Mitochondria and reactive oxygen species in brain development and pediatric brain tumors

Main Article Content

Anshu Malhotra Nicholas W. Eyrich Chad R. Potts M. Hope Robinson Anna Marie Kenney


Pediatric brain tumors, such as medulloblastomas, glioma, and ependymoma, are among the most common causes of cancer death in children, and patients that survive the current treatment paradigm (surgery, chemotherapy, and radiation) face lifelong side effects.  Increased understanding of the biological underpinnings of these tumors, which often occur as a result of aberrant regulation of brain developmental signaling pathways, is urgently needed in order to develop treatments that will improve survival and quality of life.   Approximately 30% of medulloblastomas are characterized by activation of the Sonic hedgehog (Shh) signaling pathway and its downstream effectors.  These tumors are thought to arise from cerebellar granule neuron precursors (CGNPs), whose rapid proliferation during development requires Shh signaling. In recent years there has been a resurgence of interest in how metabolism in cancer could represent a novel therapeutic target.  It has been shown that medulloblastomas are heavily dependent upon glycolysis and fatty acid synthesis.  More recent studies have shown that Shh induces mitochondrial fragmentation in proliferating medulloblastoma cells. Mitochondria are regulated by and involved in reactive oxygen species (ROS) production and function.  ROS are implicated in many processes associated with cancer growth and progression, including inflammation, vascularization, proliferation, and apoptosis. In this review, we trace the evolution of mitochondria from their prokaryotic ancestor up to their present-day role. We highlight the proteins that regulate mitochondrial biogenesis and the concurrent metabolic processes leading to ROS production and we discuss implications for mitochondrial biogenesis and ROS activity for brain development and cancer. 

Article Details

How to Cite
MALHOTRA, Anshu et al. Mitochondria and reactive oxygen species in brain development and pediatric brain tumors. Medical Research Archives, [S.l.], v. 5, n. 8, aug. 2017. ISSN 2375-1924. Available at: <>. Date accessed: 29 mar. 2023.
medulloblastoma; metabolism; cancer; brain development
Review Articles


1. Packer, R.J., Childhood medulloblastoma: progress and future challenges. Brain Dev, 1999. 21(2): p. 75-81.
2. Roddy, E. and S. Mueller, Late Effects of Treatment of Pediatric Central Nervous System Tumors. J Child Neurol, 2016. 31(2): p. 237-54.
3. Warburg, O., On respiratory impairment in cancer cells. Science, 1956. 124(3215): p. 269-70.
4. Vander Heiden, M.G., L.C. Cantley, and C.B. Thompson, Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 2009. 324(5930): p. 1029-33.
5. Cairns, R.A., I.S. Harris, and T.W. Mak, Regulation of cancer cell metabolism. Nat Rev Cancer, 2011. 11(2): p. 85-95.
6. Ramaswamy, V., et al., Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol, 2013. 14(12): p. 1200-7.
7. Northcott, P.A., et al., Medulloblastomics: the end of the beginning. Nat Rev Cancer, 2012. 12(12): p. 818-34.
8. Archer, T.C., E.L. Mahoney, and S.L. Pomeroy, Medulloblastoma: Molecular Classification-Based Personal Therapeutics. Neurotherapeutics, 2017. 14(2): p. 265-273.
9. Morrissy, A.S., et al., Divergent clonal selection dominates medulloblastoma at recurrence. Nature, 2016. 529(7586): p. 351-7.
10. Gray, M.W., Mitochondrial evolution. Cold Spring Harb Perspect Biol, 2012. 4(9): p. a011403.
11. Gray, M.W., G. Burger, and B.F. Lang, The origin and early evolution of mitochondria. Genome Biol, 2001. 2(6): p. REVIEWS1018.
12. Chen, H., et al., Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol, 2003. 160(2): p. 189-200.
13. Hoppins, S., L. Lackner, and J. Nunnari, The machines that divide and fuse mitochondria. Annu Rev Biochem, 2007. 76: p. 751-80.
14. Frezza, C., et al., OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell, 2006. 126(1): p. 177-89.
15. Elachouri, G., et al., OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. Genome Res, 2011. 21(1): p. 12-20.
16. Chen, H., A. Chomyn, and D.C. Chan, Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem, 2005. 280(28): p. 26185-92.
17. Jin, S.M., et al., Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol, 2010. 191(5): p. 933-42.
18. Deas, E., et al., PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet, 2011. 20(5): p. 867-79.
19. Greene, A.W., et al., Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep, 2012. 13(4): p. 378-85.
20. Durcan, T.M. and E.A. Fon, The three 'P's of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes Dev, 2015. 29(10): p. 989-99.
