Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.
| Title: | Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders. |
|---|---|
| Authors: | Biswas SR; Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, USA.; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.; Tomsick PL; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.; Pickrell AM; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.; Morton PD; Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA. |
| Source: | FEBS letters [FEBS Lett] 2026 Mar 30. Date of Electronic Publication: 2026 Mar 30. |
| Publication Model: | Ahead of Print |
| Publication Type: | Journal Article; Review |
| Language: | English |
| Journal Info: | Publisher: John Wiley & Sons Ltd Country of Publication: England NLM ID: 0155157 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3468 (Electronic) Linking ISSN: 00145793 NLM ISO Abbreviation: FEBS Lett Subsets: MEDLINE |
| Imprint Name(s): | Publication: Jan. 2016- : West Sussex : John Wiley & Sons Ltd.; Original Publication: Amsterdam, North-Holland on behalf of the Federation of European Biochemical Societies. |
| Abstract: | Primary mitochondrial disorders (PMDs) are inherited metabolic diseases that most often present with neurological symptoms in infancy or adolescence, underscoring the central importance of mitochondrial function to brain health. Historically, the field has emphasized neurodegeneration-consistent with the high energetic demands of postmitotic neurons. However, neurodevelopmental manifestations are now recognized as common early phenotypes, frequently preceding clinical regression in many PMDs. Given the pivotal role of mitochondria in neural stem/progenitor cell maintenance and cell fate decisions, defects in the respiratory chain are poised to disrupt neurogenesis and gliogenesis. Evidence for such developmental vulnerabilities is reviewed here. Likewise, because mitochondrial metabolism and dynamics shift across the oligodendrocyte lineage-from oligodendrocyte precursor cell expansion to differentiation and the energetically intensive phase of myelin synthesis-callosal atrophy in mitochondrial leukoencephalopathies may, at least in part, reflect developmental shortcomings in oligodendrogenesis and myelination. This possibility warrants focused investigation in cellular and in vivo models.; (© 2026 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.) |
| References: | Faria‐Pereira A and Morais VA (2022) Synapses: the Brain's energy‐demanding sites. Int J Mol Sci 23, doi: 10.3390/ijms23073627.; Belanger M, Allaman I and Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte‐neuron metabolic cooperation. Cell Metab 14, 724–738. doi: 10.1016/j.cmet.2011.08.016.; Martinez‐Reyes I and Chandel NS (2020) Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun 11, 102. doi: 10.1038/s41467‐019‐13668‐3.; Garone C, De Giorgio F and Carli S (2024) Mitochondrial metabolism in neural stem cells and implications for neurodevelopmental and neurodegenerative diseases. J Transl Med 22, 238. doi: 10.1186/s12967‐024‐05041‐w.; Scandella V, Petrelli F, Moore DL, Braun SMG and Knobloch M (2023) Neural stem cell metabolism revisited: a critical role for mitochondria. Trends Endocrinol Metab 34, 446–461. doi: 10.1016/j.tem.2023.05.008.; Khacho M, Clark A, Svoboda DS, Azzi J, MacLaurin JG, Meghaizel C, Sesaki H, Lagace DC, Germain M, Harper ME et al. (2016) Mitochondrial dynamics impacts stem cell identity and fate decisions by regulating a nuclear transcriptional program. Cell Stem Cell 19, 232–247. doi: 10.1016/j.stem.2016.04.015.; Sercel AJ, Carlson NM, Patananan AN and Teitell MA (2021) Mitochondrial DNA dynamics in reprogramming to pluripotency. Trends Cell Biol 31, 311–323. doi: 10.1016/j.tcb.2020.12.009.; Zhang J, Nuebel E, Daley GQ, Koehler CM and Teitell MA (2012) Metabolic regulation in pluripotent stem cells during reprogramming and self‐renewal. Cell Stem Cell 11, 589–595. doi: 10.1016/j.stem.2012.10.005.; Romero‐Morales AI and Gama V (2022) Revealing the impact of mitochondrial fitness during early neural development using human brain organoids. Front Mol Neurosci 15, 840265. doi: 10.3389/fnmol.2022.840265.; Iwata R, Casimir P and Vanderhaeghen P (2020) Mitochondrial dynamics in postmitotic cells regulate neurogenesis. Science 369, 858–862. doi: 10.1126/science.aba9760.; Lange C, Turrero Garcia M, Decimo I, Bifari F, Eelen G, Quaegebeur A, Boon R, Zhao H, Boeckx B, Chang J et al. (2016) Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis. EMBO