bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2020‒12‒27
eleven papers selected by
Kelsey Fisher-Wellman, East Carolina University

  1. Redox Biol. 2020 Nov 29. pii: S2213-2317(20)31023-5. [Epub ahead of print]38 101818
      Mitochondria are strategically trafficked throughout the cell by the action of microtubule motors, the actin cytoskeleton and adapter proteins. The intracellular positioning of mitochondria supports subcellular levels of ATP, Ca2+ and reactive oxygen species (ROS, i.e. hydrogen peroxide, H2O2). Previous work from our group showed that deletion of the mitochondrial adapter protein Miro1 leads to perinuclear clustering of mitochondria, leaving the cell periphery devoid of mitochondria which compromises peripheral energy status. Herein, we report that deletion of Miro1 significantly restricts subcellular H2O2 levels to the perinuclear space which directly affects intracellular responses to elevated mitochondrial ROS. Using the genetically encoded H2O2-responsive fluorescent biosensor HyPer7, we show that the highest levels of subcellular H2O2 map to sites of increased mitochondrial density. Deletion of Miro1 or disruption of microtubule dynamics with Taxol significantly reduces peripheral H2O2 levels. Following inhibition of mitochondrial complex 1 with rotenone we observe elevated spikes of H2O2 in the cell periphery and complementary oxidation of mitochondrial peroxiredoxin 3 (PRX3) and cytosolic peroxiredoxin 2 (PRX2). Conversely, in cells lacking Miro1, rotenone did not increase peripheral H2O2 or PRX2 oxidation but rather lead to increased nuclear H2O2 and an elevated DNA-damage response. Lastly, local levels of HyPer7 oxidation correlate with the size and abundance of focal adhesions (FAs) in MEFs and cells lacking Miro1 have significantly smaller focal adhesions and reduced phosphorylation levels of vinculin and p130Cas compared to Miro1+/+ MEFs. Together, we present evidence that the intracellular distribution of mitochondria influences subcellular H2O2 levels and local cellular responses dependent on mitochondrial ROS.
    Keywords:  Cell migration; Hydrogen peroxide; Miro1; Mitochondrial trafficking; Reactive oxygen species
  2. Pharmacol Res. 2020 Dec 18. pii: S1043-6618(20)31693-5. [Epub ahead of print] 105385
      The neural crest is an important group of cells with pluripotency and migratory ability that is crucially involved in tissue and cell specification during development. Craniofacial shaping, sensory neurons, body asymmetry, and pigmentation are linked to neural crest functionality. Despite its prominent role in embryogenesis, neural crest specification as well as the possible part mitochondria play in such a process remains unclarified. Mitochondria are important organelles not only for respiration, but also for regulation of cell proliferation, differentiation and death. Modulation of mitochondrial fitness and depletion of mitochondrial ATP synthesis has been shown to down-regulate Wnt signaling, both in vitro and in vivo. Since Wnt signaling is one of the crucial players during neural crest induction/specification, we hypothesized a signaling cascade connecting mitochondria to embryonic development and neural crest migration and differentiation. Here, by using pharmacological and genetic modulators of mitochondrial function, we provide evidence that a crosstalk between mitochondrial energy homeostasis and Wnt signaling is important in the development of neural crest-derived tissues. Furthermore, our results highlight the possibility to modulate neural crest cell specification by tuning mitochondrial metabolism via FoxD3, an important transcription factor that is regulated by Wnt. FoxD3 ensures the correct embryonic development and contributes to the maintenance of cell stemness and to the induction of epithelial-to-mesenchymal transition. In summary, our work offers new insights into the molecular mechanism of action of FoxD3 and demonstrates that mitochondrial fitness is linked to the regulation of this important transcription factor via Wnt signaling in the context of neural crest specification.
