Cancer’s Metabolic Puzzle: Unraveling Oxidative Phosphorylation — Part 5 of 5
By Eva Fata
This is 5th Part in a 5 Part Series I’ve written comparing cellular respiration in normal cells versus cancer cells. In this part, I will be exploring oxidative phosphorylation (OXPHOS) in cancer cells. For all parts, please see the links at the bottom of this article.
Oxidative Phosphorylation in Cancer Cells
In cancer cells, oxidative phosphorylation is often dysregulated. Many cancer cells rely on aerobic glycolysis even in the presence of oxygen which diminishes the reliance on oxidative phosphorylation for ATP production. Mitochondrial dysfunction which is often seen in cancer cells can also impair the oxidative phosphorylation efficiency contribute to the increased production of ROS and promote tumorigenesis.
I will break it into these categories mitochondria-related changes in cancer cells, and oxidative phosphorylation abnormalities in cancer cells.
Mitochondria-related Changes in Cancer Cells
Studies have shown that proliferating cancer cells prioritize the generation of biomass over maximizing their ATP production through complete glucose oxidation. Glycolysis in the cytoplasm generates ATP inefficiently, it does provide the metabolic substances which are needed for biosynthesis which supports rapid cell proliferation. It is important to know that only a portion of ATP which is required by cancer cells is gained through glycolysis typically ranging from 40% to 75%. The remaining is synthesized in the mitochondria through the citric acid cycle and oxidative phosphorylation. The availability of metabolic resources can influence the modulation of mitochondrial oxidative capacity in cancer cells. Studies have shown that altering the composition of the culture medium like replacing glucose with glutamine can encourage the increased expression of oxidative phosphorylation proteins. In HeLa cells for example, changing glucose to glutamine led to a boost in energy production from glutamine which suggests that cancer cells can adapt their mitochondrial oxidative capacity based on the availability of metabolic fuels.
Furthermore, the metabolic reprogramming that is observed in cancer cells involves many alterations in various metabolic pathways which help support their demands of rapid proliferation and survival. Evidence of this can be seen in glioblastoma cells where the flow of the citric acid cycle is supported by α-ketoglutarate through anaplerotic pathways using glutamine along with acetyl group which are sourced from pyruvate dehydrogenase reactions, which originate from sources other than glucose.
These metabolic changes are driven by genetic alterations and environmental conditions which trigger cancer cells to synthesize molecules which are essential for their survival, growth and proliferation. This includes the production of ribose and NADPH for nucleotide synthesis, as well as glycerol-3-phosphate for phospholipid production. NADPH plays a critical role in the macromolecular synthesis and redox control and cancer cells use multiple pathways to sustain its production. Other than the pentose phosphate pathway, cytosolic isocitrate dehydrogenases and malic enzymes contribute to NADPH production in cancer cells. As a result of these metabolic adaptations, many cancer cells will therefore exhibit reduced oxidative phosphorylation in the mitochondria. This reduction can be further seen in the reduced flow within the citric acid cycle, compromised mitochondrial respiration or both. Furthermore, the reduced oxygen availability because of an inadequate blood supply (hypoxia) further worsens the decrease in mitochondrial function.
HK-II
Hexokinase 2 (HK-II) is often upregulated in many tumours. The expression level and enzyme kinetics of HK-II play crucial roles in dictating the metabolic outcome of glucose in cancer cells. HK-II catalyzes the phosphorylation of glucose using ATP generated by mitochondrial oxidative phosphorylation. This process interlinks glycolysis with ATP synthesis which allows for cancer cells to maintain higher rates of glycolysis while also producing ATP for cellular processes. HK-II also contributes to the biosynthesis of molecules which are required for cell proliferation. By diverting glucose metabolism, HK-II provides different molecules for pathways which are involved in nucleotide, lipid and amino acid biosynthesis which further supports the rapid growth of cancer cells.
Other Changes
Cancer cells often have reduced oxidation of substrates mainly those which are linked to NADH. This alteration can disrupt the normal flow fi electrons through the mitochondrial respiratory chain which affects ATP production and cellular energy balance.
Changes in expression levels and activity of components of the mitochondrial respiratory change are often observed in cancer cells. The disruption of the respiratory chain complexes can impair oxidative phosphorylation and contribute to the metabolic reprogramming of cancer cells.
Cancer cells often have increased production of ROS within the mictorodontia. ROS can damage the cellular components and contribute to genomic instability which can further drive tumorigenesis.
Mutations in mtDNA (mitochondrial DNA) are often seen in many types of cancer and can impact mitochondrial function. These mutations can affect electron transport chain activity, impair mitochondrial biogenesis and contribute to metabolic dysregulation in cancer cells.
