Skip to main content
SpringerLink
Log in

Astrocyte Mitochondria in White-Matter Injury

Neurochemical Research volume 46, pages 2696–2714 (2021)Cite this article

Abstract

This review summarizes the diverse structure and function of astrocytes to describe the bioenergetic versatility required of astrocytes that are situated at different locations. The intercellular domain of astrocyte mitochondria defines their roles in supporting and regulating astrocyte-neuron coupling and survival against ischemia. The heterogeneity of astrocyte mitochondria, and how subpopulations of astrocyte mitochondria adapt to interact with other glia and regulate axon function, require further investigation. It has become clear that mitochondrial permeability transition pores play a key role in a wide variety of human diseases, whose common pathology may be based on mitochondrial dysfunction triggered by Ca2+ and potentiated by oxidative stress. Reactive oxygen species cause axonal degeneration and a reduction in axonal transport, leading to axonal dystrophies and neurodegeneration including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease. Developing new tools to allow better investigation of mitochondrial structure and function in astrocytes, and techniques to specifically target astrocyte mitochondria, can help to unravel the role of mitochondrial health and dysfunction in a more inclusive context outside of neuronal cells. Overall, this review will assess the value of astrocyte mitochondria as a therapeutic target to mitigate acute and chronic injury in the CNS.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. Verkhratsky A, Nedergaard M (2018) Physiology of Astroglia. Physiol Rev 98:239–389. https://doi.org/10.1152/physrev.00042.2016

    Article  CAS  PubMed  Google Scholar 

  2. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43–50. https://doi.org/10.1038/nn980

    Article  CAS  PubMed  Google Scholar 

  3. Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376. https://doi.org/10.1038/nn2003

    Article  CAS  PubMed  Google Scholar 

  4. Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–267. https://doi.org/10.1038/nn1623

    Article  CAS  PubMed  Google Scholar 

  5. Chesler M, Kaila K (1992) Modulation of pH by neuronal activity. Trends Neurosci 15:396–402. https://doi.org/10.1016/0166-2236(92)90191-a

    Article  CAS  PubMed  Google Scholar 

  6. Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S, Xu Q, Oberheim NA, Bekar L, Betstadt S, Silva AJ, Takano T, Goldman SA, Nedergaard M (2013) Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12:342–353. https://doi.org/10.1016/j.stem.2012.12.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang DD, Bordey A (2008) The astrocyte odyssey. Prog Neurobiol 86:342–367. https://doi.org/10.1016/j.pneurobio.2008.09.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Belanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14:724–738. https://doi.org/10.1016/j.cmet.2011.08.016

    Article  CAS  PubMed  Google Scholar 

  9. Brown AM, Tekkok SB, Ransom BR (2002) Hypoglycemia and white matter: pathophysiology of axon injury and role of glycogen. Diabetes Nutr Metab 15:290–293 discussion 293-294

    CAS  PubMed  Google Scholar 

  10. Brown AM, Tekkok SB, Ransom BR (2003) Glycogen regulation and functional role in mouse white matter. J Physiol 549:501–512. https://doi.org/10.1113/jphysiol.2003.042416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tekkok SB, Brown AM, Westenbroek R, Pellerin L, Ransom BR (2005) Transfer of glycogen-derived lactate from astrocytes to axons via specific monocarboxylate transporters supports mouse optic nerve activity. J Neurosci Res 81:644–652. https://doi.org/10.1002/jnr.20573

    Article  CAS  PubMed  Google Scholar 

  12. Gourine AV, Kasymov V, Marina N, Tang F, Figueiredo MF, Lane S, Teschemacher AG, Spyer KM, Deisseroth K, Kasparov S (2010) Astrocytes control breathing through pH-dependent release of ATP. Science 329:571–575. https://doi.org/10.1126/science.1190721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Blutstein T, Haydon PG (2013) The importance of astrocyte-derived purines in the modulation of sleep. Glia 61:129–139. https://doi.org/10.1002/glia.22422

    Article  PubMed  Google Scholar 

  14. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4:147–111. https://doi.org/10.1126/scitranslmed.3003748

    Article  CAS  Google Scholar 

  15. Iliff JJ, Nedergaard M (2013) Is there a cerebral lymphatic system? Stroke 44:S93–S95. https://doi.org/10.1161/STROKEAHA.112.678698

    Article  PubMed  PubMed Central  Google Scholar 

  16. Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA, Liao Y, Deane R, Nedergaard M (2013) Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 33:18190–18199. https://doi.org/10.1523/JNEUROSCI.1592-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sasaki T, Matsuki N, Ikegaya Y (2011) Action-potential modulation during axonal conduction. Science 331:599–601. https://doi.org/10.1126/science.1197598

    Article  CAS  PubMed  Google Scholar 

  18. Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–433. https://doi.org/10.1016/j.cell.2004.12.020

    Article  CAS  PubMed  Google Scholar 

  19. Eroglu C, Allen NJ, Susman MW, O’Rourke NA, Park CY, Ozkan E, Chakraborty C, Mulinyawe SB, Annis DS, Huberman AD, Green EM, Lawler J, Dolmetsch R, Garcia KC, Smith SJ, Luo ZD, Rosenthal A, Mosher DF, Barres BA (2009) Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139:380–392. https://doi.org/10.1016/j.cell.2009.09.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29:547–553. https://doi.org/10.1016/j.tins.2006.08.004

    Article  CAS  PubMed  Google Scholar 

  21. Zhang K, Sejnowski TJ (2000) A universal scaling law between gray matter and white matter of cerebral cortex. Proc Natl Acad Sci U S A 97:5621–5626. https://doi.org/10.1073/pnas.090504197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Emsley JG, Macklis JD (2006) Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biol 2:175–186. https://doi.org/10.1017/S1740925X06000202

    Article  PubMed  PubMed Central  Google Scholar 

  23. Nash B, Ioannidou K, Barnett SC (2011) Astrocyte phenotypes and their relationship to myelination. J Anat 219:44–52. https://doi.org/10.1111/j.1469-7580.2010.01330.x

    Article  PubMed  Google Scholar 

  24. Vaccarino FM, Fagel DM, Ganat Y, Maragnoli ME, Ment LR, Ohkubo Y, Schwartz ML, Silbereis J, Smith KM (2007) Astroglial cells in development, regeneration, and repair. Neuroscientist 13:173–185. https://doi.org/10.1177/1073858406298336

    Article  CAS  PubMed  Google Scholar 

  25. Molofsky AV, Krencik R, Ullian EM, Tsai HH, Deneen B, Richardson WD, Barres BA, Rowitch DH (2012) Astrocytes and disease: a neurodevelopmental perspective. Genes Dev 26:891–907. https://doi.org/10.1101/gad.188326.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tsai HH, Li H, Fuentealba LC, Molofsky AV, Taveira-Marques R, Zhuang H, Tenney A, Murnen AT, Fancy SP, Merkle F, Kessaris N, Alvarez-Buylla A, Richardson WD, Rowitch DH (2012) Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337:358–362. https://doi.org/10.1126/science.1222381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kettenmann H, Ransom BR (1988) Electrical coupling between astrocytes and between oligodendrocytes studied in mammalian cell cultures. Glia 1:64–73. https://doi.org/10.1002/glia.440010108

    Article  CAS  PubMed  Google Scholar 

  28. Dahl D, Bignami A (1982) Immunohistological localization of desmin, the muscle-type 100 A filament protein, in rat astrocytes and Muller glia. J Histochem Cytochem 30:207–213. https://doi.org/10.1177/30.3.7037941

    Article  CAS  PubMed  Google Scholar 

  29. Pixley SK, Kobayashi Y, de Vellis J (1984) A monoclonal antibody against vimentin: characterization. Brain Res 317:185–199. https://doi.org/10.1016/0165-3806(84)90096-8