    Keywords:  FoxD3; Mitochondria; Wnt signaling; cancer; neural crest; neurocristopathies
  3. J Physiol. 2020 Dec 21.
      Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary, permanent and universal consequence of dysfunctional/impaired mitochondria compensating for poor ATP-yield per mole of glucose. Instead, in most tumours the Warburg effect is an essential part of a "selfish" metabolic reprogramming, which results from the interplay between (normoxic/hypoxic) HIF-1-overexpression, oncogene activation (cMyc, Ras), loss of function of tumour suppressors (mutant-p53, mutant-PTEN, microRNAs and sirtuins with suppressor functions), activated (PI3K/Akt/mTORC1, Ras/Raf/Mek/Erk/cMyc, Jak/Stat3) or deactivated (LKB1/AMPK) signalling pathways, components of the tumour microenvironment, and HIF-1-cooperations with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include: (a) considerably accelerated glycolytic fluxes, (b) adequate ATP generation per unit time to maintain energy homeostasis and electrochemical gradients, (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, non-essential amino acids, lipids and hexosamines, (d) inhibition of pyruvate entry into mitochondria, (e) excessive formation and accumulation of lactate which stimulates tumour growth and suppression of anti-tumour immunity; in addition, lactate can serve as an energy source for normoxic cancer cells and drives malignant progression and resistances to conventional therapies, (f) cytosolic lactate is mainly exported through upregulated lactate-proton symporters (MCT4), working together with other H+ -transporters, and carbonic anhydrases (CAII, CAIX) which hydrate CO2 from oxidative metabolism to form H+ and bicarbonate, (g) in concert with poor vascular drainage these proton export mechanisms are responsible for extracellular acidification, driving malignant progression and resistances to conventional therapies, (h) maintenance of the cellular redox homeostasis and low ROS formation, and (i) HIF-1 overexpression, mutant-p53 and mutant-PTEN which inhibit mitochondrial biogenesis and functions, negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e., aerobic glycolysis in the presence of oxygen and -in principle- functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and poor patient outcome. However, as evidenced during the last two decades, in a minority of tumours primary mitochondrial defects can play a key role promoting the Warburg effect and tumour progression due to mutations in some Krebs cycle enzymes and mitochondrial ROS overproduction. Abstract figure legend Driving processes causing the Warburg effect during carcinogenesis (upper part), and mechanisms/consequences of metabolic reprogramming in Warburg phenotypes (lower part) leading to survival advantages, malignant progression and, ultimately, poor patient outcome. This article is protected by copyright. All rights reserved.
    Keywords:  Warburg effect; aerobic glycolysis; glycolytic phenotype; lactate accumulation; metabolic reprogramming; tumour acidosis; tumour glucose metabolism; tumour mitochondria
  4. Cells. 2020 12 11. pii: E2669. [Epub ahead of print]9(12):
      Bladder cancer is one of the most prevalent deadly diseases worldwide. Grade 2 tumors represent a good window of therapeutic intervention, whose optimization requires high resolution biomarker identification. Here we characterize energy metabolism and cellular properties associated with spreading and tumor progression of RT112 and 5637, two Grade 2 cancer cell lines derived from human bladder, representative of luminal-like and basal-like tumors, respectively. The two cell lines have similar proliferation rates, but only 5637 cells show efficient lateral migration. In contrast, RT112 cells are more prone to form spheroids. RT112 cells produce more ATP by glycolysis and OXPHOS, present overall higher metabolic plasticity and are less sensitive than 5637 to nutritional perturbation of cell proliferation and migration induced by treatment with 2-deoxyglucose and metformin. On the contrary, spheroid formation is less sensitive to metabolic perturbations in 5637 than RT112 cells. The ability of metformin to reduce, although with different efficiency, cell proliferation, sphere formation and migration in both cell lines, suggests that OXPHOS targeting could be an effective strategy to reduce the invasiveness of Grade 2 bladder cancer cells.
    Keywords:  2D and 3D cultures; Operetta CLS™; Seahorse Extracellular Flux Analyzer; bladder cancer; cellular bioenergetics; energy and redox metabolism; fatty acids oxidation; glycolysis; mitochondrial function; oxidative stress; quantitative imaging