J 35, 924–941. doi: 10.15252/embj.201592372.; Kessaris N, Fogarty M, Iannarelli P, Grist M, Wegner M and Richardson WD (2006) Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat Neurosci 9, 173–179. doi: 10.1038/nn1620.; Vincze A, Mazlo M, Seress L, Komoly S and Abraham H (2008) A correlative light and electron microscopic study of postnatal myelination in the murine corpus callosum. Int J Dev Neurosci 26, 575–584. doi: 10.1016/j.ijdevneu.2008.05.003.; Bame X and Hill RA (2024) Mitochondrial network reorganization and transient expansion during oligodendrocyte generation. Nat Commun 15, 6979. doi: 10.1038/s41467‐024‐51016‐2.; Schoenfeld R, Wong A, Silva J, Li M, Itoh A, Horiuchi M, Itoh T, Pleasure D and Cortopassi G (2010) Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation. Mitochondrion 10, 143–150. doi: 10.1016/j.mito.2009.12.141.; Yazdankhah M, Ghosh S, Shang P, Stepicheva N, Hose S, Liu H, Chamling X, Tian S, Sullivan MLG, Calderon MJ et al. (2021) BNIP3L‐mediated mitophagy is required for mitochondrial remodeling during the differentiation of optic nerve oligodendrocytes. Autophagy 17, 3140–3159. doi: 10.1080/15548627.2020.1871204.; Funfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, Brinkmann BG, Kassmann CM, Tzvetanova ID and Mobius W (2012) Glycolytic oligodendrocytes maintain myelin and long‐term axonal integrity. Nature 485, 517–521. doi: 10.1038/nature11007.; Almeida RG and Lyons DA (2017) On myelinated axon plasticity and neuronal circuit formation and function. J Neurosci 37, 10023–10034. doi: 10.1523/JNEUROSCI.3185‐16.2017.; Holguera I and Desplan C (2018) Neuronal specification in space and time. Science 362, 176–180. doi: 10.1126/science.aas9435.; Obernier K and Alvarez‐Buylla A (2019) Neural stem cells: origin, heterogeneity and regulation in the adult mammalian brain. Development 146, doi: 10.1242/dev.156059.; Gotz M and Huttner WB (2005) The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6, 777–788. doi: 10.1038/nrm1739.; Huttner WB and Brand M (1997) Asymmetric division and polarity of neuroepithelial cells. Curr Opin Neurobiol 7, 29–39. doi: 10.1016/s0959‐4388(97)80117‐1.; Kriegstein AR and Gotz M (2003) Radial glia diversity: a matter of cell fate. Glia 43, 37–43. doi: 10.1002/glia.10250.; Campbell K and Gotz M (2002) Radial glia: multi‐purpose cells for vertebrate brain development. Trends Neurosci 25, 235–238. doi: 10.1016/s0166‐2236(02)02156‐2.; Silva‐Vargas V, Delgado AC and Doetsch F (2018) Symmetric stem cell division at the heart of adult neurogenesis. Neuron 98, 246–248. doi: 10.1016/j.neuron.2018.04.005.; Martinez‐Cerdeno V and Noctor SC (2018) Neural Progenitor Cell Terminology. Front Neuroanat 12, 104. doi: 10.3389/fnana.2018.00104.; Taverna E, Gotz M and Huttner WB (2014) The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex. Annu Rev Cell Dev Biol 30, 465–502. doi: 10.1146/annurev‐cellbio‐101011‐155801.; Noctor SC, Flint AC, Weissman TA, Dammerman RS and Kriegstein AR (2001) Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 714–720. doi: 10.1038/35055553.; Englund C, Fink A, Lau C, Pham D, Daza RA, Bulfone A, Kowalczyk T and Hevner RF (2005) Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J Neurosci 25, 247–251. doi: 10.1523/JNEUROSCI.2899‐04.2005.; Tan X and Shi SH (2013) Neocortical neurogenesis and neuronal migration. Wiley Interdiscip Rev Dev Biol 2, 443–459. doi: 10.1002/wdev.88.; Miyazaki Y, Song JW and Takahashi E (2016) Asymmetry of radial and symmetry of tangential neuronal migration pathways in developing human fetal brains. Front Neuroanat 10, 2. doi: 10.3389/fnana.2016.00002.; Zhao Z, Zhang D, Yang F, Xu M, Zhao S, Pan T, Liu C, Liu Y, Wu Q, Tu Q et al. (2022) Evolutionarily conservative and non‐conservative regulatory networks during primate interneuron development revealed by single‐cell RNA and ATAC sequencing. Cell Res 32, 425–436. doi: 10.1038/s41422‐022‐00635‐9.; Xu Z, Liang Q, Song X, Zhang Z, Lindtner S, Li Z, Wen Y, Liu G, Guo T, Qi D et al. (2018) SP8 and SP9 coordinately promote D2‐type medium spiny neuron production by activating Six3 expression. Development 145, doi: 10.1242/dev.165456.; Shi Y, Wang M, Mi D, Lu T, Wang B, Dong H, Zhong S, Chen Y, Sun L, Zhou X et al. (2021) Mouse and human share conserved transcriptional programs for interneuron development. Science 374, eabj6641. doi: 10.1126/science.abj6641.; Bartkowska K, Tepper B, Turlejski K and Djavadian R (2022) Postnatal and adult neurogenesis in mammals, Including