Heterogenous mitochondrial ultrastructure and metabolism of human glioblastoma cells: differences between stem-like and differentiated cancer cells in response to chemotherapy

Bogataj, Urban; Novak, Metka; Galun, Simona Katrin; Tacer, Klementina Fon; Vittori, Milos; Noorden, Cornelis J.F. Van; Breznik, Barbara

doi:10.2478/raon-2025-0056

References

van Solinge TS, Nieland L, Chiocca EA, Broekman MLD. Advances in local therapy for glioblastoma - taking the fight to the tumour. Nat Rev Neurol 2022; 18: 221-36. doi:10.1038/S41582-022-00621-0
Open DOI Search in Google Scholar Back to article
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: 459-66. doi: 10.1016/S1470-2045(09)70025-7
Open DOI Search in Google Scholar Back to article
Neftel C, Laffy J, Filbin MG, Hara T, Shore ME, Rahme GJ, et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 2019; 178: 835-49.e21. doi: 10.1016/J.CELL.2019.06.024
Open DOI Search in Google Scholar Back to article
Prager BC, Bhargava S, Mahadev V, Hubert CG, Rich JN. Glioblastoma stem cells: driving resilience through chaos. Trends Cancer 2020; 6: 223-35. doi: 10.1016/j.trecan.2020.01.009
Open DOI Search in Google Scholar Back to article
Vlashi E, Lagadec C, Vergnes L, Matsutani T, Masui K, Poulou M, et al. Metabolic state of glioma stem cells and nontumorigenic cells. Proc Natl Acad Sci U S A 2011; 108: 16062-7. doi: 10.1073/PNAS.1106704108
Open DOI Search in Google Scholar Back to article
Badr CE, Silver DJ, Siebzehnrubl FA, Deleyrolle LP. Metabolic heterogeneity and adaptability in brain tumors. Cell Mol Life Sci 2020; 77: 5101-19. doi: 10.1007/S00018-020-03569-W
Open DOI Search in Google Scholar Back to article
Hira VVV, Breznik B, Vittori M, Loncq de Jong A, Mlakar J, Oostra RJ, et al. Similarities between stem cell niches in glioblastoma and bone marrow: rays of hope for novel treatment strategies. J Histochem Cytochem 2020; 68: 33-57. doi: 10.1369/0022155419878416
Open DOI Search in Google Scholar Back to article
Hira VVV, Aderetti DA, van Noorden CJF. Glioma stem cell niches in human glioblastoma are periarteriolar. J Histochem Cytochem 2018; 66: 349-58. doi: 10.1369/0022155417752676
Open DOI Search in Google Scholar Back to article
Schiffer D, Annovazzi L, Casalone C, Corona C, Mellai M. Glioblastoma: microenvironment and niche concept. Cancers (Basel) 2019; 11: 5. doi: 10.3390/cancers11010005
Open DOI Search in Google Scholar Back to article
Li P, Zhou C, Xu L, Xiao H. Hypoxia enhances stemness of cancer stem cells in glioblastoma: an in vitro study. Int J Med Sci 2013; 10: 399-407. doi: 10.7150/IJMS.5407
Open DOI Search in Google Scholar Back to article
Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 2009; 8: 327484. doi: 10.4161/CC.8.20.9701
Open DOI Search in Google Scholar Back to article
Iranmanesh Y, Jiang B, Favour OC, Dou Z, Wu J, Li J, et al. Mitochondria’s role in the maintenance of cancer stem cells in glioblastoma. Front Oncol 2021; 11: 582694. doi: 10.3389/FONC.2021.582694
Open DOI Search in Google Scholar Back to article
Carew JS, Huang P. Mitochondrial defects in cancer. Mol Cancer 2002; 1: 9. doi: 10.1186/1476-4598-1-9
Open DOI Search in Google Scholar Back to article
Wallace DC. Mitochondria and cancer: Warburg addressed. Cold Spring Harb Symp Quant Biol 2005;70: 363-74. doi: 10.1101/SQB.2005.70.035
Open DOI Search in Google Scholar Back to article
Seyfried TN, Flores RE, Poff AM, D’Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis 2014; 35: 515-27. doi: 10.1093/CARCIN/BGT480
Open DOI Search in Google Scholar Back to article
Peiris-Pagès M, Martinez-Outschoorn UE, Pestell RG, Sotgia F, Lisanti MP. Cancer stem cell metabolism. Breast Cancer Res 2016; 18: 55. doi: 10.1186/S13058-016-0712-6
Open DOI Search in Google Scholar Back to article
Strickland M, Stoll EA. Metabolic reprogramming in glioma. Front Cell Dev Biol 2017; 5: 43. doi: 10.3389/FCELL.2017.00043