Mitochondria play a crucial role in apoptosis regulation, and therefore changes in mitochondrial metabolism can affect apoptotic signalling pathways in cancer cells. The dysregulation of apoptosis allows cancer cells to evade cell death and promote survival and proliferation.
Oxidative Phosphorylation Abnormalities in Cancer Cells.
Respiratory chain complexes and ATP synthase
The oxidative phosphorylation system consists of the respiratory chain complexes and ATP synthase which play a critical role in cellar energy metabolism by generating ATP through the transfer of electrons along the electron transport chain (ETC) and the subsequent phosphorylation of ADP to ATP by ATP synthase. In cancer cells, alterations in the composition and activity of these complexes have been detected which can contribute to mitochondrial dysfunction and metabolic reprogramming.
Respiratory Chain Complexes
Complex I (NADH dehydrogenase) is responsible for the transfer of electrons from NADH to ubiquinone (Coenzyme Q) and is the largest complex in the respiratory chain. Studies have reported significant decreases in both activity and protein content of Complex I in certain types of cancer like renal oncocytomas and thyroid oncocytomas. Such decreases in Complex I activity have also been associated with specific mutations in the mitochondrial DNA gene like ND1 which encodes a subunit of Complex I.
ATP Synthase
ATP synthase also known as Complex V is responsible for ATP synthesis by using the proton gradient which is generated by the electron transport chain. Complex I, the dysregulation of ATP synthase activity and expression may contribute to mitochondrial dysfunction and altered energy metabolism in cancer however more research is needed.
The low content of ATP synthase is commonly seen in renal cell carcinomas which suggests that the mitochondria may be structurally and functionally compromised. However, it is also possible that these structural alterations in ATP synthase could allow a functional advantage to cancer cells with deficient respiratory chains by reserving the transmembrane electrical potential. Sometimes the reduced levels of ATP synthase may impact cancer cell metabolism as well. Studies have outlined specific alterations in the expression of the F1-ATPase β subunit (a component of ATP synthase) in tumours in different tissues. This suggests that carcinogenesis affects the mechanisms which control mitochondrial differentiation which can lead to irregular ATP synthase expression. The enhanced expression of IF1 in cancer and the reduced levels of F1-ATPase β subunit is something we do not know quite yet however there are possibilities researchers have suggested.
One possibility is that IF1 in cancer cells functions limit excessive ATP hydrolysis and prevent an increase in energy. This seems unlikely in cancer cells because of the reduced levels of ATO synthase and the high liking for the IF1 enzyme.
The other possibility is that cancer cells require reduced oxidative phosphorylation to adapt to their metabolism and gain growth advantages under unfavourable environmental conditions like hypoxia. Evidence has shown that cancer cells can thrive under the condition of reduced oxidative phosphorylation.
Analyzing mitochondrial functions could provide valuable insights into cancer diagnosis and future potential therapeutic strategies. Dysregulation of mitochondrial function is a hallmark of cancer and alteration in the mitochondrial bioenergetics can also drive tumourigenesis and have an influence on cancer progression. Assessing mitochondrial functions could help identify different biomarkers for cancer diagnosis and prognosis and could potentially help develop targets for therapeutic intervention. Furthermore, since the mitochondria play a key role in regulating cellular metabolism and apoptosis understanding these functions of mitochondria in cancer cells could help guide the development of targeted therapies which are aimed at modulation of mitochondrial function to promote cancer cell death.
Mitochondrial Membrane Potential in Cancer Cells
The electrochemical transmembrane potential is key for various mitochondrial functions in normal cells and cancer cells. In normal cells, under normoxic conditions, the mitochondrial membrane potential is mostly generated by the respiratory chain and is used to drive ATP synthesis. However, in conditions like hypoxia, the mitochondrial membrane potential can be generated by the hydrolytic activity of the ATP synthase complex and electrogenic transport of ATP in exchange for ADP across the inner mitochondrial membrane via the adenine nucleotide translocator. The disruption of the mitochondrial membrane potential (Δψm) which is also referred to as proton leak, uncouples the electron transport chain from ATP synthesis by the ATP synthase complex. This proton leak regulates mitochondrial ROS production and many pathophysiological processes such as tumorigenesis. Uncoupling these proteins that play a role in modulating proton leak suggests their involvement in cancer development.
Furthermore, the uncoupling protein UCP2 which is located in the inner mitochondrial membrane also contributes to the regulation of the mitochondrial membrane potential. Studies have shown that this overexpression in chemoresistant cancer cell lines and mostly in colon cancer which has an increased threshold for apoptosis. In addition, UCP2 has been suggested to be involved in the metabolic reprogramming of cells and is necessary for the efficient oxidation of glutamine. UCP2 may play a key role in molecular mechanisms which underly the Warburg effect where the cancer cells produce energy differently and have altered mitochondrial function.