Marsupials. Cells 11, doi: 10.3390/cells11172735.; Sorrells SF (2024) Which neurodevelopmental processes continue in humans after birth? Front Neurosci 18, 1434508. doi: 10.3389/fnins.2024.1434508.; Sorrells SF, Paredes MF, Cebrian‐Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI et al. (2018) Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377–381. doi: 10.1038/nature25975.; Lois C and Alvarez‐Buylla A (1994) Long‐distance neuronal migration in the adult mammalian brain. Science 264, 1145–1148. doi: 10.1126/science.8178174.; Eriksson PS, Perfilieva E, Bjork‐Eriksson T, Alborn AM, Nordborg C, Peterson DA and Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4, 1313–1317. doi: 10.1038/3305.; Ming GL and Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702. doi: 10.1016/j.neuron.2011.05.001.; Sanai N, Nguyen T, Ihrie RA, Mirzadeh Z, Tsai HH, Wong M, Gupta N, Berger MS, Huang E, Garcia‐Verdugo JM et al. (2011) Corridors of migrating neurons in the human brain and their decline during infancy. Nature 478, 382–386. doi: 10.1038/nature10487.; Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, Rosoklija GB, Stankov A, Arango V and Dwork AJ (2018) Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22, 589–599. doi: 10.1016/j.stem.2018.03.015.; Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp ATN, Choi J, Xu C, Li Q, Morozov YM and Andrijevic D (2022) Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 110, 452–469. doi: 10.1016/j.neuron.2021.10.036.; Moreno‐Jimenez EP, Flor‐Garcia M, Terreros‐Roncal J, Rabano A, Cafini F, Pallas‐Bazarra N, Avila J and Llorens‐Martin M (2019) Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer's disease. Nat Med 25, 554–560. doi: 10.1038/s41591‐019‐0375‐9.; Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH et al. (2009) A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213. doi: 10.1126/science.1173215.; Fuentealba LC, Rompani SB, Parraguez JI, Obernier K, Romero R, Cepko CL and Alvarez‐Buylla A (2015) Embryonic origin of postnatal neural stem cells. Cell 161, 1644–1655. doi: 10.1016/j.cell.2015.05.041.; Furutachi S, Miya H, Watanabe T, Kawai H, Yamasaki N, Harada Y, Imayoshi I, Nelson M, Nakayama KI, Hirabayashi Y et al. (2015) Slowly dividing neural progenitors are an embryonic origin of adult neural stem cells. Nat Neurosci 18, 657–665. doi: 10.1038/nn.3989.; Calzolari F, Michel J, Baumgart EV, Theis F, Gotz M and Ninkovic J (2015) Fast clonal expansion and limited neural stem cell self‐renewal in the adult subependymal zone. Nat Neurosci 18, 490–492. doi: 10.1038/nn.3963.; Obernier K, Cebrian‐Silla A, Thomson M, Parraguez JI, Anderson R, Guinto C, Rodas Rodriguez J, Garcia‐Verdugo JM and Alvarez‐Buylla A (2018) Adult neurogenesis is sustained by symmetric self‐renewal and differentiation. Cell Stem Cell 22, 221–234. doi: 10.1016/j.stem.2018.01.003.; Marcy G, Foucault L, Babina E, Capeliez T, Texeraud E, Zweifel S, Heinrich C, Hernandez‐Vargas H, Parras C, Jabaudon D et al. (2023) Single‐cell analysis of the postnatal dorsal V‐SVZ reveals a role for Bmpr1a signaling in silencing pallial germinal activity. Sci Adv 9, eabq7553. doi: 10.1126/sciadv.abq7553.; Fiorelli R, Azim K, Fischer B and Raineteau O (2015) Adding a spatial dimension to postnatal ventricular‐subventricular zone neurogenesis. Development 142, 2109–2120. doi: 10.1242/dev.119966.; Lopez‐Juarez A, Howard J, Ullom K, Howard L, Grande A, Pardo A, Waclaw R, Sun YY, Yang D and Kuan CY (2013) Gsx2 controls region‐specific activation of neural stem cells and injury‐induced neurogenesis in the adult subventricular zone. Genes Dev 27, 1272–1287. doi: 10.1101/gad.217539.113.; Young KM, Fogarty M, Kessaris N and Richardson WD (2007) Subventricular zone stem cells are heterogeneous with respect to their embryonic origins and neurogenic fates in the adult olfactory bulb. J Neurosci 27, 8286–8296. doi: 10.1523/JNEUROSCI.0476‐07.2007.; Tiveron MC, Beclin C, Murgan S, Wild S, Angelova A, Marc J, Core N, de Chevigny A, Herrera E and Bosio A (2017) Zic‐proteins are repressors of dopaminergic forebrain fate in mice and C. Elegans. J Neurosci 37, 10611–10623. doi: 10.1523/JNEUROSCI.3888‐16.2017.; Delgado RN and Lim DA (2015) Embryonic Nkx2.1‐expressing neural precursor cells contribute to the regional heterogeneity of adult V‐SVZ neural stem cells. Dev Biol 407, 265–274. doi: 10.1016/j.ydbio.2015.09.008.; Merkle FT, Fuentealba LC, Sanders TA, Magno L, Kessaris N and Alvarez‐Buylla A (2014) Adult neural stem cells in