Open DOI Search in Google Scholar Back to article
van Noorden CJF, Yetkin-Arik B, Serrano Martinez P, Bakker N, van Breest Smallenburg ME, Schlingemann RO, et al. New insights in ATP synthesis as therapeutic target in cancer and angiogenic ocular diseases. J Histochem Cytochem 2024; 72: 329-52. doi: 10.1369/00221554241249515
Open DOI Search in Google Scholar Back to article
van Noorden CJF, Breznik B, Novak M, van Dijck AJ, Tanan S, Vittori M, et al. Cell biology meets cell metabolism: energy production is similar in stem cells and in cancer stem cells in brain and bone marrow. J Histochem Cytochem 2022; 70: 29-51. doi: 10.1369/00221554211054585
Open DOI Search in Google Scholar Back to article
van Noorden CJF, Hira VVV, van Dijck AJ, Novak M, Breznik B, Molenaar RJ. Energy metabolism in IDH1 wild-type and IDH1-mutated glioblastoma stem cells: a novel target for therapy? Cells 2021; 10: 1-16. doi: 10.3390/CELLS10030705
Open DOI Search in Google Scholar Back to article
Wallace DC. Mitochondria and cancer. Nat Rev Cancer 2012; 12: 685-98. doi: 10.1038/NRC3365
Open DOI Search in Google Scholar Back to article
Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell 2016; 166: 55566. doi: 10.1016/J.CELL.2016.07.002
Open DOI Search in Google Scholar Back to article
Ordys BB, Launay S, Deighton RF, McCulloch J, Whittle IR. The role of mitochondria in glioma pathophysiology. Mol Neurobiol 2010; 42: 64-75. doi: 10.1007/S12035-010-8133-5
Open DOI Search in Google Scholar Back to article
Wai T, Langer T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab 2016; 27: 105-17. doi: 10.1016/J.TEM.2015.12.001
Open DOI Search in Google Scholar Back to article
Senft D, Ronai ZA. Regulators of mitochondrial dynamics in cancer. Curr Opin Cell Biol 2016; 39: 43-52. doi: 10.1016/J.CEB.2016.02.001
Open DOI Search in Google Scholar Back to article
Trotta AP, Chipuk JE. Mitochondrial dynamics as regulators of cancer biology. Cell Mol Life Sci 2017; 74: 1999-2017. doi: 10.1007/S00018-016-2451-3
Open DOI Search in Google Scholar Back to article
Maycotte P, Marín-Hernández A, Goyri-Aguirre M, Anaya-Ruiz M, Reyes-Leyva J, Cortés-Hernández P. Mitochondrial dynamics and cancer. Tumour Biol 2017; 39: 1010428317698391. doi: 10.1177/1010428317698391
Open DOI Search in Google Scholar Back to article
García-Heredia JM, Carnero A. Role of mitochondria in cancer stem cell resistance. Cells 2020; 9: 1693. doi: 10.3390/CELLS9071693
Open DOI Search in Google Scholar Back to article
De Luca A, Fiorillo M, Peiris-Pagès M, Ozsvari B, Smith DL, Sanchez-Alvarez R, et al. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells. Oncotarget 2015; 6: 14777-95. doi: 10.18632/ONCOTARGET.4401
Open DOI Search in Google Scholar Back to article
Arismendi-Morillo GJ, Castellano-Ramirez A V. Ultrastructural mitochondrial pathology in human astrocytic tumors: potentials implications pro-therapeutics strategies. J Electron Microsc 2008; 57: 33-9. doi: 10.1093/JMICRO/DFM038
Open DOI Search in Google Scholar Back to article
Arismendi-Morillo G. Electron microscopy morphology of the mitochondrial network in gliomas and their vascular microenvironment. Biochim Biophys Acta 2011; 1807: 602-8. doi: 10.1016/J.BBABIO.2010.11.001
Open DOI Search in Google Scholar Back to article
Scheithauer BW, Bruner JM. The ultrastructural spectrum of astrocytic neoplasms. Ultrastruct Pathol 1987; 11: 535-81. doi: 10.3109/01913128709048447
Open DOI Search in Google Scholar Back to article
Liberski PP, Kordek R. Ultrastructural pathology of glial brain tumors revisited: a review. Ultrastruct Pathol 1997; 21: 1-31. doi: 10.3109/01913129709023244
Open DOI Search in Google Scholar Back to article
Sipe, JC, Herman, MM RL. Electron microscopic observations on human glioblastomas and astrocytomas maintained in organ culture systems. Am J Pathol 1973; 73: 589-606.
