Abstract
Controlling axonal mitochondria is important for maintaining normal function of the neural network. Oxygen–glucose deprivation (OGD), a model used for mimicking ischemia, eventually induces neuronal cell death similar to axonal degeneration. Axonal mitochondria are disrupted during OGD-induced neural degeneration; however, the mechanism underlying mitochondrial dysfunction has not been completely understood. We focused on the dynamics of mitochondria in axons exposed to OGD; we observed that the number of motile mitochondria significantly reduced in 1 h following OGD exposure. In our observation, the decreased length of stationary mitochondria was affected by the following factors: first, the halt of motile mitochondria; second, the fission of longer stationary mitochondria; and third, a transformation from tubular to spherical shape in OGD-exposed axons. Motile mitochondria reduction preceded stationary mitochondria fragmentation in OGD exposure; these conditions induced the decrease of stationary mitochondria in three different ways. Our results suggest that mitochondrial morphological changes precede the axonal degeneration while ischemia-induced neurodegeneration.
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14 July 2022
A Correction to this paper has been published: https://doi.org/10.1007/s10571-022-01257-w
References
Baloh RH (2008) Mitochondrial dynamics and peripheral neuropathy. Neuroscientist 14:12–18. https://doi.org/10.1177/1073858407307354
Baltan S (2014) Excitotoxicity and mitochondrial dysfunction underlie age-dependent ischemic white matter injury. Adv Neurobiol 11:151–170. https://doi.org/10.1007/978-3-319-08894-5_8
Bastian C, Politano S, Day J, McCray A, Brunet S, Baltan S (2018a) Mitochondrial dynamics and preconditioning in white matter. Cond Med 1:64–72
Bastian C, Zaleski J, Stahon K, Parr B, McCray A, Day J, Brunet S, Baltan S (2018b) NOS3 inhibition confers post-ischemic protection to young and aging white matter integrity by conserving mitochondrial dynamics and Miro-2 levels. J Neurosci 38:6247–6266. https://doi.org/10.1523/JNEUROSCI.3017-17.2018
Berbusse GW, Woods LC, Vohra BP, Naylor K (2016) Mitochondrial dynamics decrease prior to axon degeneration induced by vincristine and are partially rescued by overexpressed cytNmnat1. Front Cell Neurosci 10:179. https://doi.org/10.3389/fncel.2016.00179
Berman SB, Chen YB, Qi B, McCaffery JM, Rucker EB, Goebbels S, Nave KA, Arnold BA, Jonas EA, Pineda FJ, Hardwick JM (2009) Bcl-x L increases mitochondrial fission, fusion, and biomass in neurons. J Cell Biol 184:707–719. https://doi.org/10.1083/jcb.200809060
Bobylev I, Joshi AR, Barham M, Neiss WF, Lehmann HC (2018) Depletion of mitofusin-2 causes mitochondrial damage in cisplatin-induced neuropathy. Mol Neurobiol 55:1227–1235. https://doi.org/10.1007/s12035-016-0364-7
Cai Q, Tammineni P (2016) Alterations in mitochondrial quality control in alzheimer’s disease. Front Cell Neurosci 10:24. https://doi.org/10.3389/fncel.2016.00024
Campbell GR, Worrall JT, Mahad DJ (2014) The central role of mitochondria in axonal degeneration in multiple sclerosis. Mult Scler 20:1806–1813. https://doi.org/10.1177/1352458514544537
Castiglione JI, Marrodan M, Alessandro L, Taratuto AL, Brand P, Nogués M, Barroso F (2021) Vasculitic peripheral neuropathy, differences between systemic and non-systemic etiologies: a case series and biopsy report. J Neuromuscul Dis 8:155–161. https://doi.org/10.3233/JND-200576
Chamberlain KA, Sheng ZH (2019) Mechanisms for the maintenance and regulation of axonal energy supply. J Neurosci Res 97:897–913. https://doi.org/10.1002/jnr.24411
Cherubini M, Ginés S (2017) Mitochondrial fragmentation in neuronal degeneration: toward an understanding of HD striatal susceptibility. Biochem Biophys Res Commun 483:1063–1068. https://doi.org/10.1016/j.bbrc.2016.08.042
Chiang H, Ohno N, Hsieh YL, Mahad DJ, Kikuchi S, Komuro H, Hsieh ST, Trapp BD (2015) Mitochondrial fission augments capsaicin-induced axonal degeneration. Acta Neuropathol 129:81–96. https://doi.org/10.1007/s00401-014-1354-3
Coderre TJ (2011) Complex regional pain syndrome: what’s in a name? J Pain 12:2–12. https://doi.org/10.1016/j.jpain.2010.06.001
Coderre TJ, Bennett GJ (2010) A hypothesis for the cause of complex regional pain syndrome-type I (reflex sympathetic dystrophy): pain due to deep-tissue microvascular pathology. Pain Med 11:1224–1238. https://doi.org/10.1111/j.1526-4637.2010.00911.x