distinct microdomains generate previously unknown interneuron types. Nat Neurosci 17, 207–214. doi: 10.1038/nn.3610.; Merkle FT, Mirzadeh Z and Alvarez‐Buylla A (2007) Mosaic organization of neural stem cells in the adult brain. Science 317, 381–384. doi: 10.1126/science.1144914.; Inta D, Alfonso J, von Engelhardt J, Kreuzberg MM, Meyer AH, van Hooft JA and Monyer H (2008) Neurogenesis and widespread forebrain migration of distinct GABAergic neurons from the postnatal subventricular zone. Proc Natl Acad Sci USA 105, 20994–20999. doi: 10.1073/pnas.0807059105.; De Marchis S, Fasolo A and Puche AC (2004) Subventricular zone‐derived neuronal progenitors migrate into the subcortical forebrain of postnatal mice. J Comp Neurol 476, 290–300. doi: 10.1002/cne.20217.; Shapiro LA, Ng K, Zhou QY and Ribak CE (2009) Subventricular zone‐derived, newly generated neurons populate several olfactory and limbic forebrain regions. Epilepsy Behav 14 (1), 74–80. doi: 10.1016/j.yebeh.2008.09.011.; Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, Possnert G, Druid H and Frisen J (2014) Neurogenesis in the striatum of the adult human brain. Cell 156, 1072–1083. doi: 10.1016/j.cell.2014.01.044.; Grangeray Vilmint A and Lelievre V (2012) The medial migratory stream: a new turn in postnatal neurogenesis! Cell Adhes Migr 6, 454–456. doi: 10.4161/cam.22806.; Nelson BR, Hodge RD, Daza RA, Tripathi PP, Arnold SJ, Millen KJ and Hevner RF (2020) Intermediate progenitors support migration of neural stem cells into dentate gyrus outer neurogenic niches. elife 9, doi: 10.7554/eLife.53777.; Matsue K, Minakawa S, Kashiwagi T, Toda K, Sato T, Shioda S and Seki T (2018) Dentate granule progenitor cell properties are rapidly altered soon after birth. Brain Struct Funct 223, 357–369. doi: 10.1007/s00429‐017‐1499‐7.; Seki T, Sato T, Toda K, Osumi N, Imura T and Shioda S (2014) Distinctive population of Gfap‐expressing neural progenitors arising around the dentate notch migrate and form the granule cell layer in the developing hippocampus. J Comp Neurol 522, 261–283. doi: 10.1002/cne.23460.; Pilz GA, Bottes S, Betizeau M, Jorg DJ, Carta S, April S, Simons BD, Helmchen F and Jessberger S (2018) Live imaging of neurogenesis in the adult mouse hippocampus. Science 359, 658–662. doi: 10.1126/science.aao5056.; Nicola Z, Fabel K and Kempermann G (2015) Development of the adult neurogenic niche in the hippocampus of mice. Front Neuroanat 9, 53. doi: 10.3389/fnana.2015.00053.; Deng W, Aimone JB and Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11, 339–350. doi: 10.1038/nrn2822.; Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O et al. (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809. doi: 10.1126/science.1083328.; Dong X, Zhang Q, Yu X, Wang D, Ma J, Ma J and Shi SH (2022) Metabolic lactate production coordinates vasculature development and progenitor behavior in the developing mouse neocortex. Nat Neurosci 25, 865–875. doi: 10.1038/s41593‐022‐01093‐7.; Prigione A, Lichtner B, Kuhl H, Struys EA, Wamelink M, Lehrach H, Ralser M, Timmermann B and Adjaye J (2011) Human induced pluripotent stem cells harbor homoplasmic and heteroplasmic mitochondrial DNA mutations while maintaining human embryonic stem cell‐like metabolic reprogramming. Stem Cells 29, 1338–1348. doi: 10.1002/stem.683.; Schell JC, Wisidagama DR, Bensard C, Zhao H, Wei P, Tanner J, Flores A, Mohlman J, Sorensen LK, Earl CS et al. (2017) Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat Cell Biol 19, 1027–1036. doi: 10.1038/ncb3593.; Takubo K, Nagamatsu G, Kobayashi CI, Nakamura‐Ishizu A, Kobayashi H, Ikeda E, Goda N, Rahimi Y, Johnson RS, Soga T et al. (2013) Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12, 49–61. doi: 10.1016/j.stem.2012.10.011.; Khacho M, Clark A, Svoboda DS, MacLaurin JG, Lagace DC, Park DS and Slack RS (2017) Mitochondrial dysfunction underlies cognitive defects as a result of neural stem cell depletion and impaired neurogenesis. Hum Mol Genet 26, 3327–3341. doi: 10.1093/hmg/ddx217.; Salscheider SL, Gerlich S, Cabrera‐Orefice A, Peker E, Rothemann RA, Murschall LM, Finger Y, Szczepanowska K, Ahmadi ZA, Guerrero‐Castillo S et al. (2022) AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5. EMBO J 41, e110784. doi: 10.15252/embj.2022110784.; Zheng X, Boyer L, Jin M, Mertens J, Kim Y, Ma L, Ma L, Hamm M, Gage FH and Hunter T (2016) Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation. elife 5, doi: 10.7554/eLife.13374.; Giacomello M, Pyakurel A, Glytsou C and