Search in Google Scholar Back to article
Khurshed M, Aarnoudse N, Hulsbos R, Hira VVV, Van Laarhoven HWM, Wilmink JW, et al. IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity. FASEB J 2018; 32: 634452. doi: 10.1096/FJ.201800547R
Open DOI Search in Google Scholar Back to article
Verberk SGS, de Goede KE, Gorki FS, van Dierendonck XAMH, Argüello RJ, Van den Bossche J. An integrated toolbox to profile macrophage immunometabolism. Cell Rep Methods 2022; 2: 100192. doi: 10.1016/J. CRMETH.2022.100192
Open DOI Search in Google Scholar Back to article
Breznik B, Ko MW, Tse C, Chen PC, Senjor E, Majc B, et al. Infiltrating natural killer cells bind, lyse and increase chemotherapy efficacy in glioblastoma stem-like tumorospheres. Commun Biol 2022; 5: 436. doi: 10.1038/S42003-022-03402-Z
Open DOI Search in Google Scholar Back to article
Porčnik A, Novak M, Breznik B, Majc B, Hrastar B, Šamec N, et al. TRIM28 selective nanobody reduces glioblastoma stem cell invasion. Molecules 2021; 26: 5141. doi: 10.3390/MOLECULES26175141
Open DOI Search in Google Scholar Back to article
Majc B, Habič A, Novak M, Rotter A, Porčnik A, Mlakar J, et al. Upregulation of cathepsin X in glioblastoma: Interplay with γ-enolase and the effects of selective cathepsin X inhibitors. Int J Mol Sci 2022; 23: 1784. doi: 10.3390/IJMS23031784
Open DOI Search in Google Scholar Back to article
Novak M, Majc B, Malavolta M, Porčnik A, Mlakar J, Hren M, et al. The Slovenian translational platform GlioBank for brain tumour research: identification of molecular signatures of glioblastoma progression. Neurooncol Adv 2025; 7: vdaf015. doi: 10.1093/NOAJNL/VDAF015
Open DOI Search in Google Scholar Back to article
Majc B, Habič A, Malavolta M, Vittori M, Porčnik A, Bošnjak R, et al. Patient-derived tumor organoids mimic treatment-induced DNA damage response in glioblastoma. iScience 2024; 27: 110604. doi: 10.1016/j.isci.2024.110604
Open DOI Search in Google Scholar Back to article
Breznik B, Motaln H, Vittori M, Rotter A, Turnšek TL. Mesenchymal stem cells differentially affect the invasion of distinct glioblastoma cell lines. Oncotarget 2017; 8: 25482-99. doi: 10.18632/oncotarget.16041
Open DOI Search in Google Scholar Back to article
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 2012; 9: 676-82. doi: 10.1038/NMETH.2019
Open DOI Search in Google Scholar Back to article
Cardona A, Saalfeld S, Schindelin J, Arganda-Carreras I, Preibisch S, Longair M, et al. TrakEM2 software for neural circuit reconstruction. PLoS One 2012; 7: e38011. doi: 10.1371/JOURNAL.PONE.0038011
Open DOI Search in Google Scholar Back to article
Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, et al. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci U S A 2013; 110: 8644-9. doi: 10.1073/PNAS.1221478110
Open DOI Search in Google Scholar Back to article
Ntafoulis I, Kleijn A, Ju J, Jimenez-Cowell K, Fabro F, Klein M, et al. Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers. Br J Cancer 2023; 129: 1327-38. doi: 10.1038/S41416-023-02402-Y,
Open DOI Search in Google Scholar Back to article
Lah TT, Novak M, Breznik B. Brain malignancies: glioblastoma and brain metastases. Semin Cancer Biol 2020; 60: 262-73. doi: 10.1016/J. SEMCANCER.2019.10.010
Open DOI Search in Google Scholar Back to article
Spehalski EI, Lee JA, Peters C, Tofilon P, Camphausen K. The quiescent metabolic phenotype of glioma stem cells. J Proteomics Bioinform 2019; 12: 96-103. doi: 10.35248/0974-276X.19.12.502
Open DOI Search in Google Scholar Back to article
Galloway CA, Lee H, Yoon Y. Mitochondrial morphology-emerging role in bioenergetics. Free Radic Biol Med 2012; 53: 2218-28. doi: 10.1016/J. FREERADBIOMED.2012.09.035
Open DOI Search in Google Scholar Back to article
Glancy B, Kim Y, Katti P, Willingham TB. The functional impact of mitochondrial structure across subcellular scales. Front Physiol 2020; 11: 541040. doi: 10.3389/FPHYS.2020.541040
