Mitochondrial Dysfunction In Cancer – Overview Of Its Importance
Mechanistic knowledge of how mitochondrial dysfunction in cancer leads to cell proliferation and carcinogenesis is emerging as an area of study under-explored in terms of its therapeutic implications.
Mitochondrial integrity is critical for effective cellular energy generation and cell survival in the face of environmental challenges such as food shortage and ischemia and genotoxic chemicals employed in cancer therapy.
How alterations in mitochondrial mass and function impact the underlying biology of cancer or dictate the clinical outcome for cancer patients stands out as a diagnostic and therapeutic opportunity that has yet to be explored.
- Mitochondria and the Warburg Effect: Otto Warburg developed a faulty mitochondria hypothesis to explain his discovery that tumor cells undergo greater aerobic glycolysis (the so-called "Warburg effect") compared to normal cells. While mutations in critical Krebs cycle enzymes support the idea that mitochondrial metabolism is essentially flawed in certain human malignancies, data shows that malfunctioning mitochondria are not the primary source of the Warburg effect. Instead, mounting data suggest that tumor cells have altered the expression and activity of essential Glycolytic enzymes.
- Mitochondrial Genome Mutations in Cancer: Although mitochondrial dysfunction may not always explain the Warburg effect, there is evidence that cancers acquire faulty mitochondria. Primary cancers feature homoplasmic abnormalities in the mitochondrial genome, associated with accelerated direct tumor development. Further evidence is that increased electron chain activity, particularly complex I activity, reduces breast tumor development and metastasis by maintaining high NAD+/NADH ratios.
- Mitochondrial Reactive Oxygen Species in Cancer: Reactive oxygen species (ROS) produced by oncogenes promotes carcinogenesis in various ways, including stabilizing hypoxia-inducible factor (HIF)-alpha and the generation of oxidative base damage to DNA. Elevated reactive oxygen species levels in tumor cells relative to normal cells have been used in experiments to destroy cancer cells selectively. For effectiveness, many contemporary genotoxic agents in clinical usage depend on reactive oxygen species generation. The harmful impact of highly reactive oxygen species on normal tissues is critically adverse to raising reactive oxygen species systemically in a therapeutic context.
- Mitochondria Are Extremely Dynamic: Mitochondria are highly dynamic organelles that adapt to cellular stress by altering their total mass, interconnectivity, and subcellular localization. Overall mitochondrial mass changes indicate a shift in the equilibrium between mitochondrial biogenesis (increased mitochondrial genome duplication associated with increased protein mass added to mitochondria) and mitophagy rates (degradation of mitochondria at the autophagosome). The degree of mitochondrial fusion determines the extent to which mitochondria are linked as a single continuous mitochondrial reticulum, while mitochondrial fission results in fragmented mitochondria with reduced overall dimensions.
COPYRIGHT_SZ: Published on https://stationzilla.com/mitochondrial-dysfunction-in-cancer/ by Alexander McCaslin on 2022-08-04T08:19:25.283Z
Mitochondria: How our ancient companion plays a role in cancer | Illumina SciMon Video
Essential proteins that govern cellular homeostasis influence mitochondrial fission and fusion. Inhibiting or removing these proteins prevents mitochondrial fusion and increases mitochondrial fragmentation.
Fission happens before mitosis but also when cells undergo mitophagy or apoptosis. Stress-induced mitochondrial hyperfusion increases ATP generation through more efficient oxidative phosphorylation (OXPHOS), suppresses mitophagy, and protects against apoptosis. Yorkie-mediated Opa-1 upregulation and mitochondrial fusion were necessary for proliferation and carcinogenesis in Drosophila.
The significance of mitochondrial fusion in controlling metabolism is crucial. Opa-1 deactivation reduces oxidative metabolism and cell growth.
In relatively short time periods, increased mitochondrial fusion has been demonstrated to boost OXPHOS. The respiratory chain's complex IV electron acceptor of choice is oxygen. Hypoxia inhibits OXPHOS in a variety of ways, one of which is the promotion of mitochondrial fission.
In tumor cells, increased fission has been associated with unregulated expression of Drp1 and Mfn2. Cyclin E expression is necessary for cell proliferation and entrance into S-phase. In this work, mitochondrial hyperfusion during the G1/S transition was necessary for cyclin E up-regulation.
Over-expression of cytokines was also necessary for replication stress, DNA damage, chromosomal instability, and genomic instability. Mitochondrial fusion may cause cytochrome c release and apoptosis to be delayed.
Mitochondrial fission and fusion proteins seem to control apoptosis through actions unrelated to mitochondrial dynamics but involving members of the Bcl-2 family. Bak and Bax are playing an increasing role in mitochondrial dynamics.
When triggered by pro-apoptotic signals, they oligomerize to create an OMM channel. Mcl-1 has been linked to mitochondrial dynamics through an amino-terminal truncated version found in the mitochondrial matrix.
Changes in mitochondrial biogenesis and mitophagy influence cell mitochondrial mass. Our findings show that mitochondrial mass varies significantly across cancers in different people.
Mitochondrial biogenesis entails the replication of the mitochondrial genome and the coordinated expression of gene products encoded by both the nuclear and mitochondrial genomes.
HIF-1 suppresses biogenesis via increasing c-myc degradation and activating Mxi-1. Melanoma patients treated with B-Raf inhibitors relied heavily on oxidative metabolism to survive.
Parkin has been demonstrated to increase hepatocyte lipid absorption via altering the turnover of the fatty acid binding protein CD36. The hypoxia-inducible genes BNIP3 and NIX are also involved in mitophagy promotion.