Scorrano L (2020) The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol 21, 204–224. doi: 10.1038/s41580‐020‐0210‐7.; Matsuzaki F and Shitamukai A (2015) Cell division modes and cleavage planes of neural progenitors during mammalian cortical development. Cold Spring Harb Perspect Biol 7, a015719. doi: 10.1101/cshperspect.a015719.; Coller HA (2019) The paradox of metabolism in quiescent stem cells. FEBS Lett 593, 2817–2839. doi: 10.1002/1873‐3468.13608.; Ito K and Suda T (2014) Metabolic requirements for the maintenance of self‐renewing stem cells. Nat Rev Mol Cell Biol 15, 243–256. doi: 10.1038/nrm3772.; Beckervordersandforth R, Ebert B, Schaffner I, Moss J, Fiebig C, Shin J, Moore DL, Ghosh L, Trinchero MF and Stockburger C (2017) Role of mitochondrial metabolism in the control of early lineage progression and aging phenotypes in adult hippocampal neurogenesis. Neuron 93, 560–573. doi: 10.1016/j.neuron.2016.12.017.; Knobloch M, Pilz GA, Ghesquiere B, Kovacs WJ, Wegleiter T, Moore DL, Hruzova M, Zamboni N, Carmeliet P and Jessberger S (2017) A fatty acid oxidation‐dependent metabolic shift regulates adult neural stem cell activity. Cell Rep 20, 2144–2155. doi: 10.1016/j.celrep.2017.08.029.; Petridi S, Dubal D, Rikhy R and van den Ameele J (2022) Mitochondrial respiration and dynamics of in vivo neural stem cells. Development 149, doi: 10.1242/dev.200870.; Reid MA, Dai Z and Locasale JW (2017) The impact of cellular metabolism on chromatin dynamics and epigenetics. Nat Cell Biol 19, 1298–1306. doi: 10.1038/ncb3629.; Liu Y, Wang M, Guo Y, Wang L and Guo W (2023) D‐2‐hydroxyglutarate dehydrogenase governs adult neural stem cell activation and promotes histone acetylation via ATP‐citrate lyase. Cell Rep 42, 112067. doi: 10.1016/j.celrep.2023.112067.; Nave KA and Werner HB (2014) Myelination of the nervous system: mechanisms and functions. Annu Rev Cell Dev Biol 30, 503–533. doi: 10.1146/annurev‐cellbio‐100913‐013101.; Waxman SG and Bennett MV (1972) Relative conduction velocities of small myelinated and non‐myelinated fibres in the central nervous system. Nat New Biol 238, 217–219. doi: 10.1038/newbio238217a0.; Bergles DE and Richardson WD (2015) Oligodendrocyte development and plasticity. Cold Spring Harb Perspect Biol 8, a020453. doi: 10.1101/cshperspect.a020453.; Huang W, Bhaduri A, Velmeshev D, Wang S, Wang L, Rottkamp CA, Alvarez‐Buylla A, Rowitch DH and Kriegstein AR (2020) Origins and proliferative states of human oligodendrocyte precursor cells. Cell 182, 594–608. doi: 10.1016/j.cell.2020.06.027.; Naruse M, Ishizaki Y, Ikenaka K, Tanaka A and Hitoshi S (2017) Origin of oligodendrocytes in mammalian forebrains: a revised perspective. J Physiol Sci 67, 63–70. doi: 10.1007/s12576‐016‐0479‐7.; Zheng K, Wang C, Yang J, Huang H, Zhao X, Zhang Z and Qiu M (2018) Molecular and genetic evidence for the PDGFRalpha‐independent population of oligodendrocyte progenitor cells in the developing mouse brain. J Neurosci 38, 9505–9513. doi: 10.1523/JNEUROSCI.1510‐18.2018.; Buchet D, Garcia C, Deboux C, Nait‐Oumesmar B and Baron‐Van Evercooren A (2011) Human neural progenitors from different foetal forebrain regions remyelinate the adult mouse spinal cord. Brain 134, 1168–1183. doi: 10.1093/brain/awr030.; Orduz D, Benamer N, Ortolani D, Coppola E, Vigier L, Pierani A and Angulo MC (2019) Developmental cell death regulates lineage‐related interneuron‐oligodendroglia functional clusters and oligodendrocyte homeostasis. Nat Commun 10, 4249. doi: 10.1038/s41467‐019‐11904‐4.; de Castro F, Bribian A and Ortega MC (2013) Regulation of oligodendrocyte precursor migration during development, in adulthood and in pathology. Cell Mol Life Sci 70, 4355–4368. doi: 10.1007/s00018‐013‐1365‐6.; Dimou L, Simon C, Kirchhoff F, Takebayashi H and Gotz M (2008) Progeny of Olig2‐expressing progenitors in the gray and white matter of the adult mouse cerebral cortex. J Neurosci 28, 10434–10442. doi: 10.1523/JNEUROSCI.2831‐08.2008.; Carlstrom KE, Zhu K, Ewing E, Krabbendam IE, Harris RA, Falcao AM, Jagodic M, Castelo‐Branco G and Piehl F (2020) Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria‐associated Fas‐Casp8‐bid‐axis. Nat Commun 11, 4071. doi: 10.1038/s41467‐020‐17871‐5.; Hughes EG and Stockton ME (2021) Premyelinating oligodendrocytes: mechanisms underlying cell survival and integration. Front Cell Dev Biol 9, 714169. doi: 10.3389/fcell.2021.714169.; Hughes EG, Orthmann‐Murphy JL, Langseth AJ and Bergles DE (2018) Myelin remodeling through experience‐dependent