  5. Biochem Cell Biol. 2020 Dec 20.
      Mitochondria modify their function and morphology to satisfice the bioenergetic demand of the cells. Cancer cells take advantage of these features to sustain their metabolic, proliferative, metastatic, and survival necessities. Therefore, the understanding of mitochondrial morphologic changes of the different grades of Triple-Negative Breast Cancer (TNBC) could be relevant for the design of novel treatments. Consequently, this research aimed to explore the mitochondria morphology and gene expression of some proteins related to mitochondrial dynamics as well as proteins related to oxidative and non-oxidative metabolism of metastatic and non-metastatic TNBC. We found that mitochondrial-morphology and metabolism are different between metastatic and non-metastatic TNBC. Metastatic TNBC showed overexpression of genes related to mitochondrial dynamics, fatty acids, and glycolytic metabolism. These features were accompanied by a fused mitochondrial morphology. In contrast, the non-metastatic TNBC presented a stress-associated mitochondrial morphology, hyperfragmented mitochondria accompanied by upregulated expression of mitochondrial biogenesis-related genes, both characteristics related to the higher ROS production observed in this cell line. These differences found between metastatic and non-metastatic TNBC will allow a better understanding of the metastasis process and the improvement of the development of a specific and personalized TNBC therapy.
  6. Mol Cell. 2020 Dec 15. pii: S1097-2765(20)30827-3. [Epub ahead of print]
      In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.
    Keywords:  MCT2; PHGDH; breast cancer; lung environment; mTORC1; metastasis formation; pyruvate; serine biosynthesis; α-ketoglutarate
  7. Front Oncol. 2020 ;10 523860
      Background: Previous studies have shown the value in studying lineage tracing in slices of human tumors. However, a tumor is not a two-dimensional structure and to better understand how a tumor, and its corresponding metastasis grow, a three-dimensional (3-D) view is necessary.Results: Using somatic mitochondrial mutations as a marker for lineage tracing, it is possible to identify and follow tumor specific cell lineages. Using cycling temperature capillary electrophoresis (CTCE) a total of 8 tissues from 5 patients (4 primary tumors and 4 metastasis) containing clear mitochondrial markers of tumor lineages were selected. From these 8 tissues over 9,500 laser capture microdisection (LCM) samples were taken and analyzed, in a way that allows 3-D rendering of the observations.
    Conclusion: Using CTCE combined with LCM makes it possible to study the 3-D patterns formed by tumors and metastasis as they grow. These results clearly show that the majority of the volume occupied by a tumor is not composed of tumor derived cells. These cells are most likely recruited from the neighboring tissue.
    Keywords:  human; lineage tracing; metastasis; three dimension; tumor
  8. J Cancer Res Ther. 2020 Oct-Dec;16(6):16(6): 1517-1521
      Background and Objective: Meningiomas are among the most common intracranial tumors of the central nervous system. It is widely accepted that the initiation and progression of meningiomas involve the accumulation of nucleus genetic alterations, but little is known about the implication of mitochondrial genomic alterations during development of these tumors. The human mitochondrial DNA (mtDNA) contains a short hypervariable, noncoding displacement loop control region known as the D-Loop. Alterations in the mtDNA D-loop have been reported to occur in most types of human cancers. The purpose of this study was to assess the mtDNA D-loop mutations in Malaysian meningioma patients.Materials and Methods: Genomic DNA was extracted from 21 fresh-frozen tumor tissues and blood samples of the same meningioma patients. The entire mtDNA D-loop region (positions 16024-576) was polymerase chain reaction amplified using designed primers, and then amplification products were purified before the direct DNA sequencing proceeds.
    Results: Overall, 10 (47.6%) patients were detected to harbor a total of 27 somatic mtDNA D-loop mutations. Most of these mtDNA mutations were identified in the hypervariable segment II (40.7%), with 33.3% being located mainly in the conserved sequence block II of the D310 sequence. Furthermore, 58 different germline variations were observed at 21 nucleotide positions.
    Conclusion: Our results suggest that mtDNA alterations in the D-loop region may be an important and early event in developing meningioma. Further studies are needed, including validation in a larger patient cohort, to verify the clinicopathological outcomes of mtDNA mutation biomarkers in meningiomas.