Autophagy inhibition may result in the buildup of faulty mitochondria, which release cytochrome c and activate the apoptosome. Mitophagy inhibition in combination with medications that generate other types of mitochondrial stress signals may be synergistic and aid in tumor cell death.
Mitochondrial dysfunction has been found to influence nuclear gene expression in many distinct ways. These include a decrease in membrane potential, abnormal respiration, problems with iron-sulfur cluster production, and abnormalities with the mitochondrial unfolded protein response.
In glioblastoma and AML, mutations in the genes encoding TCA cycle enzymes are associated with cancer development. These genes' substrates, fumarate, and succinate pile up when they are mutated in cancer.
Succinate and fumarate may covalently change important signaling molecules to control cell development. By rerouting the utilization of metabolites, tumor cells are able to survive IDH1, FH, or SDH-related abnormalities in the TCA cycle. Mitochondria are essential for maintaining healthy intracellular calcium levels.
High Ca2+-containing mitochondria quickly absorb the divalent cation. VDACs are regulated at several levels, including protein-protein interactions, post-translational modification, and expression levels.
Reactive oxygen signaling from mitochondria affects how cells grow and differentiate. One of the principal effects of malfunctioning mitochondria on the cell is dysregulated calcium homeostasis. Along with having an impact on cell motility and metabolism, NF-pro-tumorigenic B's functions also encourage resistance to apoptosis.
Numerous recognized tumorigenic consequences of HIF activity are exacerbated by increased reactive oxygen species, including enhanced angiogenesis, EMT, a switch to glycolytic metabolism, and priming of the pre-metastatic niche. A cell's response to mitochondrial malfunction in terms of cell proliferation and carcinogenesis is strongly influenced by NRF2 activity.
By encouraging metabolic reprogramming toward anabolic pathways, including g nucleotide production, NRF2 stabilization promotes the development of tumor cells. When activated by mitochondrial malfunction, AMPK plays a critical role in maintaining mitochondrial homeostasis and feeds back to encourage both mitochondrial biogenesis and mitophagy.
The amount of NAD+ in the mitochondria, which is in turn influenced by the mitochondrion's metabolic activity, affects the sensitivity of the mitochondrial sirtuins. A significant growth-promoting kinase, AKT prevents apoptosis when there is glucose and activates mTOR. additional-3, a cellular enzyme situated in the mitochondria, is also lated and inactive by AKT.
It is most likely related to AMPK's capacity to control mitochondrial metabolism that it is localized to the mitochondria. Under energy stress, AMPK's inhibition of ACC2 (and ACC1) increases NADPH homeostasis, promoting tumor cell survival, anchorage-independent growth, and tumor development.
The most frequently altered gene in human cancer is the p53 tumor suppressor gene. Many of p53's actions are due to its functioning as a nuclear-encoded gene transcriptional regulator. When normal p53 is activated in response to stress, it activates downstream target genes such as p21Waf1, which causes a G1 cell cycle arrest.
It has been discovered that p53 may govern cell growth mechanisms other than proliferation and death. Recent research has shown that p53 has a function in preventing the accumulation of damaged mitochondria in cancer.
Malic enzyme inhibition by p53 leads to much decreased NADPH generation necessary for lipid synthesis. P53 is a transcriptional activator of genes that influence mitochondrial turnover and metabolism. In the mitochondrial matrix, it has been found to interact directly with cyclophilin D.
P53 absorption by mitochondria was influenced by mitochondrial membrane potential and interactions with chaperones. The RB tumor suppressor gene is often lost in human retinoblastoma, osteosarcoma, and small cell lung cancer.
At late phases of disease development, some tumors retain functional RB. Together, pRB and E2Fs may influence metabolism and mitochondrial homeostasis genes.
Overexpression of the c-Myc oncogene is seen in more than 70% of all human malignancies. When Myc is inhibited/turned off, cancers regress swiftly. It remains to be seen if other mitochondrial roles for pRB can be identified.
Tumors rely on glutamine to produce ATP and lipids by reductive carboxylation at the mitochondria. Myc-driven tumor cells apoptosis when glutamine is removed. Myc controls glucose metabolism by activating necessary glycolytic enzymes.
KRas activation is one of the most common oncogenic events in the pancreatic, lung, and small intestine cancers. Tumors become more reliant on mitochondrial function as a result of Myc oncogenes. This might imply that Myc-dependent cancers are more vulnerable to mitophagy deficiencies.
Cancer mtDNA mutations may be classified into two types: tumorigenic and adaptive. Tumorigenic mutations include heteroplasmic insertion-deletion mutations, chain termination mutations, and missense mutations that modify highly conserved amino acids.
Mitochondrial dysfunction occurs when the mitochondria do not operate properly due to another illness or condition. Various diseases, including Alzheimer's, may cause secondary mitochondrial dysfunction. Dystrophy of the muscles
Physiologically, mitochondrial dysfunction is caused by environmental variables (such as some pharmaceutical medicines, occupational toxins, and cigarette smoke) or hereditary defects (of both mitochondrial and nuclear DNA).
Mitochondria play a crucial role in cancer via macromolecular synthesis and energy generation. Tumors with pathogenic mitochondrial DNA mutations are benign, but tumors with the benign mitochondrial genome and ETC function are malignant, showing the role of respiration in cancer development.
As the cell's primary energy source and metabolites, it comes to reason that mitochondrial activity is disrupted in cancer. There is rising interest in determining how altered mitochondrial function might be targeted to suppress tumor development.
New evidence points to essential oncogenes and tumor suppressors as modulators of several aspects of mitochondrial metabolism and dynamics.
Interestingly, depending on which oncogenic mutations drive the tumor, various tumor types may be more or less responsive to modification of mitochondrial activity. This novel is an intriguing development in the ongoing "battle against cancer."