    Article  CAS  PubMed  Google Scholar 

  30. Hirako Y, Yamakawa H, Tsujimura Y, Nishizawa Y, Okumura M, Usukura J, Matsumoto H, Jackson KW, Owaribe K, Ohara O (2003) Characterization of mammalian synemin, an intermediate filament protein present in all four classes of muscle cells and some neuroglial cells: co-localization and interaction with type III intermediate filament proteins and keratins. Cell Tissue Res 313:195–207. https://doi.org/10.1007/s00441-003-0732-2

    Article  CAS  PubMed  Google Scholar 

  31. Oberheim NA, Takano T, Han X, He W, Lin JH, Wang F, Xu Q, Wyatt JD, Pilcher W, Ojemann JG, Ransom BR, Goldman SA, Nedergaard M (2009) Uniquely hominid features of adult human astrocytes. J Neurosci 29:3276–3287. https://doi.org/10.1523/JNEUROSCI.4707-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kaaijk P, Pals ST, Morsink F, Bosch DA, Troost D (1997) Differential expression of CD44 splice variants in the normal human central nervous system. J Neuroimmunol 73:70–76. https://doi.org/10.1016/s0165-5728(96)00167-1

    Article  CAS  PubMed  Google Scholar 

  33. Goursaud S, Kozlova EN, Maloteaux JM, Hermans E (2009) Cultured astrocytes derived from corpus callosum or cortical grey matter show distinct glutamate handling properties. J Neurochem 108:1442–1452. https://doi.org/10.1111/j.1471-4159.2009.05889.x

    Article  CAS  PubMed  Google Scholar 

  34. Ludwin SK, Kosek JC, Eng LF (1976) The topographical distribution of S-100 and GFA proteins in the adult rat brain: an immunohistochemical study using horseradish peroxidase-labelled antibodies. J Comp Neurol 165:197–207. https://doi.org/10.1002/cne.901650206

    Article  CAS  PubMed  Google Scholar 

  35. Bushong EA, Martone ME, Jones YZ, Ellisman MH (2002) Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 22:183–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686. https://doi.org/10.1016/s0896-6273(00)80086-0

    Article  CAS  PubMed  Google Scholar 

  37. Goursaud S, Maloteaux JM, Hermans E (2009) Distinct expression and regulation of the glutamate transporter isoforms GLT-1a and GLT-1b in cultured astrocytes from a rat model of amyotrophic lateral sclerosis (hSOD1G93A). Neurochem Int 55:28–34. https://doi.org/10.1016/j.neuint.2009.02.003

    Article  CAS  PubMed  Google Scholar 

  38. Parpura V, Fisher ES, Lechleiter JD, Schousboe A, Waagepetersen HS, Brunet S, Baltan S, Verkhratsky A (2017) Glutamate and ATP at the interface between signaling and metabolism in Astroglia: examples from pathology. Neurochem Res 42:19–34. https://doi.org/10.1007/s11064-016-1848-6

    Article  CAS  PubMed  Google Scholar 

  39. Hassel B, Boldingh KA, Narvesen C, Iversen EG, Skrede KK (2003) Glutamate transport, glutamine synthetase and phosphate-activated glutaminase in rat CNS white matter. A quantitative study. J Neurochem 87:230–237. https://doi.org/10.1046/j.1471-4159.2003.01984.x

    Article  CAS  PubMed  Google Scholar 

  40. Oka A, Belliveau MJ, Rosenberg PA, Volpe JJ (1993) Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. J Neurosci 13:1441–1453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Garcia-Barcina JM, Matute C (1996) Expression of kainate-selective glutamate receptor subunits in glial cells of the adult bovine white matter. Eur J Neurosci 8:2379–2387. https://doi.org/10.1111/j.1460-9568.1996.tb01201.x

    Article  CAS  PubMed  Google Scholar 

  42. Sanchez-Gomez MV, Matute C (1999) AMPA and kainate receptors each mediate excitotoxicity in oligodendroglial cultures. Neurobiol Dis 6:475–485. https://doi.org/10.1006/nbdi.1999.0264

    Article  CAS  PubMed  Google Scholar 

  43. Matute C (2006) Oligodendrocyte NMDA receptors: a novel therapeutic target. Trends Mol Med 12:289–292. https://doi.org/10.1016/j.molmed.2006.05.004

    Article  CAS  PubMed  Google Scholar 

  44. Jourdain P, Bergersen LH, Bhaukaurally K, Bezzi P, Santello M, Domercq M, Matute C, Tonello F, Gundersen V, Volterra A (2007) Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci 10:331–339. https://doi.org/10.1038/nn1849

    Article  CAS  PubMed  Google Scholar 

  45. Alberdi E, Sanchez-Gomez MV, Marino A, Matute C (2002) Ca(2+) influx through AMPA or kainate receptors alone is sufficient to initiate excitotoxicity in cultured oligodendrocytes. Neurobiol Dis 9:234–243. https://doi.org/10.1006/nbdi.2001.0457

    Article  CAS  PubMed  Google Scholar 

  46. Tekkok SB, Goldberg MP (2001) Ampa/kainate receptor activation mediates hypoxic oligodendrocyte death and axonal injury in cerebral white matter. J Neurosci 21:4237–4248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tekkok SB, Faddis BT, Goldberg MP (2005) AMPA/kainate receptors mediate axonal morphological disruption in hypoxic white matter. Neurosci Lett 382:275–279. https://doi.org/10.1016/j.neulet.2005.03.054

    Article  CAS  PubMed  Google Scholar 

  48. Tekkok SB, Ye Z, Ransom BR (2007) Excitotoxic mechanisms of ischemic injury in myelinated white matter. J Cereb Blood Flow Metab 27:1540–1552. https://doi.org/10.1038/sj.jcbfm.9600455

    Article  CAS  PubMed  Google Scholar 

  49. Saab AS, Tzvetavona ID, Trevisiol A, Baltan S, Dibaj P, Kusch K, Mobius W, Goetze B, Jahn HM, Huang W, Steffens H, Schomburg ED, Perez-Samartin A, Perez-Cerda F, Bakhtiari D, Matute C, Lowel S, Griesinger C, Hirrlinger J, Kirchhoff F, Nave KA (2016) Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 91:119–132. https://doi.org/10.1016/j.neuron.2016.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Charles AC, Merrill JE, Dirksen ER, Sanderson MJ (1991) Intercellular signaling in glial cells: calcium waves and oscillations in response to mechanical stimulation and glutamate. Neuron 6:983–992. https://doi.org/10.1016/0896-6273(91)90238-u

    Article  CAS  PubMed  Google Scholar 

  51. Orthmann-Murphy JL, Abrams CK, Scherer SS (2008) Gap junctions couple astrocytes and oligodendrocytes. J Mol Neurosci 35:101–116. https://doi.org/10.1007/s12031-007-9027-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Parpura V, Scemes E, Spray DC (2004) Mechanisms of glutamate release from astrocytes: gap junction “hemichannels”, purinergic receptors and exocytotic release. Neurochem Int 45:259–264. https://doi.org/10.1016/j.neuint.2003.12.011

    Article  CAS  PubMed  Google Scholar 

  53. Scemes E, Spray DC (2009) Connexin expression (gap junctions and hemichannels) in astrocytes. In: Haydon PG, Parpura V (eds) Astrocytes in (Patho)physiology of the nervous system. Springer, Boston, pp 107–150. https://doi.org/10.1007/978-0-387-79492-1_5

    Chapter  Google Scholar 

  54. Lee SH, Kim WT, Cornell-Bell AH, Sontheimer H (1994) Astrocytes exhibit regional specificity in gap-junction coupling. Glia 11:315–325. https://doi.org/10.1002/glia.440110404