21. Chu, C.T., A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease. Hum Mol Genet, 2010. 19(R1): p. R28-37.
22. Hara, Y., et al., Presynaptic mitochondrial morphology in monkey prefrontal cortex correlates with working memory and is improved with estrogen treatment. Proc Natl Acad Sci U S A, 2014. 111(1): p. 486-91.
23. Picard, M. and B.S. McEwen, Mitochondria impact brain function and cognition. Proc Natl Acad Sci U S A, 2014. 111(1): p. 7-8.
24. Ding, W.X., et al., Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. J Biol Chem, 2012. 287(50): p. 42379-88.
25. Khalil, B., et al., PINK1-induced mitophagy promotes neuroprotection in Huntington's disease. Cell Death Dis, 2015. 6: p. e1617.
26. Malhotra, A., et al., Sonic Hedgehog Signaling Drives Mitochondrial Fragmentation by Suppressing Mitofusins in Cerebellar Granule Neuron Precursors and Medulloblastoma. Mol Cancer Res, 2015.
27. Chan, D.C., Fusion and fission: interlinked processes critical for mitochondrial health. Annu Rev Genet, 2012. 46: p. 265-87.
28. Ishihara, N., et al., Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol, 2009. 11(8): p. 958-66.
29. Wakabayashi, J., et al., The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J Cell Biol, 2009. 186(6): p. 805-16.
30. Chang, D.T. and I.J. Reynolds, Mitochondrial trafficking and morphology in healthy and injured neurons. Prog Neurobiol, 2006. 80(5): p. 241-68.
31. Li, H., et al., Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci U S A, 2008. 105(6): p. 2169-74.
32. Liu, Q.A. and H. Shio, Mitochondrial morphogenesis, dendrite development, and synapse formation in cerebellum require both Bcl-w and the glutamate receptor delta2. PLoS Genet, 2008. 4(6): p. e1000097.
33. Li, Z., et al., The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell, 2004. 119(6): p. 873-87.
34. Hagberg, H., et al., Mitochondria: hub of injury responses in the developing brain. Lancet Neurol, 2014. 13(2): p. 217-32.
35. Waterham, H.R., et al., A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med, 2007. 356(17): p. 1736-41.
36. Xie, Q., et al., Mitochondrial control by DRP1 in brain tumor initiating cells. Nat Neurosci, 2015. 18(4): p. 501-10.
37. Wirtz, S. and M. Schuelke, Region-specific expression of mitochondrial complex I genes during murine brain development. PLoS One, 2011. 6(4): p. e18897.
38. Ross, J.M., et al., Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature, 2013. 501(7467): p. 412-5.
39. Polster, B.M., et al., Postnatal brain development and neural cell differentiation modulate mitochondrial Bax and BH3 peptide-induced cytochrome c release. Cell Death Differ, 2003. 10(3): p. 365-70.
40. Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. Cell, 2011. 144(5): p. 646-74.
41. Magistretti, P.J. and I. Allaman, A cellular perspective on brain energy metabolism and functional imaging. Neuron, 2015. 86(4): p. 883-901.
42. Vaishnavi, S.N., et al., Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci U S A, 2010. 107(41): p. 17757-62.
43. Bauernfeind, A.L., et al., Aerobic glycolysis in the primate brain: reconsidering the implications for growth and maintenance. Brain Struct Funct, 2014. 219(4): p. 1149-67.
44. Goyal, M.S., et al., Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. Cell Metab, 2014. 19(1): p. 49-57.
45. Belanger, M., I. Allaman, and P.J. Magistretti, Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab, 2011. 14(6): p. 724-38.
46. Belanger, M., et al., Role of the glyoxalase system in astrocyte-mediated neuroprotection. J Neurosci, 2011. 31(50): p. 18338-52.
47. Nehlig, A., A.P. de Vasconcelos, and S. Boyet, Quantitative autoradiographic measurement of local cerebral glucose utilization in freely moving rats during postnatal development. J Neurosci, 1988. 8(7): p. 2321-33.
48. Kreisman, N.R., et al., Cerebral oxygenation and blood flow in infant and young adult rats. Am J Physiol, 1989. 256(1 Pt 2): p. R78-85.
49. Duffy, T.E., S.J. Kohle, and R.C. Vannucci, Carbohydrate and energy metabolism in perinatal rat brain: relation to survival in anoxia. J Neurochem, 1975. 24(2): p. 271-6.
50. Samson, F.E., Jr., W.M. Balfour, and N.A. Dahl, The effect of age and temperature on the cerebral energy requirement in the rat. J Gerontol, 1958. 13(3): p. 248-51.
51. Vannucci, R.C. and S.J. Vannucci, Cerebral carbohydrate metabolism during hypoglycemia and anoxia in newborn rats. Ann Neurol, 1978. 4(1): p. 73-9.