Open DOI Search in Google Scholar Back to article
Wang R, Lei H, Wang H, Qi L, Liu Y, Liu Y, et al. Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography. Proc Natl Acad Sci U S A 2024; 121: e2311160121. doi: 10.1073/PNAS.2311160121
Open DOI Search in Google Scholar Back to article
Peixoto J, Lima J. Metabolic traits of cancer stem cells. Dis Model Mech 2018; 11: dmm033464. doi: 10.1242/DMM.033464
Open DOI Search in Google Scholar Back to article
Duraj T, García-romero N, Carrión-navarro J, Madurga R, de Mendivil AO, Prat-acin R, et al. Beyond the Warburg effect: oxidative and glycolytic phenotypes coexist within the metabolic heterogeneity of glioblastoma. Cells 2021; 10: 1-23. doi: 10.3390/CELLS10020202
Open DOI Search in Google Scholar Back to article
Arismendi-Morillo G, Castellano-Ramírez A, Seyfried TN. Ultrastructural characterization of the mitochondria-associated membranes abnormalities in human astrocytomas: functional and therapeutics implications. Ultrastruct Pathol 2017; 41: 234-44. doi: 10.1080/01913123.2017.1300618
Open DOI Search in Google Scholar Back to article
Galindo MF, Jordán J, González-García C, Ceña V. Reactive oxygen species induce swelling and cytochrome c release but not transmembrane depolarization in isolated rat brain mitochondria. Br J Pharmacol 2003; 139: 797-804. doi: 10.1038/SJ.BJP.0705309
Open DOI Search in Google Scholar Back to article
Peng TI, Jou MJ. Mitochondrial swelling and generation of reactive oxygen species induced by photoirradiation are heterogeneously distributed. Ann N Y Acad Sci 2004; 1011: 112-22. doi: 10.1007/978-3-662-41088-2_12
Open DOI Search in Google Scholar Back to article
Kaasik A, Safiulina D, Zharkovsky A, Veksler V. Regulation of mitochondrial matrix volume. Am J Physiol Cell Physiol 2007; 292: C157-63. doi: 10.1152/AJPCELL.00272.2006
Open DOI Search in Google Scholar Back to article
Moscheni C, Malucelli E, Castiglioni S, Procopio A, De Palma C, Sorrentino A, et al. 3D quantitative and ultrastructural analysis of mitochondria in a model of doxorubicin sensitive and resistant human colon carcinoma cells. Cancers 2019; 11: 1254. doi: 10.3390/CANCERS11091254
Open DOI Search in Google Scholar Back to article
Szczepanowska J, Malinska D, Wieckowski MR, Duszynski J. Effect of mtDNA point mutations on cellular bioenergetics. Biochim Biophys Acta 2012; 1817: 1740-6. doi: 10.1016/j.bbabio.2012.02.028
Open DOI Search in Google Scholar Back to article
Zhang C, Meng Y, Han J. Emerging roles of mitochondrial functions and epigenetic changes in the modulation of stem cell fate. Cell Mol Life Sci 2024; 81: 26. doi: 10.1007/S00018-023-05070-6
Open DOI Search in Google Scholar Back to article
Smith ALM, Whitehall JC, Greaves LC. Mitochondrial DNA mutations in ageing and cancer. Mol Oncol 2022; 16: 3276-94. doi: 10.1002/18780261.13291
Open DOI Search in Google Scholar Back to article
Fu Y, Sacco O, DeBitetto E, Kanshin E, Ueberheide B, Sfeir A. Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis. Mol Cell 2023; 83: 3740-53.e9. doi: 10.1016/j.molcel.2023.09.026
Open DOI Search in Google Scholar Back to article
Chatterjee D, Das P, Chakrabarti O. Mitochondrial epigenetics regulating inflammation in cancer and aging. Front Cell Dev Biol 2022; 10: 929708. doi: 10.3389/FCELL.2022.929708
Open DOI Search in Google Scholar Back to article
Uittenbogaard M, Brantner CA, Chiaramello A. Epigenetic modifiers promote mitochondrial biogenesis and oxidative metabolism leading to enhanced differentiation of neuroprogenitor cells. Cell Death Dis 2018; 9: 360. doi: 10.1038/S41419-018-0396-1
Open DOI Search in Google Scholar Back to article
Kondadi AK, Anand R, Reichert AS. Cristae membrane dynamics - a paradigm change. Trends Cell Biol 2020; 30: 923-36. doi: 10.1016/J.TCB.2020.08.008
Open DOI Search in Google Scholar Back to article