    Article  CAS  PubMed  Google Scholar 

  55. Verkhratsky A, Semyanov A, Zorec R (2020) Physiology of Astroglial excitability. Function 1. https://doi.org/10.1093/function/zqaa016

  56. Bernardinelli Y, Magistretti PJ, Chatton JY (2004) Astrocytes generate Na+-mediated metabolic waves. Proc Natl Acad Sci U S A 101:14937–14942. https://doi.org/10.1073/pnas.0405315101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Langer J, Stephan J, Theis M, Rose CR (2012) Gap junctions mediate intercellular spread of sodium between hippocampal astrocytes in situ. Glia 60:239–252. https://doi.org/10.1002/glia.21259

    Article  PubMed  Google Scholar 

  58. Verkhratsky A, Rose CR (2020) Na(+)-dependent transporters: the backbone of astroglial homeostatic function. Cell Calcium 85:102136. https://doi.org/10.1016/j.ceca.2019.102136

    Article  CAS  PubMed  Google Scholar 

  59. Verkhratsky A, Untiet V, Rose CR (2020) Ionic signalling in astroglia beyond calcium. J Physiol 598:1655–1670. https://doi.org/10.1113/JP277478

    Article  CAS  PubMed  Google Scholar 

  60. Rose CR, Verkhratsky A (2016) Principles of sodium homeostasis and sodium signalling in astroglia. Glia 64:1611–1627. https://doi.org/10.1002/glia.22964

    Article  PubMed  Google Scholar 

  61. Larsen BR, Assentoft M, Cotrina ML, Hua SZ, Nedergaard M, Kaila K, Voipio J, MacAulay N (2014) Contributions of the Na(+)/K(+)-ATPase, NKCC1, and Kir4.1 to hippocampal K(+) clearance and volume responses. Glia 62:608–622. https://doi.org/10.1002/glia.22629

    Article  PubMed  PubMed Central  Google Scholar 

  62. Hertz L, Song D, Xu J, Peng L, Gibbs ME (2015) Role of the astrocytic Na(+), K(+)-ATPase in K(+) homeostasis in brain: K(+) uptake, signaling pathways and substrate utilization. Neurochem Res 40:2505–2516. https://doi.org/10.1007/s11064-014-1505-x

    Article  CAS  PubMed  Google Scholar 

  63. Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32:1152–1166. https://doi.org/10.1038/jcbfm.2011.149

    Article  CAS  PubMed  Google Scholar 

  64. Pellerin L, Magistretti PJ (1997) Glutamate uptake stimulates Na+, K+-ATPase activity in astrocytes via activation of a distinct subunit highly sensitive to ouabain. J Neurochem 69:2132–2137. https://doi.org/10.1046/j.1471-4159.1997.69052132.x

    Article  CAS  PubMed  Google Scholar 

  65. Chatton JY, Marquet P, Magistretti PJ (2000) A quantitative analysis of L-glutamate-regulated Na+ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics. Eur J Neurosci 12:3843–3853. https://doi.org/10.1046/j.1460-9568.2000.00269.x

    Article  CAS  PubMed  Google Scholar 

  66. Kimura J, Miyamae S, Noma A (1987) Identification of sodium-calcium exchange current in single ventricular cells of guinea-pig. J Physiol 384:199–222. https://doi.org/10.1113/jphysiol.1987.sp016450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kirischuk S, Kettenmann H, Verkhratsky A (1997) Na+/Ca2+ exchanger modulates kainate-triggered Ca2+ signaling in Bergmann glial cells in situ. FASEB J 11:566–572. https://doi.org/10.1096/fasebj.11.7.9212080

    Article  CAS  PubMed  Google Scholar 

  68. Reyes RC, Verkhratsky A, Parpura V (2012) Plasmalemmal Na+/Ca2+ exchanger modulates Ca2+-dependent exocytotic release of glutamate from rat cortical astrocytes. ASN Neuro 4. https://doi.org/10.1042/AN20110059

  69. Paluzzi S, Alloisio S, Zappettini S, Milanese M, Raiteri L, Nobile M, Bonanno G (2007) Adult astroglia is competent for Na+/Ca2+ exchanger-operated exocytotic glutamate release triggered by mild depolarization. J Neurochem 103:1196–1207. https://doi.org/10.1111/j.1471-4159.2007.04826.x

    Article  CAS  PubMed  Google Scholar 

  70. Hernandez-SanMiguel E, Vay L, Santo-Domingo J, Lobaton CD, Moreno A, Montero M, Alvarez J (2006) The mitochondrial Na+/Ca2+ exchanger plays a key role in the control of cytosolic Ca2+ oscillations. Cell Calcium 40:53–61. https://doi.org/10.1016/j.ceca.2006.03.009

    Article  CAS  PubMed  Google Scholar 

  71. Palty R, Silverman WF, Hershfinkel M, Caporale T, Sensi SL, Parnis J, Nolte C, Fishman D, Shoshan-Barmatz V, Herrmann S, Khananshvili D, Sekler I (2010) NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci U S A 107:436–441. https://doi.org/10.1073/pnas.0908099107

    Article  CAS  PubMed  Google Scholar 

  72. Parnis J, Montana V, Delgado-Martinez I, Matyash V, Parpura V, Kettenmann H, Sekler I, Nolte C (2013) Mitochondrial exchanger NCLX plays a major role in the intracellular Ca2+ signaling, gliotransmission, and proliferation of astrocytes. J Neurosci 33:7206–7219. https://doi.org/10.1523/JNEUROSCI.5721-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Liddelow SA, Sofroniew MV (2019) Astrocytes usurp neurons as a disease focus. Nat Neurosci 22:512–513. https://doi.org/10.1038/s41593-019-0367-6

    Article  CAS  PubMed  Google Scholar 

  74. Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V, Terada M, Ellisman MH, Pekny M (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci U S A 103:17513–17518. https://doi.org/10.1073/pnas.0602841103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Burda JE, Bernstein AM, Sofroniew MV (2016) Astrocyte roles in traumatic brain injury. Exp Neurol 275(Pt 3):305–315. https://doi.org/10.1016/j.expneurol.2015.03.020

    Article  CAS  PubMed  Google Scholar 

  76. Burda JE, Sofroniew MV (2017) Seducing astrocytes to the dark side. Cell Res 27:726–727. https://doi.org/10.1038/cr.2017.37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Verkhratsky A, Ho MS, Vardjan N, Zorec R, Parpura V (2019) General pathophysiology of Astroglia. Adv Exp Med Biol 1175:149–179. https://doi.org/10.1007/978-981-13-9913-8_7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sofroniew MV (2015) Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 16:249–263. https://doi.org/10.1038/nrn3898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pekny M, Pekna M, Messing A, Steinhauser C, Lee JM, Parpura V, Hol EM, Sofroniew MV, Verkhratsky A (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131:323–345. https://doi.org/10.1007/s00401-015-1513-1

    Article  CAS  PubMed  Google Scholar 

  80. Choi SS, Lee HJ, Lim I, Satoh J, Kim SU (2014) Human astrocytes: secretome profiles of cytokines and chemokines. PLoS One 9:e92325. https://doi.org/10.1371/journal.pone.0092325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Clarke LE, Liddelow SA, Chakraborty C, Munch AE, Heiman M, Barres BA (2018) Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci U S A 115:E1896–E1905. https://doi.org/10.1073/pnas.1800165115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28:138–145. https://doi.org/10.1016/j.it.2007.01.005

    Article  CAS  PubMed  Google Scholar 

  83. Zhu D, Hu C, Sheng W, Tan KS, Haidekker MA, Sun AY, Sun GY, Lee JC (2009) NAD(P)H oxidase-mediated reactive oxygen species production alters astrocyte membrane molecular order via phospholipase A2. Biochem J 421:201–210. https://doi.org/10.1042/BJ20090356