oligodendrogenesis in the adult somatosensory cortex. Nat Neurosci 21, 696–706. doi: 10.1038/s41593‐018‐0121‐5.; Domingues HS, Portugal CC, Socodato R and Relvas JB (2016) Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol 4, 71. doi: 10.3389/fcell.2016.00071.; Dugas JC, Cuellar TL, Scholze A, Ason B, Ibrahim A, Emery B, Zamanian JL, Foo LC, McManus MT and Barres BA (2010) Dicer1 and miR‐219 are required for normal oligodendrocyte differentiation and myelination. Neuron 65, 597–611. doi: 10.1016/j.neuron.2010.01.027.; Rouillard ME, Hu J, Sutter PA, Kim HW, Huang JK and Crocker SJ (2022) The cellular senescence factor extracellular HMGB1 directly inhibits oligodendrocyte progenitor cell differentiation and impairs CNS Remyelination. Front Cell Neurosci 16, 833186. doi: 10.3389/fncel.2022.833186.; Stolt CC, Rehberg S, Ader M, Lommes P, Riethmacher D, Schachner M, Bartsch U and Wegner M (2002) Terminal differentiation of myelin‐forming oligodendrocytes depends on the transcription factor Sox10. Genes Dev 16, 165–170. doi: 10.1101/gad.215802.; Solly SK, Thomas JL, Monge M, Demerens C, Lubetzki C, Gardinier MV, Matthieu JM and Zalc B (1996) Myelin/oligodendrocyte glycoprotein (MOG) expression is associated with myelin deposition. Glia 18, 39–48. doi: 10.1002/(SICI)1098‐1136(199609)18:13.0.CO;2‐Z.; Kuhn S, Gritti L, Crooks D and Dombrowski Y (2019) Oligodendrocytes in Development, Myelin Generation and beyond. Cells 8, doi: 10.3390/cells8111424.; Harlow DE, Saul KE, Culp CM, Vesely EM and Macklin WB (2014) Expression of proteolipid protein gene in spinal cord stem cells and early oligodendrocyte progenitor cells is dispensable for normal cell migration and myelination. J Neurosci 34, 1333–1343. doi: 10.1523/JNEUROSCI.2477‐13.2014.; Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, Kessaris N and Richardson WD (2008) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11, 1392–1401. doi: 10.1038/nn.2220.; Hill RA, Li AM and Grutzendler J (2018) Lifelong cortical myelin plasticity and age‐related degeneration in the live mammalian brain. Nat Neurosci 21, 683–695. doi: 10.1038/s41593‐018‐0120‐6.; Schmithorst VJ and Yuan W (2010) White matter development during adolescence as shown by diffusion MRI. Brain Cogn 72, 16–25. doi: 10.1016/j.bandc.2009.06.005.; Gunning‐Dixon FM and Raz N (2000) The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. Neuropsychology 14, 224–232. doi: 10.1037//0894‐4105.14.2.224.; Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Wood LS, Inema I, Miller SE, Bieri G, Zuchero JB et al. (2014) Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344, 1252304. doi: 10.1126/science.1252304.; Fields RD (2008) White matter in learning, cognition and psychiatric disorders. Trends Neurosci 31, 361–370. doi: 10.1016/j.tins.2008.04.001.; Rao VTS, Khan D, Cui QL, Fuh SC, Hossain S, Almazan G, Multhaup G, Healy LM, Kennedy TE and Antel JP (2017) Distinct age and differentiation‐state dependent metabolic profiles of oligodendrocytes under optimal and stress conditions. PLoS One 12, e0182372. doi: 10.1371/journal.pone.0182372.; Rinholm JE, Hamilton NB, Kessaris N, Richardson WD, Bergersen LH and Attwell D (2011) Regulation of oligodendrocyte development and myelination by glucose and lactate. J Neurosci 31, 538–548. doi: 10.1523/JNEUROSCI.3516‐10.2011.; Schulz H (1991) Beta oxidation of fatty acids. Biochim Biophys Acta 1081, 109–120. doi: 10.1016/0005‐2760(91)90015‐a.; Viader A, Sasaki Y, Kim S, Strickland A, Workman CS, Yang K, Gross RW and Milbrandt J (2013) Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron 77, 886–898. doi: 10.1016/j.neuron.2013.01.012.; Neumann B, Baror R, Zhao C, Segel M, Dietmann S, Rawji KS, Foerster S, McClain CR, Chalut K and van Wijngaarden P (2019) Metformin restores CNS Remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell 25, 473–485. doi: 10.1016/j.stem.2019.08.015.; Wender R, Brown AM, Fern R, Swanson RA, Farrell K and Ransom BR (2000) Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J Neurosci 20, 6804–6810. doi: 10.1523/JNEUROSCI.20‐18‐06804.2000.; Orthmann‐Murphy JL, Abrams CK and Scherer SS (2008) Gap junctions couple astrocytes and oligodendrocytes. J Mol Neurosci 35, 101–116. doi: 10.1007/s12031‐007‐9027‐5.; Magistretti PJ and Allaman I (2015) A cellular perspective on brain energy metabolism and functional imaging. Neuron 86, 883–901. doi: 10.1016/j.neuron.2015.03.035.; Brown AM and Ransom BR (2007) Astrocyte glycogen and brain energy metabolism. Glia 55, 