Mitochondria and reactive oxygen species in brain development and pediatric brain tumors
Main Article Content
Abstract
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: <https://esmed.org/MRA/mra/article/view/1401>. Date accessed: 15 dec. 2024.
Keywords
medulloblastoma; metabolism; cancer; brain development
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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6. Ramaswamy, V., et al., Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol, 2013. 14(12): p. 1200-7.
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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.
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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.
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