    Article  CAS  PubMed  Google Scholar 

  84. Ishii T, Takanashi Y, Sugita K, Miyazawa M, Yanagihara R, Yasuda K, Onouchi H, Kawabe N, Nakata M, Yamamoto Y, Hartman PS, Ishii N (2017) Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain. Aging Cell 16:39–51. https://doi.org/10.1111/acel.12523

    Article  CAS  PubMed  Google Scholar 

  85. Dossi E, Vasile F, Rouach N (2018) Human astrocytes in the diseased brain. Brain Res Bull 136:139–156. https://doi.org/10.1016/j.brainresbull.2017.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Schousboe A, Waagepetersen HS (2005) Role of astrocytes in glutamate homeostasis: implications for excitotoxicity. Neurotox Res 8:221–225. https://doi.org/10.1007/BF03033975

    Article  CAS  PubMed  Google Scholar 

  87. Sompol P, Furman JL, Pleiss MM, Kraner SD, Artiushin IA, Batten SR, Quintero JE, Simmerman LA, Beckett TL, Lovell MA, Murphy MP, Gerhardt GA, Norris CM (2017) Calcineurin/NFAT signaling in activated astrocytes drives network hyperexcitability in Abeta-bearing mice. J Neurosci 37:6132–6148. https://doi.org/10.1523/JNEUROSCI.0877-17.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, Van Eldik LJ, Norris CM (2012) Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci 32:16129–16140. https://doi.org/10.1523/JNEUROSCI.2323-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Furman JL, Sompol P, Kraner SD, Pleiss MM, Putman EJ, Dunkerson J, Mohmmad Abdul H, Roberts KN, Scheff SW, Norris CM (2016) Blockade of astrocytic calcineurin/NFAT signaling helps to normalize hippocampal synaptic function and plasticity in a rat model of traumatic brain injury. J Neurosci 36:1502–1515. https://doi.org/10.1523/JNEUROSCI.1930-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA (2017) Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med 9. https://doi.org/10.1126/scitranslmed.aaf6295

  91. Verkhratsky A, Steardo L, Parpura V, Montana V (2016) Translational potential of astrocytes in brain disorders. Prog Neurobiol 144:188–205. https://doi.org/10.1016/j.pneurobio.2015.09.003

    Article  CAS  PubMed  Google Scholar 

  92. Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144:810–823. https://doi.org/10.1016/j.cell.2011.02.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bastian C, Quinn J, Doherty C, Franke C, Faris A, Brunet S, Baltan S (2019) Role of brain glycogen during ischemia, aging and cell-to-cell interactions. Adv Neurobiol 23:347–361. https://doi.org/10.1007/978-3-030-27480-1_12

    Article  PubMed  Google Scholar 

  94. Rich LR, Harris W, Brown AM (2019) The role of brain glycogen in supporting physiological function. Front Neurosci 13:1176. https://doi.org/10.3389/fnins.2019.01176

    Article  PubMed  PubMed Central  Google Scholar 

  95. Bak LK, Walls AB, Schousboe A, Waagepetersen HS (2018) Astrocytic glycogen metabolism in the healthy and diseased brain. J Biol Chem 293:7108–7116. https://doi.org/10.1074/jbc.R117.803239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143–2155. https://doi.org/10.1523/JNEUROSCI.3547-03.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A, Iwamoto Y, Toyama Y, Okano H (2006) Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12:829–834. https://doi.org/10.1038/nm1425

    Article  CAS  PubMed  Google Scholar 

  98. Wang H, Song G, Chuang H, Chiu C, Abdelmaksoud A, Ye Y, Zhao L (2018) Portrait of glial scar in neurological diseases. Int J Immunopathol Pharmacol 31:2058738418801406. https://doi.org/10.1177/2058738418801406

    Article  PubMed  PubMed Central  Google Scholar 

  99. Liddelow S, Barres B (2015) SnapShot: astrocytes in health and disease. Cell 162(1170–1170):e1171. https://doi.org/10.1016/j.cell.2015.08.029

    Article  CAS  Google Scholar 

  100. Liddelow SA, Barres BA (2017) Reactive astrocytes: production, function, and therapeutic potential. Immunity 46:957–967. https://doi.org/10.1016/j.immuni.2017.06.006

    Article  CAS  PubMed  Google Scholar 

  101. Perez-Nievas BG, Serrano-Pozo A (2018) Deciphering the astrocyte reaction in Alzheimer’s disease. Front Aging Neurosci 10:114. https://doi.org/10.3389/fnagi.2018.00114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. https://doi.org/10.1007/s00401-009-0619-8

    Article  PubMed  Google Scholar 

  103. Bluml S, Moreno-Torres A, Shic F, Nguy CH, Ross BD (2002) Tricarboxylic acid cycle of glia in the in vivo human brain. NMR Biomed 15:1–5. https://doi.org/10.1002/nbm.725

    Article  CAS  PubMed  Google Scholar 

  104. Lovatt D, Sonnewald U, Waagepetersen HS, Schousboe A, He W, Lin JH, Han X, Takano T, Wang S, Sim FJ, Goldman SA, Nedergaard M (2007) The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. J Neurosci 27:12255–12266. https://doi.org/10.1523/JNEUROSCI.3404-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Agarwal A, Wu PH, Hughes EG, Fukaya M, Tischfield MA, Langseth AJ, Wirtz D, Bergles DE (2017) Transient opening of the mitochondrial permeability transition pore induces microdomain calcium transients in astrocyte processes. Neuron 93(587–605):e587. https://doi.org/10.1016/j.neuron.2016.12.034

    Article  CAS  Google Scholar 

  106. Derouiche A, Haseleu J, Korf HW (2015) Fine astrocyte processes contain very small mitochondria: glial oxidative capability may fuel transmitter metabolism. Neurochem Res 40:2402–2413. https://doi.org/10.1007/s11064-015-1563-8

    Article  CAS  PubMed  Google Scholar 

  107. Genda EN, Jackson JG, Sheldon AL, Locke SF, Greco TM, O’Donnell JC, Spruce LA, Xiao R, Guo W, Putt M, Seeholzer S, Ischiropoulos H, Robinson MB (2011) Co-compartmentalization of the astroglial glutamate transporter, GLT-1, with glycolytic enzymes and mitochondria. J Neurosci 31:18275–18288. https://doi.org/10.1523/JNEUROSCI.3305-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Jackson JG, O’Donnell JC, Takano H, Coulter DA, Robinson MB (2014) Neuronal activity and glutamate uptake decrease mitochondrial mobility in astrocytes and position mitochondria near glutamate transporters. J Neurosci 34:1613–1624. https://doi.org/10.1523/JNEUROSCI.3510-13.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Motori E, Puyal J, Toni N, Ghanem A, Angeloni C, Malaguti M, Cantelli-Forti G, Berninger B, Conzelmann KK, Gotz M, Winklhofer KF, Hrelia S, Bergami M (2013) Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. Cell Metab 18:844–859. https://doi.org/10.1016/j.cmet.2013.11.005

    Article  CAS  PubMed  Google Scholar 

  110. Stephen TL, Higgs NF, Sheehan DF, Al Awabdh S, Lopez-Domenech G, Arancibia-Carcamo IL, Kittler JT (2015) Miro1 regulates activity-driven positioning of mitochondria within astrocytic processes apposed to synapses to regulate intracellular calcium signaling. J Neurosci 35:15996–16011. https://doi.org/10.1523/JNEUROSCI.2068-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Dugan LL, Kim-Han JS (2004) Astrocyte mitochondria in in vitro models of ischemia. J Bioenerg Biomembr 36:317–321. https://doi.org/10.1023/B:JOBB.0000041761.61554.44