STAT3 transcription factor in the mitochondria could also have an impact on cellular respiration. STAT3 can modulate respiration by regulating the activity of Complexes I and II. Furthermore, human RAS oncoproteins rely on mitochondrial STAT3 for their transforming potential and cancer cells expressing STAT3 have increased levels of mitochondrial membrane potential and lactate dehydrogenase which are characteristics of malignant transformation.
Mutation of Nuclear Genes Encoding Mitochondrial Proteins
Mutations in the nuclear-encoded mitochondrial proteins have been involved in cancer with examples like succinate dehydrogenase (SDH) and fumarate hydratase (FH) and enzymes of the citric acid cycle. Mutations in sDH and FH have been associated with renal cancers. In both cases, the accumulation of the citric acid cycle molecules succinate and fumarate has been observed. This accumulation stabilizies (HIF-1α). In addition, mutations in isocitrate dehydrogenase (IDH) have also been seen in many grade II and grade III gliomas and secondary glioblastomas. Furthermore, mutations in nuclear genes which encode proteins involved in mtDNA replication and assembly of respiratory chain complexes have been seen. For example, some breast tumours have mutations in the polymerase γ gene which could lead to mtDNA depletion and impairment of oxidative phosphorylation. All of these findings show the different ways in which mutations in nuclear-encoded mitochondria contribute to cancer development and cancer.
Mitochondrial DNA Mutation and Cancer
The presence of somatic mtDNA mutations has been seen in colorectal tumours where homoplasmic mutations were found in a subset of cell lines. These mutations from the study by Polyak et al did not seem to affect mitochondrial functions. However other studies have provided evidence of mtDNA mutation in tumorigenesis. For example, Petros et al found that prostate cancer patients had mutations in the cytochrome c oxidase subunit I gene which in prostate cancer cells increased tumorigenicity in animal models.
Furthermore, the mTOR pathway which is often hyperactivated in human cancer has also been involved in cancer progression and is known to have control over mitochondrial function.
Further research has also shown the association of mtDNA mutations in different types of cancer like gastric cancer and thyroid oncocytic carcinoma. Some studies have also linked mtDNA mutations to an increased amount of ROS production and others have said that mtDNA mutation activates the signalling pathways of the PI3K/AKT pathway, contributing to increased metastasis.
Overall this suggests that mtDNA mutations may play a key role in the development and progression of cancer however further research is needed to understand these mechanisms and potential therapeutic implications.
Hypoxia and Oxidative Phosphorylation in Cancer Cells
Tumour cells experience a wide range of oxygen levels from normal oxygen tension (2–4%) to hypoxia or anoxia (< 0.1% oxygen). The growth of a tumour beyond a certain size is dependent on sufficient blood supply for nutrient and oxygen delivery via diffusion. Cells which are located farther away from capillaries experience lower oxygen concentration which could lead to hypoxia occuring the farther you go.
Hypoxia leads to the reduction of mitochondrial activity which is controlled by the hypoxia-inducible factor 1 (HIF-1). The mitochondria play a key role in sensing oxygen levels and the supply of substances which influence the activity of HIF-1α prolyl hydroxylase, α-ketoglutarate and reactive oxygen species (ROS) which can inhibit HIF-1α removal, and therefore can promote its stabilization. However, HIF-1 can also modulate mitochondrial function through there various mechanisms like metabolic reprogramming, alteration of mitochondrial structure and dynamics and regulation of gene expression related to mitochondrial function. Overall, the interaction between hypoxia, HIF-1, and mitochondrial dysfunction contributes to tumour progression and resistance to therapy.
The reduced respiration rate during hypoxia can also lead to an increase in ROS production mostly by Complex III, which contributes to the stabilization of HIF and promotion of anti-apoptotic properties. In addition, hypoxia also inhibits ATP synthase through in protein inhibitor IF1, which can promote aerobic glycolysis which is a hallmark of cancer transformation.
Researchers are exploring how hyperoxia could be beneficial in cancer therapies. Different studies have shown that hyperoxia can induce growth inhibition and cell cycle disruption in neuroblastoma cell lines as well as apoptosis in glioma cells. Further research is needed to fully understand these mechanisms and potential cancer treatments and therapies.
Why Should I Learn About This?
Cancer cells have a lot of metabolic changes which are associated with alterations in mitochondrial structure dynamics and function which could impact tumour growth and survival. Mitochondria play a role in regulating tumorigenesis: they modulate tumor growth through the TCA cycle and oxidative phosphorylation, while also controlling redox homeostasis and apoptosis sensitivity. Understanding this molecular basis of tumorigenesis could help reduce tumorigenicity and enhance the effect of anti-cancer drugs which target the mitochondria. Overall targeting different mitochondrial pathways and functions could be promising for the development of new cancer therapies.
Articles in The Series
To explore the previous parts of the series: Part 1, Part 2, Part 3, Part 4