52. Nehlig, A., A. Pereira de Vasconcelos, and S. Boyet, Postnatal changes in local cerebral blood flow measured by the quantitative autoradiographic [14C]iodoantipyrine technique in freely moving rats. J Cereb Blood Flow Metab, 1989. 9(5): p. 579-88.
53. Hagberg, H., et al., Hypoxia-ischaemia model in the 7-day-old rat: possibilities and shortcomings. Acta Paediatr Suppl, 1997. 422: p. 85-8.
54. Gershon, T.R., et al., Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma. Cancer Metab, 2013. 1(1): p. 2.
55. Samson, F.E., Jr., W.M. Balfour, and N.A. Dahl, Rate of cerebral ATP utilization in rats. Am J Physiol, 1960. 198: p. 213-6.
56. Dahl, D.R. and F.E. Samson, Jr., Metabolism of rat brain mitochondria during postnatal development. Am J Physiol, 1959. 196(2): p. 470-2.
57. Land, J.M., et al., Development of mitochondrial energy metabolism in rat brain. Biochem J, 1977. 164(2): p. 339-48.
58. Zhu, C., et al., Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain. J Neurochem, 2003. 86(2): p. 306-17.
59. Cannino, G., et al., Analysis of cytochrome C oxidase subunits III and IV expression in developing rat brain. Neuroscience, 2004. 128(1): p. 91-8.
60. Gregson, N.A. and P.L. Williams, A comparative study of brain and liver mitochondria from new-born and adult rats. J Neurochem, 1969. 16(4): p. 617-26.
61. Pysh, J.J., Mitochondrial changes in rat inferior colliculus during postnatal development: an electron microscopic study. Brain Res, 1970. 18(2): p. 325-42.
62. Hambardzumyan, D., O.J. Becher, and E.C. Holland, Cancer stem cells and survival pathways. Cell Cycle, 2008. 7(10): p. 1371-8.
63. Wolf, A., et al., Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med, 2011. 208(2): p. 313-26.
64. Fernandez, L.A., et al., YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev, 2009. 23(23): p. 2729-41.
65. Fernandez, L.A., et al., Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation. Oncogene, 2012. 31(15): p. 1923-37.
66. Zhao, B., et al., Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev, 2007. 21(21): p. 2747-61.
67. Fernandez, L.A. and A.M. Kenney, The Hippo in the room: A new look at a key pathway in cell growth and transformation. Cell cycle, 2010. 9(12): p. 2292-9.
68. Thompson, E.M., et al., Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. Lancet Oncol, 2016. 17(4): p. 484-95.
69. Nagaraj, R., et al., Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway. Genes Dev, 2012. 26(18): p. 2027-37.
70. Bhatia, B., et al., Hedgehog-mediated regulation of PPARgamma controls metabolic patterns in neural precursors and shh-driven medulloblastoma. Acta Neuropathol, 2012. 123(4): p. 587-600.
71. Bhatia, B., et al., Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and medulloblastoma. Oncogene, 2011. 30(4): p. 410-22.
72. Zaidi, N., J.V. Swinnen, and K. Smans, ATP-citrate lyase: a key player in cancer metabolism. Cancer Res, 2012. 72(15): p. 3709-14.
73. Dikalov, S., Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med, 2011. 51(7): p. 1289-301.
74. Taguchi, K. and M. Yamamoto, The KEAP1-NRF2 System in Cancer. Front Oncol, 2017. 7: p. 85.
75. Waris, G. and H. Ahsan, Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog, 2006. 5: p. 14.
76. Galloway, C.A. and Y. Yoon, Perspectives on: SGP symposium on mitochondrial physiology and medicine: what comes first, misshape or dysfunction? The view from metabolic excess. J Gen Physiol, 2012. 139(6): p. 455-63.
77. Sablina, A.A., et al., The antioxidant function of the p53 tumor suppressor. Nat Med, 2005. 11(12): p. 1306-13.
78. Davies, K.J., The broad spectrum of responses to oxidants in proliferating cells: a new paradigm for oxidative stress. IUBMB Life, 1999. 48(1): p. 41-7.
79. Scherz-Shouval, R. and Z. Elazar, ROS, mitochondria and the regulation of autophagy. Trends Cell Biol, 2007. 17(9): p. 422-7.
80. Bras, M., B. Queenan, and S.A. Susin, Programmed cell death via mitochondria: different modes of dying. Biochemistry (Mosc), 2005. 70(2): p. 231-9.
81. Meng, T.C., T. Fukada, and N.K. Tonks, Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol Cell, 2002. 9(2): p. 387-99.
82. Lee, J.G., et al., Reversible inactivation of deubiquitinases by reactive oxygen species in vitro and in cells. Nat Commun, 2013. 4: p. 1568.