Paumard P, Vaillier J, Coulary B, Schaeffer J, Soubannier V, Mueller DM, et al. The ATP synthase is involved in generating mitochondrial cristae morphology. EMBO J 2002; 21: 221-30. doi: 10.1093/EMBOJ/21.3.221
Open DOI Search in Google Scholar Back to article
Stephan T, Brüser C, Deckers M, Steyer AM, Balzarotti F, Barbot M, et al. MICOS assembly controls mitochondrial inner membrane remodeling and crista junction redistribution to mediate cristae formation. EMBO J 2020; 39: e104105. doi: 10.15252/EMBJ.2019104105
Open DOI Search in Google Scholar Back to article
Klecker T, Westermann B. Pathways shaping the mitochondrial inner membrane. Open Biol 2021; 11: 210238. doi: 10.1098/RSOB.210238
Open DOI Search in Google Scholar Back to article
Plecitá-Hlavatá L, Ježek P. Integration of superoxide formation and cristae morphology for mitochondrial redox signaling. Int J Biochem Cell Biol 2016; 80: 31-50. doi: 10.1016/J.BIOCEL.2016.09.010
Open DOI Search in Google Scholar Back to article
Zick M, Rabl R, Reichert AS. Cristae formation-linking ultrastructure and function of mitochondria. Biochim Biophys Acta 2009; 1793: 5-19. doi: 10.1016/J.BBAMCR.2008.06.013
Open DOI Search in Google Scholar Back to article
Vaupel P, Multhoff G. Revisiting the Warburg effect: historical dogma versus current understanding. J Physiol 2021; 599: 1745-57. doi: 10.1113/JP278810
Open DOI Search in Google Scholar Back to article
Campos-Sandoval JA, Gómez-García MC, Santos-Jiménez J de los, Matés JM, Alonso FJ, Márquez J. Antioxidant responses related to temozolomide resistance in glioblastoma. Neurochem Int 2021; 149: 105136. doi: 10.1016/J. NEUINT.2021.105136
Open DOI Search in Google Scholar Back to article
Zhang W Bin, Wang Z, Shu F, Jin YH, Liu HY, Wang QJ, et al. Activation of AMP-activated protein kinase by temozolomide contributes to apoptosis in glioblastoma cells via p53 activation and mTORC1 inhibition. J Biol Chem 2010; 285: 40461-71. doi: 10.1074/JBC.M110.164046
Open DOI Search in Google Scholar Back to article
Gaiaschi L, Favaron C, Casali C, Gola F, De Luca F, Ravera M, et al. Study on the activation of cell death mechanisms: in search of new therapeutic targets in glioblastoma multiforme. Apoptosis 2023; 28: 1241-57. doi: 10.1007/S10495-023-01857-X
Open DOI Search in Google Scholar Back to article
Fleury C, Mignotte B, Vayssière JL. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 2002; 84: 131-41. doi: 10.1016/S0300-9084(02)01369-X
Open DOI Search in Google Scholar Back to article
Li HY, Feng YH, Lin CL, Hsu TI. Mitochondrial mechanisms in temozolomide resistance: unraveling the complex interplay and therapeutic strategies in glioblastoma. Mitochondrion 2024; 75: 101836. doi: 10.1016/J. MITO.2023.101836
Open DOI Search in Google Scholar Back to article
Oliva CR, Nozell SE, Diers A, McClugage SG, Sarkaria JN, Markert JM, et al. Acquisition of temozolomide chemoresistance in gliomas leads to remodeling of mitochondrial electron transport chain. J Biol Chem 2010; 285: 39759-67. doi: 10.1074/JBC.M110.147504
Open DOI Search in Google Scholar Back to article
Oliva CR, Moellering DR, Gillespie GY, Griguer CE. Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production. PLoS One 2011; 6: e24665. doi: 10.1371/JOURNAL.PONE.0024665
Open DOI Search in Google Scholar Back to article
Dolgin E. Venerable brain-cancer cell line faces identity crisis. Nature 2016; 537: 149-50. doi: 10.1038/NATURE.2016.20515,
Open DOI Search in Google Scholar Back to article
Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016; 355: i4919. doi: 10.1136/bmj.i4919
Open DOI Search in Google Scholar Back to article

Heterogenous mitochondrial ultrastructure and metabolism of human glioblastoma cells: differences between stem-like and differentiated cancer cells in response to chemotherapy

References

Paradigm

My account