Collins MP, Hadden RD (2017) The nonsystemic vasculitic neuropathies. Nat Rev Neurol 13:302–316. https://doi.org/10.1038/nrneurol.2017.42
Dyck PJ, Benstead TJ, Conn DL, Stevens JC, Windebank AJ, Low PA (1987) Nonsystemic vasculitic neuropathy. Brain 110:843–853. https://doi.org/10.1093/brain/110.4.843
Fabricius C, Berthold CH, Rydmark M (1993) Axoplasmic organelles at nodes of Ranvier. II. Occurrence and distribution in large myelinated spinal cord axons of the adult cat. J Neurocytol 22:941–954. https://doi.org/10.1007/BF01218352
Fex Svenningsen A, Shan WS, Colman DR, Pedraza L (2003) Rapid method for culturing embryonic neuron-glial cell cocultures. J Neurosci Res 72:565–573. https://doi.org/10.1002/jnr.10610
Fulas OA, Laferrière A, Coderre TJ (2021) Novel co-crystal of pentoxifylline and protocatechuic acid relieves allodynia in rat models of peripheral neuropathic pain and CRPS by alleviating local tissue hypoxia. ACS Chem Neurosci 12:3855–3863. https://doi.org/10.1021/acschemneuro.1c00312
Granatiero V, Manfredi G (2019) Mitochondrial transport and turnover in the pathogenesis of amyotrophic lateral sclerosis. Biology (basel) 8:36. https://doi.org/10.3390/biology8020036
Hollenbeck PJ, Saxton WM (2005) The axonal transport of mitochondria. J Cell Sci 118:5411–5419. https://doi.org/10.1242/jcs.02745
Jin KL, Mao XO, Greenberg DA (2000) Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci USA 97:10242–10247. https://doi.org/10.1073/pnas.97.18.10242
Kanda Y (2013) Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48:452–458. https://doi.org/10.1038/bmt.2012.244
Karbowski M, Arnoult D, Chen H, Chan DC, Smith CL, Youle RJ (2004) Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J Cell Biol 164:493–499. https://doi.org/10.1083/jcb.200309082
Kikuchi S, Ninomiya T, Kohno T, Kojima T, Tatsumi H (2018) Cobalt inhibits motility of axonal mitochondria and induces axonal degeneration in cultured dorsal root ganglion cells of rat. Cell Biol Toxicol 34:93–107. https://doi.org/10.1007/s10565-017-9402-0
Kiryu-Seo S, Ohno N, Kidd GJ, Komuro H, Trapp BD (2010) Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. J Neurosci 30:6658–6666. https://doi.org/10.1523/JNEUROSCI.5265-09.2010
Ko KW, Devault L, Sasaki Y, Milbrandt J, DiAntonio A (2021) Live imaging reveals the cellular events downstream of SARM1 activation. Elife 10:e71148. https://doi.org/10.7554/eLife.71148
Kraus F, Roy K, Pucadyil TJ, Ryan MT (2021) Function and regulation of the divisome for mitochondrial fission. Nature 590:57–66. https://doi.org/10.1038/s41586-021-03214-x
Li X, Li H, Xu Z, Ma C, Wang T, You W, Yu Z, Shen H, Chen G (2022) Ischemia-induced cleavage of OPA1 at S1 site aggravates mitochondrial fragmentation and reperfusion injury in neurons. Cell Death Dis 13:321. https://doi.org/10.1038/s41419-022-04782-0
Lopez Sanchez MI, Crowston JG, Mackey DA, Trounce IA (2016) Emerging mitochondrial therapeutic targets in optic neuropathies. Pharmacol Ther 165:132–152. https://doi.org/10.1016/j.pharmthera.2016.06.004
Lubana SS, Singh N, Sanelli-Russo S, Abrudescu A (2015) Non-systemic vasculitic neuropathy An enigmatic clinical entity. Am J Case Rep. https://doi.org/10.12659/AJCR.894601
Maday S, Twelvetrees AE, Moughamian AJ, Holzbaur EL (2014) Axonal transport: cargo-specific mechanisms of motility and regulation. Neuron 84:292–309. https://doi.org/10.1016/j.neuron.2014.10.019
Miller KE, Sheetz MP (2004) Axonal mitochondrial transport and potential are correlated. J Cell Sci 117:2791–2804. https://doi.org/10.1242/jcs.01130
Morris RL, Hollenbeck PJ (1995) Axonal transport of mitochondria along microtubules and F-actin in living vertebrate neurons. J Cell Biol 131:1315–1326. https://doi.org/10.1083/jcb.131.5.1315
Nicholls DG, Budd SL (2000) Mitochondria and neuronal survival. Physiol Rev 80:315–360. https://doi.org/10.1152/physrev.2000.80.1.315
Ohno N, Kidd GJ, Mahad D, Kiryu-Seo S, Avishai A, Komuro H, Trapp BD (2011) Myelination and axonal electrical activity modulate the distribution and motility of mitochondria at CNS nodes of ranvier. J Neurosci 31:7249–7258. https://doi.org/10.1523/JNEUROSCI.0095-11.2011
Pathak D, Shields LY, Mendelsohn BA, Haddad D, Lin W, Gerencser AA, Kim H, Brand MD, Edwards RH, Nakamura K (2015) The role of mitochondrially derived ATP in synaptic vesicle recycling. J Biol Chem 290:22325–22336. https://doi.org/10.1074/jbc.M115.656405