    Keywords:  D-loop; meningioma; mitochondrial DNA; somatic mutations
  9. Life (Basel). 2020 Dec 17. pii: E357. [Epub ahead of print]10(12):
      The role of canonical Wnt signaling in metabolic regulation and development of physiological cardiac hypertrophy remains largely unknown. To explore the function of β-catenin in the regulation of cardiac metabolism and physiological cardiac hypertrophy development, we used mice heterozygous for cardiac-specific β-catenin knockout that were subjected to a swimming training model. β-Catenin haploinsufficient mice subjected to endurance training displayed a decreased β-catenin transcriptional activity, attenuated cardiomyocytes hypertrophic growth, and enhanced activation of AMP-activated protein kinase (AMPK), phosphoinositide-3-kinase-Akt (Pi3K-Akt), and mitogen-activated protein kinase/extracellular signal-regulated kinases 1/2 (MAPK/Erk1/2) signaling pathways compared to trained wild type mice. We further observed an increased level of proteins involved in glucose aerobic metabolism and β-oxidation along with perturbed activity of mitochondrial oxidative phosphorylation complexes (OXPHOS) in trained β-catenin haploinsufficient mice. Taken together, Wnt/β-catenin signaling appears to govern metabolic regulatory programs, sustaining metabolic plasticity in adult hearts during the adaptation to endurance training.
    Keywords:  Wnt/β-catenin signaling; glucose metabolism; lipid metabolism; oxidative phosphorylation; training-induced heart hypertrophy; β-oxidation
  10. Cell Death Dis. 2020 Dec 15. 11(12): 1075
      Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy to treat many degenerative diseases. Accumulating evidence shows that the function of MSCs declines with age, thus limiting their regenerative capacity. Nonetheless, the underlying mechanisms that control MSC ageing are not well understood. We show that compared with bone marrow-MSCs (BM-MSCs) isolated from young and aged samples, NADH dehydrogenase (ubiquinone) iron-sulfur protein 6 (Ndufs6) is depressed in aged MSCs. Similar to that of Ndufs6 knockout (Ndufs6-/-) mice, MSCs exhibited a reduced self-renewal and differentiation capacity with a tendency to senescence in the presence of an increased p53/p21 level. Downregulation of Ndufs6 by siRNA also accelerated progression of wild-type BM-MSCs to an aged state. In contrast, replenishment of Ndufs6 in Ndufs6-/--BM-MSCs significantly rejuvenated senescent cells and restored their proliferative ability. Compared with BM-MSCs, Ndufs6-/--BM-MSCs displayed increased intracellular and mitochondrial reactive oxygen species (ROS), and decreased mitochondrial membrane potential. Treatment of Ndufs6-/--BM-MSCs with mitochondrial ROS inhibitor Mito-TEMPO notably reversed the cellular senescence and reduced the increased p53/p21 level. We provide direct evidence that impairment of mitochondrial Ndufs6 is a putative accelerator of adult stem cell ageing that is associated with excessive ROS accumulation and upregulation of p53/p21. It also indicates that manipulation of mitochondrial function is critical and can effectively protect adult stem cells against senescence.
  11. Free Radic Biol Med. 2020 Dec 18. pii: S0891-5849(20)31676-2. [Epub ahead of print]
      Mitochondrial unfolded protein response (UPRmt) is a mitochondria stress response, which the transcriptional activation programs of mitochondrial chaperone proteins and proteases are initiated to maintain proteostasis in mitochondria. Additionally, the activation of UPRmt delays aging and extends lifespan by maintaining mitochondrial proteostasis. Growing evidences suggests that UPRmt plays an important role in diverse human diseases, especially ageing-related diseases. Therefore, this review focuses on the role of UPRmt in ageing and ageing-related neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease. The activation of UPRmt and the high expression of UPRmt components contribute to longevity extension. The activation of UPRmt may ameliorate Alzheimer's disease, Parkinson's disease and Huntington's disease. Besides, UPRmt is also involved in the occurrence and development of cancers and heart diseases. UPRmt contributes to the growth, invasive and metastasis of cancers. UPRmt has paradoxical roles in heart diseases. UPRmt not only protects against heart damage, but may sometimes aggravates the development of heart diseases. Considering the pleiotropic actions of UPRmt system, targeting UPRmt pathway may be a potent therapeutic avenue for neurodegenerative diseases, cancers and heart diseases.
    Keywords:  UPR(mt); ageing; cancers; diseases; heart; neurodegenerative