in aerobic glycolysis is much lower compared to OXPHOS, the glycolytic pathway can provide precursors for biomolecules necessary for proliferation. (8,35) Indeed, Sato-Tadano et al (15) showed that immunoreactivity of hexokinase II, which is involved in the rate-limiting step of glycolysis, was detected in 44% of invasive breast carcinomas and it was a potent worse prognostic factor. However, both OXPHOS and glycolysis are active inside tumor cells at various rates; for instance, the contribution of OXPHOS to the total cellular energy was 80% in MCF-7 breast carcinoma cells.…”

Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

“…[54] Malfunctions in mitochondrial activities are associated with neurodegenerative diseases,s uch as Parkinsonsa nd Alzheimers. [56] With several exceptions,t housands of mitochondria are found in each eukaryotic cell and al arge portion of the cytoplasm is occupied by this organelle. [56] With several exceptions,t housands of mitochondria are found in each eukaryotic cell and al arge portion of the cytoplasm is occupied by this organelle.…”

Isolation of functional mitochondria by inertial microfluidics – a new method to sort intracellular organelles from a small scale biological sample

“…For instance, isolation of mitochondria, the so-called "power houses" of the cells, may help to investigate the anabolic and catabolic processes in which the mitochondria are involved. [1][2][3] Elucidating the functions of mitochondria in detail is particularly important since defective mitochondria have been linked to several important human diseases including cancers, [4][5][6] premature aging syndromes, 7 diabetes 8,9 and neurodegenerative disorders. 10,11 To this end, it becomes imperative to develop a platform capable of isolating functional mitochondria particularly from a small amount of sample, since in practice clinical samples are oen limited in size.…”