Picard M, Gentil BJ, McManus MJ, White K, St Louis K, Gartside SE, Wallace DC, Turnbull DM (2013) Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle. J Appl Physiol 115:1562–1571. https://doi.org/10.1152/japplphysiol.00819.2013
Pivovarova NB, Andrews SB (2010) Calcium-dependent mitochondrial function and dysfunction in neurons. FEBS J 277:3622–3636. https://doi.org/10.1111/j.1742-4658.2010.07754.x
Rey F, Ottolenghi S, Zuccotti GV, Samaja M, Carelli S (2022) Mitochondrial dysfunctions in neurodegenerative diseases: role in disease pathogenesis, strategies for analysis and therapeutic prospects. Neural Regen Res 17:754–758. https://doi.org/10.4103/1673-5374.322430
Sheng ZH (2017) The interplay of axonal energy homeostasis and mitochondrial trafficking and anchoring. Trends Cell Biol 27:403–416. https://doi.org/10.1016/j.tcb.2017.01.005
Sommer CJ (2017) Ischemic stroke: experimental models and reality. Acta Neuropathol 133:245–261. https://doi.org/10.1007/s00401-017-1667-0
Sommer C, Geber C, Young P, Forst R, Birklein F, Schoser B (2018) Polyneuropathies. Dtsch Arztebl Int 115:83–90. https://doi.org/10.3238/arztebl.2018.083
Song M, Zhou Y, Fan X (2022) Mitochondrial quality and quantity control: mitophagy is a potential therapeutic target for ischemic stroke. Mol Neurobiol 59:3110–3123. https://doi.org/10.1007/s12035-022-02795-6
Stecker MM, Stevenson M (2015) Effects of pH on the response of peripheral nerve to anoxia. Int J Neurosci 125:221–227. https://doi.org/10.3109/00207454.2014.922971
Suh BK, Lee SA, Park C, Suh Y, Kim SJ, Woo Y, Nhung TTM, Lee SB, Mun DJ, Goo BS, Choi HS, Kim SJ, Park SK (2021) Schizophrenia-associated dysbindin modulates axonal mitochondrial movement in cooperation with p150glued. Mol Brain 14:14. https://doi.org/10.1186/s13041-020-00720-3
Tasca CI, Dal-Cim T, Cimarosti H (2015) In vitro oxygen-glucose deprivation to study ischemic cell death. Methods Mol Biol 1254:197–210. https://doi.org/10.1007/978-1-4939-2152-2_15
Tornabene E, Helms HCC, Pedersen SF, Brodin B (2019) Effects of oxygen-glucose deprivation (OGD) on barrier properties and mRNA transcript levels of selected marker proteins in brain endothelial cells/astrocyte co-cultures. PLoS ONE 14:e0221103. https://doi.org/10.1371/journal.pone.0221103
Ubogu EE (2020) Biology of the human blood-nerve barrier in health and disease. Exp Neurol 328:113272. https://doi.org/10.1016/j.expneurol.2020.113272
van der Bliek AM, Shen Q, Kawajiri S (2013) Mechanisms of mitochondrial fission and fusion. Cold Spring Harb Perspect Biol 5:a011072. https://doi.org/10.1101/cshperspect.a011072
Wang C, Nguyen HN, Maguire JL, Perry DC (2002) Role of intracellular calcium stores in cell death from oxygen-glucose deprivation in a neuronal cell line. J Cereb Blood Flow Metab 22:206–214. https://doi.org/10.1097/00004647-200202000-00008
Xu M, Feng J, Tang M, Guo Q, Zhan J, Zhu F, Lei H, Kang Q (2021) Blocking retrograde axonal transport of autophagosomes contributes to sevoflurane-induced neuron apoptosis in APP/PS1 mice. Acta Neurol Belg 121:1207–1215. https://doi.org/10.1007/s13760-020-01359-6
Zheng Y, Zhang X, Wu X, Jiang L, Ahsan A, Ma S, Xiao Z, Han F, Qin ZH, Hu W, Chen Z (2019) Somatic autophagy of axonal mitochondria in ischemic neurons. J Cell Biol 218:1891–1907. https://doi.org/10.1083/jcb.201804101
Acknowledgements
We wish to thank H. Okushima and Y. Hayakawa of Sapporo Medical University for technical support.
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This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (15K01419 and 18K10678) to S. Kikuchi, (19K05736) T. Kohno, (19K07464) T. Kojima and (21K06733) Y. Ohsaki.
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SK and TN designed the experiments; SK, TK, TK, and TN performed the research and data analysis; SK, HT, YO and TN drafted the paper.
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Kikuchi, S., Kohno, T., Kojima, T. et al. Oxygen–Glucose Deprivation Decreases the Motility and Length of Axonal Mitochondria in Cultured Dorsal Root Ganglion Cells of Rats. Cell Mol Neurobiol 43, 1267–1280 (2023). https://doi.org/10.1007/s10571-022-01247-y
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DOI: https://doi.org/10.1007/s10571-022-01247-y