    Article  CAS  PubMed  Google Scholar 

  112. Bindocci E, Savtchouk I, Liaudet N, Becker D, Carriero G, Volterra A (2017) Three-dimensional Ca(2+) imaging advances understanding of astrocyte biology. Science 356. https://doi.org/10.1126/science.aai8185

  113. Gunter TE, Yule DI, Gunter KK, Eliseev RA, Salter JD (2004) Calcium and mitochondria. FEBS Lett 567:96–102. https://doi.org/10.1016/j.febslet.2004.03.071

    Article  CAS  PubMed  Google Scholar 

  114. Jackson JG, O’Donnell JC, Krizman E, Robinson MB (2015) Displacing hexokinase from mitochondrial voltage-dependent anion channel impairs GLT-1-mediated glutamate uptake but does not disrupt interactions between GLT-1 and mitochondrial proteins. J Neurosci Res 93:999–1008. https://doi.org/10.1002/jnr.23533

    Article  CAS  PubMed  Google Scholar 

  115. Magi S, Arcangeli S, Castaldo P, Nasti AA, Berrino L, Piegari E, Bernardini R, Amoroso S, Lariccia V (2013) Glutamate-induced ATP synthesis: relationship between plasma membrane Na+/Ca2+ exchanger and excitatory amino acid transporters in brain and heart cell models. Mol Pharmacol 84:603–614. https://doi.org/10.1124/mol.113.087775

    Article  CAS  PubMed  Google Scholar 

  116. Rojas H, Colina C, Ramos M, Benaim G, Jaffe E, Caputo C, Di Polo R (2013) Sodium-calcium exchanger modulates the L-glutamate Ca(i) (2+) signalling in type-1 cerebellar astrocytes. Adv Exp Med Biol 961:267–274. https://doi.org/10.1007/978-1-4614-4756-6_22

    Article  CAS  PubMed  Google Scholar 

  117. Dienel GA (2013) Astrocytic energetics during excitatory neurotransmission: what are contributions of glutamate oxidation and glycolysis? Neurochem Int 63:244–258. https://doi.org/10.1016/j.neuint.2013.06.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ito U, Hakamata Y, Kawakami E, Oyanagi K (2009) Degeneration of astrocytic processes and their mitochondria in cerebral cortical regions peripheral to the cortical infarction: heterogeneity of their disintegration is closely associated with disseminated selective neuronal necrosis and maturation of injury. Stroke 40:2173–2181. https://doi.org/10.1161/STROKEAHA.108.534990

    Article  PubMed  Google Scholar 

  119. Dienel GA, Hertz L (2005) Astrocytic contributions to bioenergetics of cerebral ischemia. Glia 50:362–388. https://doi.org/10.1002/glia.20157

    Article  PubMed  Google Scholar 

  120. Voloboueva LA, Suh SW, Swanson RA, Giffard RG (2007) Inhibition of mitochondrial function in astrocytes: implications for neuroprotection. J Neurochem 102:1383–1394. https://doi.org/10.1111/j.1471-4159.2007.04634.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Brand MD, Evans SM, Mendes-Mourao J, Chappell JB (1973) Fluorocitrate inhibition of aconitate hydratase and the tricarboxylate carrier of rat liver mitochondria. Biochem J 134:217–224. https://doi.org/10.1042/bj1340217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Reichert SA, Kim-Han JS, Dugan LL (2001) The mitochondrial permeability transition pore and nitric oxide synthase mediate early mitochondrial depolarization in astrocytes during oxygen-glucose deprivation. J Neurosci 21:6608–6616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Thoren AE, Helps SC, Nilsson M, Sims NR (2005) Astrocytic function assessed from 1-14C-acetate metabolism after temporary focal cerebral ischemia in rats. J Cereb Blood Flow Metab 25:440–450. https://doi.org/10.1038/sj.jcbfm.9600035

    Article  CAS  PubMed  Google Scholar 

  124. Bruno A (1994) Anterior choroidal artery territory infarcts. Stroke 25:1884–1885. https://doi.org/10.1161/01.str.25.9.1884

    Article  CAS  PubMed  Google Scholar 

  125. Goldberg MP, Choi DW (1993) Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury. J Neurosci 13:3510–3524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Dugan LL, Bruno VM, Amagasu SM, Giffard RG (1995) Glia modulate the response of murine cortical neurons to excitotoxicity: glia exacerbate AMPA neurotoxicity. J Neurosci 15:4545–4555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rosenberg PA, Aizenman E (1989) Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci Lett 103:162–168. https://doi.org/10.1016/0304-3940(89)90569-7

    Article  CAS  PubMed  Google Scholar 

  128. Fiebig C, Keiner S, Ebert B, Schaffner I, Jagasia R, Lie DC, Beckervordersandforth R (2019) Mitochondrial dysfunction in astrocytes impairs the generation of reactive astrocytes and enhances neuronal cell death in the cortex upon photothrombotic lesion. Front Mol Neurosci 12:40. https://doi.org/10.3389/fnmol.2019.00040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Baltan S (2015) Can lactate serve as an energy substrate for axons in good times and in bad, in sickness and in health? Metab Brain Dis 30:25–30. https://doi.org/10.1007/s11011-014-9595-3

    Article  CAS  PubMed  Google Scholar 

  130. Jackson JG, Robinson MB (2015) Reciprocal regulation of mitochondrial dynamics and calcium signaling in astrocyte processes. J Neurosci 35:15199–15213. https://doi.org/10.1523/JNEUROSCI.2049-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Palmer CS, Osellame LD, Stojanovski D, Ryan MT (2011) The regulation of mitochondrial morphology: intricate mechanisms and dynamic machinery. Cell Signal 23:1534–1545. https://doi.org/10.1016/j.cellsig.2011.05.021

    Article  CAS  PubMed  Google Scholar 

  132. O’Donnell JC, Jackson JG, Robinson MB (2016) Transient oxygen/glucose deprivation causes a delayed loss of mitochondria and increases spontaneous calcium signaling in astrocytic processes. J Neurosci 36:7109–7127. https://doi.org/10.1523/JNEUROSCI.4518-15.2016

    Article  PubMed  PubMed Central  Google Scholar 

  133. Leary S, Moyes C (2000) The effects of bioenergetic stress and redox balance on the expression of genes critical to mitochondrial function. In: Storey K, Storey J (eds) Cell and molecular responses to stress, vol 1. Elsevier, Amsterdam, pp 209–229

    Google Scholar 

  134. Agulhon C, Petravicz J, McMullen AB, Sweger EJ, Minton SK, Taves SR, Casper KB, Fiacco TA, McCarthy KD (2008) What is the role of astrocyte calcium in neurophysiology? Neuron 59:932–946. https://doi.org/10.1016/j.neuron.2008.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ (2009) Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323:1211–1215. https://doi.org/10.1126/science.1169096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Hunter DR, Haworth RA, Southard JH (1976) Relationship between configuration, function, and permeability in calcium-treated mitochondria. J Biol Chem 251:5069–5077

    Article  CAS  PubMed  Google Scholar 

  137. Krajewski S, Krajewska M, Ellerby LM, Welsh K, Xie Z, Deveraux QL, Salvesen GS, Bredesen DE, Rosenthal RE, Fiskum G, Reed JC (1999) Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci U S A 96:5752–5757. https://doi.org/10.1073/pnas.96.10.5752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Abramov AY, Canevari L, Duchen MR (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575. https://doi.org/10.1523/JNEUROSCI.4042-03.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Verkhratsky A, Rodriguez-Arellano JJ, Parpura V, Zorec R (2017) Astroglial calcium signalling in Alzheimer’s disease. Biochem Biophys Res Commun 483:1005–1012. https://doi.org/10.1016/j.bbrc.2016.08.088