83. Le Belle, J.E., et al., Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell, 2011. 8(1): p. 59-71.
84. Zhou, D., L. Shao, and D.R. Spitz, Reactive oxygen species in normal and tumor stem cells. Adv Cancer Res, 2014. 122: p. 1-67.
85. Bigarella, C.L., R. Liang, and S. Ghaffari, Stem cells and the impact of ROS signaling. Development, 2014. 141(22): p. 4206-18.
86. Case, A.J., et al., Mitochondrial-localized NADPH oxidase 4 is a source of superoxide in angiotensin II-stimulated neurons. Am J Physiol Heart Circ Physiol, 2013. 305(1): p. H19-28.
87. Graham, K.A., et al., NADPH oxidase 4 is an oncoprotein localized to mitochondria. Cancer Biol Ther, 2010. 10(3): p. 223-31.
88. Bedard, K. and K.H. Krause, The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev, 2007. 87(1): p. 245-313.
89. Brandes, R.P., N. Weissmann, and K. Schroder, Nox family NADPH oxidases: Molecular mechanisms of activation. Free Radic Biol Med, 2014. 76: p. 208-26.
90. Heppner, D.E. and A. van der Vliet, Redox-dependent regulation of epidermal growth factor receptor signaling. Redox Biol, 2016. 8: p. 24-7.
91. Jiang, F., Y. Zhang, and G.J. Dusting, NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol Rev, 2011. 63(1): p. 218-42.
92. Roy, K., et al., NADPH oxidases and cancer. Clin Sci (Lond), 2015. 128(12): p. 863-75.
93. Teixeira, G., et al., Therapeutic potential of NADPH oxidase 1/4 inhibitors. Br J Pharmacol, 2016.
94. Mondol, A.S., N.K. Tonks, and T. Kamata, Nox4 redox regulation of PTP1B contributes to the proliferation and migration of glioblastoma cells by modulating tyrosine phosphorylation of coronin-1C. Free Radic Biol Med, 2014. 67: p. 285-91.
95. Schroder, K., et al., Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase. Circ Res, 2012. 110(9): p. 1217-25.
96. Geiszt, M., et al., Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A, 2000. 97(14): p. 8010-4.
97. Helmcke, I., et al., Identification of structural elements in Nox1 and Nox4 controlling localization and activity. Antioxid Redox Signal, 2009. 11(6): p. 1279-87.
98. von Lohneysen, K., et al., Constitutive NADPH oxidase 4 activity resides in the composition of the B-loop and the penultimate C terminus. J Biol Chem, 2012. 287(12): p. 8737-45.
99. Kawahara, T., et al., Point mutations in the proline-rich region of p22phox are dominant inhibitors of Nox1- and Nox2-dependent reactive oxygen generation. J Biol Chem, 2005. 280(36): p. 31859-69.
100. Lassegue, B. and K.K. Griendling, NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb Vasc Biol, 2010. 30(4): p. 653-61.
101. Carnesecchi, S., et al., A key role for NOX4 in epithelial cell death during development of lung fibrosis. Antioxid Redox Signal, 2011. 15(3): p. 607-19.
102. Zhang, M., et al., NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. Proc Natl Acad Sci U S A, 2010. 107(42): p. 18121-6.
103. Jha, J.C., et al., Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy. Diabetologia, 2016. 59(2): p. 379-89.
104. Ma, M.W., et al., NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener, 2017. 12(1): p. 7.
105. Hughes, G., M.P. Murphy, and E.C. Ledgerwood, Mitochondrial reactive oxygen species regulate the temporal activation of nuclear factor kappaB to modulate tumour necrosis factor-induced apoptosis: evidence from mitochondria-targeted antioxidants. Biochem J, 2005. 389(Pt 1): p. 83-9.
106. Chen, X.L., et al., Superoxide, H2O2, and iron are required for TNF-alpha-induced MCP-1 gene expression in endothelial cells: role of Rac1 and NADPH oxidase. Am J Physiol Heart Circ Physiol, 2004. 286(3): p. H1001-7.
107. Deshpande, S.S., et al., Rac1 inhibits TNF-alpha-induced endothelial cell apoptosis: dual regulation by reactive oxygen species. FASEB J, 2000. 14(12): p. 1705-14.
108. Covarrubias, L., et al., Function of reactive oxygen species during animal development: passive or active? Dev Biol, 2008. 320(1): p. 1-11.
109. Tsatmali, M., et al., Reactive oxygen species modulate the differentiation of neurons in clonal cortical cultures. Mol Cell Neurosci, 2006. 33(4): p. 345-57.
110. Wilhelm, J., et al., Oxidative Stress in the Developing Rat Brain due to Production of Reactive Oxygen and Nitrogen Species. Oxid Med Cell Longev, 2016. 2016: p. 5057610.