1263–1271. doi: 10.1002/glia.20557.; Shaw JC, Crombie GK, Palliser HK and Hirst JJ (2021) Impaired oligodendrocyte development following preterm birth: promoting GABAergic action to improve outcomes. Front Pediatr 9, 618052. doi: 10.3389/fped.2021.618052.; Sanchez‐Abarca LI, Tabernero A and Medina JM (2001) Oligodendrocytes use lactate as a source of energy and as a precursor of lipids. Glia 36, 321–329. doi: 10.1002/glia.1119.; Ichihara Y, Doi T, Ryu Y, Nagao M, Sawada Y and Ogata T (2017) Oligodendrocyte progenitor cells directly utilize lactate for promoting cell cycling and differentiation. J Cell Physiol 232, 986–995. doi: 10.1002/jcp.25690.; Morland C, Henjum S, Iversen EG, Skrede KK and Hassel B (2007) Evidence for a higher glycolytic than oxidative metabolic activity in white matter of rat brain. Neurochem Int 50, 703–709. doi: 10.1016/j.neuint.2007.01.003.; Nunnari J and Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148, 1145–1159. doi: 10.1016/j.cell.2012.02.035.; Gorman GS, Chinnery PF, Di Mauro S, Hirano M, Koga Y, McFarland R, Suomalainen A, Thorburn DR, Zeviani M and Turnbull DM (2016) Mitochondrial diseases. Nat Rev Dis Primers 2, 16080. doi: 10.1038/nrdp.2016.80.; Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, Feeney C, Horvath R, Yu‐Wai‐Man P, Chinnery PF et al. (2015) Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 77, 753–759. doi: 10.1002/ana.24362.; Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF and Turnbull DM (2008) Prevalence of mitochondrial DNA disease in adults. Ann Neurol 63, 35–39. doi: 10.1002/ana.21217.; Nesbitt V, Pitceathly RD, Turnbull DM, Taylor RW, Sweeney MG, Mudanohwo EE, Rahman S, Hanna MG and McFarland R (2013) The UK MRC mitochondrial disease patient cohort study: clinical phenotypes associated with the m.3243A>G mutation‐‐implications for diagnosis and management. J Neurol Neurosurg Psychiatry 84, 936–938. doi: 10.1136/jnnp‐2012‐303528.; Muraresku CC, McCormick EM and Falk MJ (2018) Mitochondrial disease: advances in clinical diagnosis, management, therapeutic development, and preventative strategies. Curr Genet Med Rep 6, 62–72. doi: 10.1007/s40142‐018‐0138‐9.; McFarland R, Taylor RW and Turnbull DM (2010) A neurological perspective on mitochondrial disease. Lancet Neurol 9, 829–840. doi: 10.1016/S1474‐4422(10)70116‐2.; Pareyson D, Piscosquito G, Moroni I, Salsano E and Zeviani M (2013) Peripheral neuropathy in mitochondrial disorders. Lancet Neurol 12, 1011–1124. doi: 10.1016/S1474‐4422(13)70158‐3.; Falk MJ (2010) Neurodevelopmental manifestations of mitochondrial disease. J Dev Behav Pediatr 31, 610–621. doi: 10.1097/DBP.0b013e3181ef42c1.; Tinker RJ, Falk MJ, Goldstein A, George‐Sankoh I, Xiao R, Adang L and Ganetzky R (2022) Early developmental delay in Leigh syndrome spectrum disorders is associated with poor clinical prognosis. Mol Genet Metab 135, 342–349. doi: 10.1016/j.ymgme.2022.02.006.; Shi G, Miller C, Kuno S, Rey Hipolito AG, El Nagar S, Riboldi GM, Korn M, Tran WC, Wang Z and Ficaro L (2025) Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy. Nature doi: 10.1038/s41586‐025‐09246‐x.; Eom S and Lee YM (2017) Long‐term developmental trends of pediatric mitochondrial diseases: the five stages of developmental decline. Front Neurol 8, 208. doi: 10.3389/fneur.2017.00208.; Lee HF, Lee HJ, Chi CS, Tsai CR, Chang TK and Wang CJ (2007) The neurological evolution of Pearson syndrome: case report and literature review. Eur J Paediatr Neurol 11, 208–214. doi: 10.1016/j.ejpn.2006.12.008.; Romero‐Morales AI, Robertson GL, Rastogi A, Rasmussen ML, Temuri H, GS ME, Chakrabarty RP, Hsu L, Almonacid PM and Millis BA (2022) Human iPSC‐derived cerebral organoids model features of Leigh syndrome and reveal abnormal corticogenesis. Development 149, doi: 10.1242/dev.199914.; Lorenz C, Lesimple P, Bukowiecki R, Zink A, Inak G, Mlody B, Singh M, Semtner M, Mah N and Aure K (2017) Human iPSC‐derived neural progenitors are an effective drug discovery model for neurological mtDNA disorders. Cell Stem Cell 20, 659–674. doi: 10.1016/j.stem.2016.12.013.; Inak G, Rybak‐Wolf A, Lisowski P, Pentimalli TM, Juttner R, Glazar P, Uppal K, Bottani E, Brunetti D and Secker C (2021) Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome. Nat Commun 12, 1929. doi: 10.1038/s41467‐021‐22117‐z.; Quadalti C, Brunetti D, Lagutina I, Duchi R, Perota A, Lazzari G, Cerutti R, Di Meo I, Johnson M and Bottani E (2018) SURF1 knockout cloned pigs: early onset of a severe lethal phenotype. Biochim Biophys Acta (BBA) ‐ Mol Basis Dis 1864, 2131–2142. doi: 10.1016/j.bbadis.2018.03.021.; Winanto, Khong ZJ, Soh BS, Fan Y and Ng SY (2020) Organoid cultures of MELAS neural cells reveal hyperactive notch signaling that impacts neurodevelopment. Cell Death Dis 11, 182. doi: 10.1038/s41419‐020‐2383‐6.; Vahsen N, Cande C, Briere JJ, Benit P, Joza N, Larochette N, Mastroberardino PG, Pequignot MO, Casares N and Lazar V (2004) AIF deficiency compromises oxidative phosphorylation. EMBO J 23, 4679–4689. doi: 10.1038/sj.emboj.7600461.; Cabello‐Rivera D, Sarmiento‐Soto H, Lopez‐Barneo J and Munoz‐Cabello AM (2019) Mitochondrial complex I function is essential for neural stem/progenitor cells proliferation and differentiation. Front Neurosci 13, 664. doi: 10.3389/fnins.2019.00664.; Filippi M, Preziosa P, Banwell BL, Barkhof F, Ciccarelli O, De Stefano N, JJG G, Paul F, Reich DS and Toosy AT (2019) Assessment of lesions on magnetic resonance imaging in multiple sclerosis: practical guidelines. Brain 142, 1858–1875. doi: 10.1093/brain/awz144.; Lynch DS, Wade C, ARB P, John N, Kinsella JA, Merwick A, Ahmed RM, Warren JD, Mummery CJ and Schott JM (2019) Practical approach to the diagnosis of adult‐onset leukodystrophies: an updated guide in the genomic era. J Neurol Neurosurg Psychiatry 90, 543–554. doi: 10.1136/jnnp‐2018‐319481.; Back SA (2017) White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol 134, 331–349. doi: 10.1007/s00401‐017‐1718‐6.; Roosendaal SD, van de Brug T, Alves C, Blaser S, Vanderver A, Wolf NI and van der Knaap MS (2021) Imaging patterns characterizing mitochondrial Leukodystrophies. AJNR Am J Neuroradiol 42, 1334–1340. doi: 10.3174/ajnr.A7097.; Oliveira R, Sommerville EW, Thompson K, Nunes J, Pyle A, Grazina M, Chinnery PF, Diogo L, Garcia P and Taylor RW (2017) Lethal neonatal LTBL associated with Biallelic EARS2 variants: case report and review of the reported Neuroradiological features. JIMD Rep 33, 61–68. doi: 10.1007/8904_2016_581.; Shevell MI, Matthews PM, Scriver CR, Brown RM, Otero LJ, Legris M, Brown GK and Arnold DL (1994) Cerebral dysgenesis and lactic acidemia: an MRI/MRS phenotype associated with pyruvate dehydrogenase deficiency. Pediatr Neurol 11, 224–229. doi: 10.1016/0887‐8994(94)90107‐4.; Tang Y, Qin Q, Xing Y, Guo D, Di L and Jia J (2019) AARS2 leukoencephalopathy: a new variant of mitochondrial encephalomyopathy. Mol Genet Genomic Med 7, e00582. doi: 10.1002/mgg3.582.; Ardissone A, Bruno C, Diodato D, Donati A, Ghezzi D, Lamantea E, Lamperti C, Mancuso M, Martinelli D, Primiano G et al. (2021) Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases. Orphanet J Rare Dis 16, 413. doi: 10.1186/s13023‐021‐02029‐3.; Kakkar C, Gupta S, Kakkar S, Gupta K and Saggar K (2022) Spectrum of magnetic resonance abnormalities in leigh syndrome with emphasis on correlation of diffusion‐weighted imaging findings with clinical presentation. Ann Afr Med 21, 426–431. doi: 10.4103/aam.aam_160_21.; Topcu M, Saatci I, Apak RA, Soylemezoglu F and Akcoren Z (2000) Leigh syndrome in a 3‐year‐old boy with unusual brain MR imaging and pathologic findings. AJNR Am J Neuroradiol 21, 224–227.; Biswas SR, Tomsick PL, Kelly C, Lester BA, Milner JP, Henry SN, Soto Y, Brindley S, DeFoor N and Morton PD (2025) Impaired complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice. EMBO Mol Med doi: 10.1038/s44321‐025‐00367‐4.; Zehnder T, Petrelli F, Romanos J, De Oliveira Figueiredo EC, Lewis TL Jr, Deglon N, Polleux F, Santello M and Bezzi P (2021) Mitochondrial biogenesis in developing astrocytes regulates astrocyte maturation and synapse formation. Cell Rep 35, 108952. doi: 10.1016/j.celrep.2021.108952.; Salazar MPR, Kolanukuduru S, Ramirez V, Lyu B, Manigault G, Sejourne G, Sesaki H, Yu G and Eroglu C (2025) Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex. bioRxiv doi: 10.1101/2024.10.22.619706.; Pellerin L and Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci USA 91, 10625–10629. doi: 10.1073/pnas.91.22.10625. |
| Grant Information: | R01 ES035013 United States ES NIEHS NIH HHS; R35 GM142368 United States GM NIGMS NIH HHS; R35GM142368 United States GM NIGMS NIH HHS; R01ES035013 United States ES NIEHS NIH HHS |
| Contributed Indexing: | Keywords: mitochondria; mitochondria disorders; neural stem cells; oligodendrocytes; white matter |
| Entry Date(s): | Date Created: 20260330 Latest Revision: 20260422 |
| Update Code: | 20260422 |
| DOI: | 10.1002/1873-3468.70335 |
| PMID: | 41911312 |
| Database: | MEDLINE |
Journal Article; Review