    Article  CAS  PubMed  Google Scholar 

  140. Kubik LL, Philbert MA (2015) The role of astrocyte mitochondria in differential regional susceptibility to environmental neurotoxicants: tools for understanding neurodegeneration. Toxicol Sci 144:7–16. https://doi.org/10.1093/toxsci/kfu254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Mine N, Taniguchi W, Nishio N, Izumi N, Miyazaki N, Yamada H, Nakatsuka T, Yoshida M (2015) Synaptic modulation of excitatory synaptic transmission by nicotinic acetylcholine receptors in spinal ventral horn neurons. Neuroscience 290:18–30. https://doi.org/10.1016/j.neuroscience.2015.01.015

    Article  CAS  PubMed  Google Scholar 

  142. Nahirnyj A, Livne-Bar I, Guo X, Sivak JM (2013) ROS detoxification and proinflammatory cytokines are linked by p38 MAPK signaling in a model of mature astrocyte activation. PLoS One 8:e83049. https://doi.org/10.1371/journal.pone.0083049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Stobart JL, Ferrari KD, Barrett MJP, Gluck C, Stobart MJ, Zuend M, Weber B (2018) Cortical circuit activity evokes rapid astrocyte calcium signals on a similar timescale to neurons. Neuron 98(726–735):e724. https://doi.org/10.1016/j.neuron.2018.03.050

    Article  CAS  Google Scholar 

  144. Quintana DD, Garcia JA, Sarkar SN, Jun S, Engler-Chiurazzi EB, Russell AE, Cavendish JZ, Simpkins JW (2019) Hypoxia-reoxygenation of primary astrocytes results in a redistribution of mitochondrial size and mitophagy. Mitochondrion 47:244–255. https://doi.org/10.1016/j.mito.2018.12.004

    Article  CAS  PubMed  Google Scholar 

  145. Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, Ji X, Lo EH (2016) Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535:551–555. https://doi.org/10.1038/nature18928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Gao L, Zhang Z, Lu J, Pei G (2019) Mitochondria are dynamically transferring between human neural cells and Alexander disease-associated GFAP mutations impair the astrocytic transfer. Front Cell Neurosci 13:316. https://doi.org/10.3389/fncel.2019.00316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Fransson S, Ruusala A, Aspenstrom P (2006) The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking. Biochem Biophys Res Commun 344:500–510. https://doi.org/10.1016/j.bbrc.2006.03.163

    Article  CAS  PubMed  Google Scholar 

  148. Lee KS, Lu B (2014) The myriad roles of Miro in the nervous system: axonal transport of mitochondria and beyond. Front Cell Neurosci 8:330. https://doi.org/10.3389/fncel.2014.00330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Ahmad T, Mukherjee S, Pattnaik B, Kumar M, Singh S, Kumar M, Rehman R, Tiwari BK, Jha KA, Barhanpurkar AP, Wani MR, Roy SS, Mabalirajan U, Ghosh B, Agrawal A (2014) Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J 33:994–1010. https://doi.org/10.1002/embj.201386030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zhang Y, Yu Z, Jiang D, Liang X, Liao S, Zhang Z, Yue W, Li X, Chiu SM, Chai YH, Liang Y, Chow Y, Han S, Xu A, Tse HF, Lian Q (2016) iPSC-MSCs with high intrinsic MIRO1 and sensitivity to TNF-alpha yield efficacious mitochondrial transfer to rescue Anthracycline-induced cardiomyopathy. Stem Cell Rep 7:749–763. https://doi.org/10.1016/j.stemcr.2016.08.009

    Article  CAS  Google Scholar 

  151. Fransson A, Ruusala A, Aspenstrom P (2003) Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J Biol Chem 278:6495–6502. https://doi.org/10.1074/jbc.M208609200

    Article  CAS  PubMed  Google Scholar 

  152. Bosson A, Paumier A, Boisseau S, Jacquier-Sarlin M, Buisson A, Albrieux M (2017) TRPA1 channels promote astrocytic Ca(2+) hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-beta peptide. Mol Neurodegener 12:53. https://doi.org/10.1186/s13024-017-0194-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Cannon JR, Sew T, Montero L, Burton EA, Greenamyre JT (2011) Pseudotype-dependent lentiviral transduction of astrocytes or neurons in the rat substantia nigra. Exp Neurol 228:41–52. https://doi.org/10.1016/j.expneurol.2010.10.016

    Article  CAS  PubMed  Google Scholar 

  154. Terashima T, Ogawa N, Nakae Y, Sato T, Katagi M, Okano J, Maegawa H, Kojima H (2018) Gene therapy for neuropathic pain through siRNA-IRF5 gene delivery with homing peptides to microglia. Mol Ther Nucleic Acids 11:203–215. https://doi.org/10.1016/j.omtn.2018.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Valiante S, Falanga A, Cigliano L, Iachetta G, Busiello RA, La Marca V, Galdiero M, Lombardi A, Galdiero S (2015) Peptide gH625 enters into neuron and astrocyte cell lines and crosses the blood-brain barrier in rats. Int J Nanomedicine 10:1885–1898. https://doi.org/10.2147/IJN.S77734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Valori CF, Guidotti G, Brambilla L, Rossi D (2019) Astrocytes in motor neuron diseases. Adv Exp Med Biol 1175:227–272. https://doi.org/10.1007/978-981-13-9913-8_10

    Article  CAS  PubMed  Google Scholar 

  157. Wilhelmsson U, Li L, Pekna M, Berthold CH, Blom S, Eliasson C, Renner O, Bushong E, Ellisman M, Morgan TE, Pekny M (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 24:5016–5021. https://doi.org/10.1523/JNEUROSCI.0820-04.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Ceyzeriat K, Ben Haim L, Denizot A, Pommier D, Matos M, Guillemaud O, Palomares MA, Abjean L, Petit F, Gipchtein P, Gaillard MC, Guillermier M, Bernier S, Gaudin M, Auregan G, Josephine C, Dechamps N, Veran J, Langlais V, Cambon K, Bemelmans AP, Baijer J, Bonvento G, Dhenain M, Deleuze JF, Oliet SHR, Brouillet E, Hantraye P, Carrillo-de Sauvage MA, Olaso R, Panatier A, Escartin C (2018) Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease. Acta Neuropathol Commun 6:104. https://doi.org/10.1186/s40478-018-0606-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Fernandez AM, Hervas R, Dominguez-Fraile M, Garrido VN, Gomez-Gutierrez P, Vega M, Vitorica J, Perez JJ, Torres Aleman I (2016) Blockade of the interaction of calcineurin with FOXO in astrocytes protects against amyloid-beta-induced neuronal death. J Alzheimers Dis 52:1471–1478. https://doi.org/10.3233/JAD-160149

    Article  CAS  PubMed  Google Scholar 

  160. Li T, Chen X, Zhang C, Zhang Y, Yao W (2019) An update on reactive astrocytes in chronic pain. J Neuroinflammation 16:140. https://doi.org/10.1186/s12974-019-1524-2

    Article  PubMed  PubMed Central  Google Scholar 

  161. Gaudet AD, Fonken LK (2018) Glial cells shape pathology and repair after spinal cord injury. Neurotherapeutics 15:554–577. https://doi.org/10.1007/s13311-018-0630-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Huang L, Nakamura Y, Lo EH, Hayakawa K (2019) Astrocyte signaling in the neurovascular unit after central nervous system injury. Int J Mol Sci 20. https://doi.org/10.3390/ijms20020282

  163. Emani SM, McCully JD (2018) Mitochondrial transplantation: applications for pediatric patients with congenital heart disease. Transl Pediatr 7:169–175. https://doi.org/10.21037/tp.2018.02.02

    Article  PubMed  PubMed Central  Google Scholar 

  164. Chang JC, Wu SL, Liu KH, Chen YH, Chuang CS, Cheng FC, Su HL, Wei YH, Kuo SJ, Liu CS (2016) Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson’s disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine-induced neurotoxicity. Transl Res 170(40–56):e43. https://doi.org/10.1016/j.trsl.2015.12.003

    Article  CAS  Google Scholar 

  165. Cowan DB, Yao R, Akurathi V, Snay ER, Thedsanamoorthy JK, Zurakowski D, Ericsson M, Friehs I, Wu Y, Levitsky S, Del Nido PJ, Packard AB, McCully JD (2016) Intracoronary delivery of mitochondria to the ischemic heart for cardioprotection. PLoS One 11:e0160889. https://doi.org/10.1371/journal.pone.0160889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Gollihue JL, Patel SP, Eldahan KC, Cox DH, Donahue RR, Taylor BK, Sullivan PG, Rabchevsky AG (2018) Effects of mitochondrial transplantation on bioenergetics, cellular incorporation, and functional recovery after spinal cord injury. J Neurotrauma 35:1800–1818. https://doi.org/10.1089/neu.2017.5605

    Article  PubMed  PubMed Central  Google Scholar 

  167. McCully JD, Cowan DB, Pacak CA, Toumpoulis IK, Dayalan H, Levitsky S (2009) Injection of isolated mitochondria during early reperfusion for cardioprotection. Am J Physiol Heart Circ Physiol 296:H94–H105. https://doi.org/10.1152/ajpheart.00567.2008

    Article  CAS  PubMed  Google Scholar 

  168. Sun C, Liu X, Wang B, Wang Z, Liu Y, Di C, Si J, Li H, Wu Q, Xu D, Li J, Li G, Wang Y, Wang F, Zhang H (2019) Endocytosis-mediated mitochondrial transplantation: transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity. Theranostics 9:3595–3607. https://doi.org/10.7150/thno.33100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Chang JC, Liu KH, Chuang CS, Su HL, Wei YH, Kuo SJ, Liu CS (2013) Treatment of human cells derived from MERRF syndrome by peptide-mediated mitochondrial delivery. Cytotherapy 15:1580–1596. https://doi.org/10.1016/j.jcyt.2013.06.008

    Article  CAS  PubMed  Google Scholar 

  170. von Bartheld CS, Bahney J, Herculano-Houzel S (2016) The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol 524:3865–3895. https://doi.org/10.1002/cne.24040

    Article  Google Scholar 

  171. Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927. https://doi.org/10.1152/physrev.2001.81.2.871

    Article  CAS  PubMed  Google Scholar 

  172. Prinz M, Jung S, Priller J (2019) Microglia biology: one century of evolving concepts. Cell 179:292–311. https://doi.org/10.1016/j.cell.2019.08.053

    Article  CAS  PubMed  Google Scholar 

  173. Bozic M, Verkhratsky A, Zorec R, Stenovec M (2020) Exocytosis of large-diameter lysosomes mediates interferon gamma-induced relocation of MHC class II molecules toward the surface of astrocytes. Cell Mol Life Sci 77:3245–3264. https://doi.org/10.1007/s00018-019-03350-8

    Article  CAS  PubMed  Google Scholar 

  174. Finsen B, Owens T (2011) Innate immune responses in central nervous system inflammation. FEBS Lett 585:3806–3812. https://doi.org/10.1016/j.febslet.2011.05.030

    Article  CAS  PubMed  Google Scholar 

  175. Hanisch UK (2013) Proteins in microglial activation – inputs and outputs by subsets. Curr Protein Pept Sci 14:3–15. https://doi.org/10.2174/1389203711314010003

    Article  CAS  PubMed  Google Scholar 

  176. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394. https://doi.org/10.1038/nn1997

    Article  CAS  PubMed  Google Scholar 

  177. Zhang X, Haaf M, Todorich B, Grosstephan E, Schieremberg H, Surguladze N, Connor JR (2005) Cytokine toxicity to oligodendrocyte precursors is mediated by iron. Glia 52:199–208. https://doi.org/10.1002/glia.20235

    Article  PubMed  Google Scholar 

  178. Funfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, Brinkmann BG, Kassmann CM, Tzvetanova ID, Mobius W, Diaz F, Meijer D, Suter U, Hamprecht B, Sereda MW, Moraes CT, Frahm J, Goebbels S, Nave KA (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485:517–521. https://doi.org/10.1038/nature11007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Swalwell H, Latimer J, Haywood RM, Birch-Machin MA (2012) Investigating the role of melanin in UVA/UVB- and hydrogen peroxide-induced cellular and mitochondrial ROS production and mitochondrial DNA damage in human melanoma cells. Free Radic Biol Med 52:626–634. https://doi.org/10.1016/j.freeradbiomed.2011.11.019

    Article  CAS  PubMed  Google Scholar 

  180. Viader A, Sasaki Y, Kim S, Strickland A, Workman CS, Yang K, Gross RW, Milbrandt J (2013) Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron 77:886–898. https://doi.org/10.1016/j.neuron.2013.01.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Lin CS, Sharpley MS, Fan W, Waymire KG, Sadun AA, Carelli V, Ross-Cisneros FN, Baciu P, Sung E, McManus MJ, Pan BX, Gil DW, Macgregor GR, Wallace DC (2012) Mouse mtDNA mutant model of Leber hereditary optic neuropathy. Proc Natl Acad Sci U S A 109:20065–20070. https://doi.org/10.1073/pnas.1217113109

    Article  PubMed  PubMed Central  Google Scholar 

  182. Boitier E, Rea R, Duchen MR (1999) Mitochondria exert a negative feedback on the propagation of intracellular Ca2+ waves in rat cortical astrocytes. J Cell Biol 145:795–808. https://doi.org/10.1083/jcb.145.4.795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Simpson PB, Russell JT (1996) Mitochondria support inositol 1,4,5-trisphosphate-mediated Ca2+ waves in cultured oligodendrocytes. J Biol Chem 271:33493–33501. https://doi.org/10.1074/jbc.271.52.33493

    Article  CAS  PubMed  Google Scholar 

  184. Smith IF, Boyle JP, Kang P, Rome S, Pearson HA, Peers C (2005) Hypoxic regulation of Ca2+ signaling in cultured rat astrocytes. Glia 49:153–157. https://doi.org/10.1002/glia.20083

    Article  CAS  PubMed  Google Scholar 

  185. Reyes RC, Parpura V (2008) Mitochondria modulate Ca2+-dependent glutamate release from rat cortical astrocytes. J Neurosci 28:9682–9691. https://doi.org/10.1523/JNEUROSCI.3484-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Wu J, Holstein JD, Upadhyay G, Lin DT, Conway S, Muller E, Lechleiter JD (2007) Purinergic receptor-stimulated IP3-mediated Ca2+ release enhances neuroprotection by increasing astrocyte mitochondrial metabolism during aging. J Neurosci 27:6510–6520. https://doi.org/10.1523/JNEUROSCI.1256-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Li H, Wang X, Zhang N, Gottipati MK, Parpura V, Ding S (2014) Imaging of mitochondrial Ca2+ dynamics in astrocytes using cell-specific mitochondria-targeted GCaMP5G/6s: mitochondrial Ca2+ uptake and cytosolic Ca2+ availability via the endoplasmic reticulum store. Cell Calcium 56:457–466. https://doi.org/10.1016/j.ceca.2014.09.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Parpura V, Grubisic V, Verkhratsky A (2011) Ca(2+) sources for the exocytotic release of glutamate from astrocytes. Biochim Biophys Acta 1813:984–991. https://doi.org/10.1016/j.bbamcr.2010.11.006

    Article  CAS  PubMed  Google Scholar 

  189. Lundgaard I, Osorio MJ, Kress BT, Sanggaard S, Nedergaard M (2014) White matter astrocytes in health and disease. Neuroscience 276:161–173. https://doi.org/10.1016/j.neuroscience.2013.10.050

    Article  CAS  PubMed  Google Scholar 

  190. Gimeno-Bayon J, Lopez-Lopez A, Rodriguez MJ, Mahy N (2014) Glucose pathways adaptation supports acquisition of activated microglia phenotype. J Neurosci Res 92:723–731. https://doi.org/10.1002/jnr.23356

    Article  CAS  PubMed  Google Scholar 

  191. Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649–665. https://doi.org/10.1111/bph.13139

    Article  CAS  PubMed  Google Scholar 

  192. Voloboueva LA, Emery JF, Sun X, Giffard RG (2013) Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin. FEBS Lett 587:756–762. https://doi.org/10.1016/j.febslet.2013.01.067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Shaikh SB, Nicholson LF (2009) Effects of chronic low dose rotenone treatment on human microglial cells. Mol Neurodegener 4:55. https://doi.org/10.1186/1750-1326-4-55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Ye J, Jiang Z, Chen X, Liu M, Li J, Liu N (2016) Electron transport chain inhibitors induce microglia activation through enhancing mitochondrial reactive oxygen species production. Exp Cell Res 340:315–326. https://doi.org/10.1016/j.yexcr.2015.10.026

    Article  CAS  PubMed  Google Scholar 

  195. Yuan YH, Sun JD, Wu MM, Hu JF, Peng SY, Chen NH (2013) Rotenone could activate microglia through NFkappaB associated pathway. Neurochem Res 38:1553–1560. https://doi.org/10.1007/s11064-013-1055-7

    Article  CAS  PubMed  Google Scholar 

  196. Park J, Choi H, Min JS, Park SJ, Kim JH, Park HJ, Kim B, Chae JI, Yim M, Lee DS (2013) Mitochondrial dynamics modulate the expression of pro-inflammatory mediators in microglial cells. J Neurochem 127:221–232. https://doi.org/10.1111/jnc.12361

    Article  CAS  PubMed  Google Scholar 

  197. Ferger AI, Campanelli L, Reimer V, Muth KN, Merdian I, Ludolph AC, Witting A (2010) Effects of mitochondrial dysfunction on the immunological properties of microglia. J Neuroinflammation 7:45. https://doi.org/10.1186/1742-2094-7-45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53:1181–1194. https://doi.org/10.1007/s12035-014-9070-5

    Article  CAS  PubMed  Google Scholar 

  199. Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–787. https://doi.org/10.1038/nri3086

    Article  CAS  PubMed  Google Scholar 

  200. Facci L, Barbierato M, Marinelli C, Argentini C, Skaper SD, Giusti P (2014) Toll-like receptors 2, -3 and -4 prime microglia but not astrocytes across central nervous system regions for ATP-dependent interleukin-1beta release. Sci Rep 4:6824. https://doi.org/10.1038/srep06824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Marinelli C, Di Liddo R, Facci L, Bertalot T, Conconi MT, Zusso M, Skaper SD, Giusti P (2015) Ligand engagement of Toll-like receptors regulates their expression in cortical microglia and astrocytes. J Neuroinflammation 12:244. https://doi.org/10.1186/s12974-015-0458-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Lopez-Fabuel I, Le Douce J, Logan A, James AM, Bonvento G, Murphy MP, Almeida A, Bolanos JP (2016) Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes. Proc Natl Acad Sci U S A 113:13063–13068. https://doi.org/10.1073/pnas.1613701113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Hollensworth SB, Shen C, Sim JE, Spitz DR, Wilson GL, LeDoux SP (2000) Glial cell type-specific responses to menadione-induced oxidative stress. Free Radic Biol Med 28:1161–1174. https://doi.org/10.1016/s0891-5849(00)00214-8

    Article  CAS  PubMed  Google Scholar 

  204. Schreiner B, Romanelli E, Liberski P, Ingold-Heppner B, Sobottka-Brillout B, Hartwig T, Chandrasekar V, Johannssen H, Zeilhofer HU, Aguzzi A, Heppner F, Kerschensteiner M, Becher B (2015) Astrocyte depletion impairs redox homeostasis and triggers neuronal loss in the adult CNS. Cell Rep 12:1377–1384. https://doi.org/10.1016/j.celrep.2015.07.051

    Article  CAS  PubMed  Google Scholar 

  205. Vasquez OL, Almeida A, Bolanos JP (2001) Depletion of glutathione up-regulates mitochondrial complex I expression in glial cells. J Neurochem 76:1593–1596. https://doi.org/10.1046/j.1471-4159.2001.00223.x

    Article  CAS  PubMed  Google Scholar 

  206. Fang C, Bourdette D, Banker G (2012) Oxidative stress inhibits axonal transport: implications for neurodegenerative diseases. Mol Neurodegener 7:29. https://doi.org/10.1186/1750-1326-7-29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Decker H, Lo KY, Unger SM, Ferreira ST, Silverman MA (2010) Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3beta in primary cultured hippocampal neurons. J Neurosci 30:9166–9171. https://doi.org/10.1523/JNEUROSCI.1074-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Bilsland LG, Sahai E, Kelly G, Golding M, Greensmith L, Schiavo G (2010) Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci U S A 107:20523–20528. https://doi.org/10.1073/pnas.1006869107

    Article  PubMed  PubMed Central  Google Scholar 

  209. Sasaki S, Warita H, Abe K, Iwata M (2005) Impairment of axonal transport in the axon hillock and the initial segment of anterior horn neurons in transgenic mice with a G93A mutant SOD1 gene. Acta Neuropathol 110:48–56. https://doi.org/10.1007/s00401-005-1021-9

    Article  CAS  PubMed  Google Scholar 

  210. Her LS, Goldstein LS (2008) Enhanced sensitivity of striatal neurons to axonal transport defects induced by mutant huntingtin. J Neurosci 28:13662–13672. https://doi.org/10.1523/JNEUROSCI.4144-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Sileikyte J, Roy S, Porubsky P, Neuenswander B, Wang J, Hedrick M, Pinkerton AB, Salaniwal S, Kung P, Mangravita-Novo A, Smith LH, Bourdette DN, Jackson MR, Aube J, Chung TDY, Schoenen FJ, Forte MA, Bernardi P (2010) Small molecules targeting the mitochondrial permeability transition. In: Probe reports from the NIH molecular libraries program. National Institutes of Health (US), Bethesda

    Google Scholar 

Download references

Acknowledgements

This work was supported by grants from National Institute of Aging (NIA, AG033720) and National Institute of Neurological Diseases (NINDS, NS094881) to S.B. We thank Dr. Chris Nelson for help editing this paper.

Funding

This work was supported by grants from National Institute of Aging (NIA, AG033720) and National Institute of Neurological Diseases (NINDS, NS094881) to S.B.

Author information

Author notes

  1. Hung Nguyen and Sarah Zerimech contributed equally to this work.

Authors and Affiliations

  1. Anesthesiology and Peri-Operative Medicine (APOM), Oregon Health and Science University, Portland, OR, 97239, USA

    Hung Nguyen, Sarah Zerimech & Selva Baltan

Authors
  1. Hung Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah Zerimech
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Selva Baltan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Selva Baltan.

Ethics declarations

Conflict of Interest

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Special Issue: In Honor of Prof. Vladimir Parpura.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nguyen, H., Zerimech, S. & Baltan, S. Astrocyte Mitochondria in White-Matter Injury. Neurochem Res 46, 2696–2714 (2021). https://doi.org/10.1007/s11064-021-03239-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-021-03239-8

Keywords

search

Navigation