{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T04:44:40Z","timestamp":1784349880314,"version":"3.55.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,11,9]],"date-time":"2017-11-09T00:00:00Z","timestamp":1510185600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,11,9]],"date-time":"2017-11-09T00:00:00Z","timestamp":1510185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mitochondrial dysfunction is a critical step in the pathogenesis of many neurodegenerative diseases. The p32\/ C1qbp gene functions as an essential RNA and protein chaperone in mitochondrial translation, and is indispensable for embryonic development. However, little is known about the consequences of mitochondrial dysfunction of p32 deletion in the brain development. Here, we found that mice lacking p32 in the central nervous system (p32cKO mice) showed white matter degeneration accompanied by progressive oligodendrocyte loss, axon degeneration and vacuolation in the mid brain and brain stem regions. Furthermore, p32cKO mice died within 8 weeks of birth. We also found that p32-deficient oligodendrocytes and neurons showed reduced oligodendrocyte differentiation and axon degeneration in primary culture. We show that mitochondrial disruption activates an adaptive program known as the integrated stress response (ISR). Mitochondrial respiratory chain function in oligodendrocytes and neurons is, therefore, essential for myelination and axon maintenance, respectively, suggesting that mitochondrial respiratory chain dysfunction in the central nervous system contributes to leukoencephalopathy.<\/jats:p>","DOI":"10.1038\/s41598-017-15414-5","type":"journal-article","created":{"date-parts":[[2017,11,3]],"date-time":"2017-11-03T14:18:02Z","timestamp":1509718682000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Neural-specific deletion of mitochondrial p32\/C1qbp leads to leukoencephalopathy due to undifferentiated oligodendrocyte and axon degeneration"],"prefix":"10.1038","volume":"7","author":[{"given":"Mikako","family":"Yagi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Uchiumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriaki","family":"Sagata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiki","family":"Setoyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Amamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Matsushima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongchon","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,9]]},"reference":[{"key":"15414_CR1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1146\/annurev.neuro.30.051606.094302","volume":"31","author":"S DiMauro","year":"2008","unstructured":"DiMauro, S. & Schon, E. A. Mitochondrial disorders in the nervous system. Annu Rev Neurosci 31, 91\u2013123 (2008).","journal-title":"Annu Rev Neurosci"},{"key":"15414_CR2","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1126\/science.283.5407.1482","volume":"283","author":"DC Wallace","year":"1999","unstructured":"Wallace, D. C. Mitochondrial diseases in man and mouse. Science 283, 1482\u20131488 (1999).","journal-title":"Science"},{"key":"15414_CR3","doi-asserted-by":"publisher","first-page":"10726","DOI":"10.1073\/pnas.0403649101","volume":"101","author":"PE Coskun","year":"2004","unstructured":"Coskun, P. E., Beal, M. F. & Wallace, D. C. Alzheimer\u2019s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA 101, 10726\u201310731 (2004).","journal-title":"Proc Natl Acad Sci USA"},{"key":"15414_CR4","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1111\/j.1600-0404.2006.00671.x","volume":"114","author":"J Finsterer","year":"2006","unstructured":"Finsterer, J. Central nervous system manifestations of mitochondrial disorders. Acta Neurol Scand 114, 217\u2013238 (2006).","journal-title":"Acta Neurol Scand"},{"key":"15414_CR5","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/S0197-0186(01)00124-3","volume":"40","author":"M Orth","year":"2002","unstructured":"Orth, M. & Schapira, A. H. Mitochondrial involvement in Parkinson\u2019s disease. Neurochem Int 40, 533\u2013541 (2002).","journal-title":"Neurochem Int"},{"key":"15414_CR6","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.1002\/glia.22670","volume":"62","author":"L Morato","year":"2014","unstructured":"Morato, L. et al. Mitochondrial dysfunction in central nervous system white matter disorders. Glia 62, 1878\u20131894 (2014).","journal-title":"Glia"},{"key":"15414_CR7","doi-asserted-by":"publisher","first-page":"24363","DOI":"10.1074\/jbc.272.39.24363","volume":"272","author":"T Muta","year":"1997","unstructured":"Muta, T., Kang, D., Kitajima, S., Fujiwara, T. & Hamasaki, N. p32 protein, a splicing factor 2-associated protein, is localized in mitochondrial matrix and is functionally important in maintaining oxidative phosphorylation. J Biol Chem 272, 24363\u201324370 (1997).","journal-title":"J Biol Chem"},{"key":"15414_CR8","doi-asserted-by":"crossref","first-page":"3534","DOI":"10.4049\/jimmunol.160.7.3534","volume":"160","author":"J Dedio","year":"1998","unstructured":"Dedio, J., Jahnen-Dechent, W., Bachmann, M. & Muller-Esterl, W. The multiligand-binding protein gC1qR, putative C1q receptor, is a mitochondrial protein. J Immunol 160, 3534\u20133542 (1998).","journal-title":"J Immunol"},{"key":"15414_CR9","doi-asserted-by":"publisher","first-page":"9717","DOI":"10.1093\/nar\/gks774","volume":"40","author":"M Yagi","year":"2012","unstructured":"Yagi, M. et al. p32\/gC1qR is indispensable for fetal development and mitochondrial translation: importance of its RNA-binding ability. Nucleic Acids Res 40, 9717\u20139737 (2012).","journal-title":"Nucleic Acids Res"},{"key":"15414_CR10","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1128\/MCB.01101-09","volume":"30","author":"V Fogal","year":"2010","unstructured":"Fogal, V. et al. Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol Cell Biol 30, 1303\u20131318 (2010).","journal-title":"Mol Cell Biol"},{"key":"15414_CR11","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1111\/j.1349-7006.2010.01828.x","volume":"102","author":"R Amamoto","year":"2011","unstructured":"Amamoto, R. et al. Mitochondrial p32\/C1QBP is highly expressed in prostate cancer and is associated with shorter prostate-specific antigen relapse time after radical prostatectomy. Cancer Sci 102, 639\u2013647 (2011).","journal-title":"Cancer Sci"},{"key":"15414_CR12","doi-asserted-by":"publisher","first-page":"e1005679","DOI":"10.1371\/journal.pgen.1005679","volume":"12","author":"M Kohda","year":"2016","unstructured":"Kohda, M. et al. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet 12, e1005679 (2016).","journal-title":"PLoS Genet"},{"key":"15414_CR13","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1152\/physrev.2001.81.2.871","volume":"81","author":"N Baumann","year":"2001","unstructured":"Baumann, N. & Pham-Dinh, D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81, 871\u2013927 (2001).","journal-title":"Physiol Rev"},{"key":"15414_CR14","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1002\/glia.440120406","volume":"12","author":"M Suzuki","year":"1994","unstructured":"Suzuki, M. & Raisman, G. Multifocal pattern of postnatal development of the macroglial framework of the rat fimbria. Glia 12, 294\u2013308 (1994).","journal-title":"Glia"},{"key":"15414_CR15","doi-asserted-by":"publisher","first-page":"4260","DOI":"10.1523\/JNEUROSCI.4000-04.2005","volume":"25","author":"R Kovacs","year":"2005","unstructured":"Kovacs, R., Kardos, J., Heinemann, U. & Kann, O. Mitochondrial calcium ion and membrane potential transients follow the pattern of epileptiform discharges in hippocampal slice cultures. J Neurosci 25, 4260\u20134269 (2005).","journal-title":"J Neurosci"},{"key":"15414_CR16","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1016\/0002-9394(79)90565-8","volume":"88","author":"PB Johnston","year":"1979","unstructured":"Johnston, P. B., Gaster, R. N., Smith, V. C. & Tripathi, R. C. A clinicopathologic study of autosomal dominant optic atrophy. Am J Ophthalmol 88, 868\u2013875 (1979).","journal-title":"Am J Ophthalmol"},{"key":"15414_CR17","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1212\/WNL.45.6.1188","volume":"45","author":"H Rusanen","year":"1995","unstructured":"Rusanen, H. et al. Demyelinating polyneuropathy in a patient with the tRNA(Leu)(UUR) mutation at base pair 3243 of the mitochondrial DNA. Neurology 45, 1188\u20131192 (1995).","journal-title":"Neurology"},{"key":"15414_CR18","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.mito.2009.12.141","volume":"10","author":"R Schoenfeld","year":"2010","unstructured":"Schoenfeld, R. et al. Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation. Mitochondrion 10, 143\u2013150 (2010).","journal-title":"Mitochondrion"},{"key":"15414_CR19","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1007\/s00429-013-0662-z","volume":"219","author":"AL Bauernfeind","year":"2014","unstructured":"Bauernfeind, A. L. et al. Aerobic glycolysis in the primate brain: reconsidering the implications for growth and maintenance. Brain Struct Funct 219, 1149\u20131167 (2014).","journal-title":"Brain Struct Funct"},{"key":"15414_CR20","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.cmet.2015.07.006","volume":"22","author":"A Volkenhoff","year":"2015","unstructured":"Volkenhoff, A. et al. Glial Glycolysis Is Essential for Neuronal Survival in Drosophila. Cell Metab 22, 437\u2013447 (2015).","journal-title":"Cell Metab"},{"key":"15414_CR21","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1055\/s-0032-1306387","volume":"32","author":"LJ Wong","year":"2012","unstructured":"Wong, L. J. Mitochondrial syndromes with leukoencephalopathies. Semin Neurol 32, 55\u201361 (2012).","journal-title":"Semin Neurol"},{"key":"15414_CR22","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.cmet.2013.05.019","volume":"18","author":"E Harno","year":"2013","unstructured":"Harno, E., Cottrell, E. C. & White, A. Metabolic pitfalls of CNS Cre-based technology. Cell Metab 18, 21\u201328 (2013).","journal-title":"Cell Metab"},{"key":"15414_CR23","doi-asserted-by":"publisher","first-page":"1819","DOI":"10.1212\/01.wnl.0000436068.43384.ef","volume":"81","author":"RL Davis","year":"2013","unstructured":"Davis, R. L. et al. Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Neurology 81, 1819\u20131826 (2013).","journal-title":"Neurology"},{"key":"15414_CR24","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1016\/S1474-4422(11)70155-7","volume":"10","author":"A Suomalainen","year":"2011","unstructured":"Suomalainen, A. et al. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 10, 806\u2013818 (2011).","journal-title":"Lancet Neurol"},{"key":"15414_CR25","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/S0167-7799(03)00026-X","volume":"21","author":"NM Hooper","year":"2003","unstructured":"Hooper, N. M. Could inhibition of the proteasome cause mad cow disease? Trends Biotechnol 21, 144\u2013145 (2003).","journal-title":"Trends Biotechnol"},{"key":"15414_CR26","doi-asserted-by":"publisher","first-page":"6698","DOI":"10.1073\/pnas.0303859101","volume":"101","author":"K Akassoglou","year":"2004","unstructured":"Akassoglou, K. et al. Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis. Proc Natl Acad Sci USA 101, 6698\u20136703 (2004).","journal-title":"Proc Natl Acad Sci USA"},{"key":"15414_CR27","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.cell.2004.09.013","volume":"119","author":"J Lin","year":"2004","unstructured":"Lin, J. et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119, 121\u2013135 (2004).","journal-title":"Cell"},{"key":"15414_CR28","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1016\/j.biochi.2012.10.023","volume":"95","author":"MH Baslow","year":"2013","unstructured":"Baslow, M. H. & Guilfoyle, D. N. Canavan disease, a rare early-onset human spongiform leukodystrophy: insights into its genesis and possible clinical interventions. Biochimie 95, 946\u2013956 (2013).","journal-title":"Biochimie"},{"key":"15414_CR29","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/j.cell.2012.12.029","volume":"152","author":"D Zala","year":"2013","unstructured":"Zala, D. et al. Vesicular glycolysis provides on-board energy for fast axonal transport. Cell 152, 479\u2013491 (2013).","journal-title":"Cell"},{"key":"15414_CR30","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.neuron.2012.01.030","volume":"74","author":"J Penney","year":"2012","unstructured":"Penney, J. et al. TOR is required for the retrograde regulation of synaptic homeostasis at the Drosophila neuromuscular junction. Neuron 74, 166\u2013178 (2012).","journal-title":"Neuron"},{"key":"15414_CR31","doi-asserted-by":"publisher","first-page":"2448","DOI":"10.1093\/brain\/awq180","volume":"133","author":"M Geva","year":"2010","unstructured":"Geva, M. et al. A mouse model for eukaryotic translation initiation factor 2B-leucodystrophy reveals abnormal development of brain white matter. Brain 133, 2448\u20132461 (2010).","journal-title":"Brain"},{"key":"15414_CR32","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/S1474-4422(06)70440-9","volume":"5","author":"MS van der Knaap","year":"2006","unstructured":"van der Knaap, M. S., Pronk, J. C. & Scheper, G. C. Vanishing white matter disease. Lancet Neurol 5, 413\u2013423 (2006).","journal-title":"Lancet Neurol"},{"key":"15414_CR33","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.3346\/jkms.2012.27.10.1241","volume":"27","author":"IS Moon","year":"2012","unstructured":"Moon, I. S., Lee, H. J. & Park, I. S. Dendritic eIF4E-binding protein 1 (eIF4E-BP1) mRNA is upregulated by neuronal activation. J Korean Med Sci 27, 1241\u20131247 (2012).","journal-title":"J Korean Med Sci"},{"key":"15414_CR34","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1126\/science.1209038","volume":"334","author":"P Walter","year":"2011","unstructured":"Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081\u20131086 (2011).","journal-title":"Science"},{"key":"15414_CR35","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1034\/j.1600-0404.2003.00152.x","volume":"108","author":"T Hammen","year":"2003","unstructured":"Hammen, T., Stefan, H., Eberhardt, K. E., B. H., W. H. & Tomandl, B. F. Clinical applications of 1H-MR spectroscopy in the evaluation of epilepsies\u2013what do pathological spectra stand for with regard to current results and what answers do they give to common clinical questions concerning the treatment of epilepsies? Acta Neurol Scand 108, 223\u2013238 (2003).","journal-title":"Acta Neurol Scand"},{"issue":"Suppl 4","key":"15414_CR36","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1111\/j.1528-1167.2007.01241.x","volume":"48","author":"GK Hiremath","year":"2007","unstructured":"Hiremath, G. K. & Najm, I. M. Magnetic resonance spectroscopy in animal models of epilepsy. Epilepsia 48(Suppl 4), 47\u201355 (2007).","journal-title":"Epilepsia"},{"key":"15414_CR37","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1146\/annurev.me.24.020173.001415","volume":"24","author":"L Sokoloff","year":"1973","unstructured":"Sokoloff, L. Metabolism of ketone bodies by the brain. Annu Rev Med 24, 271\u2013280 (1973).","journal-title":"Annu Rev Med"},{"key":"15414_CR38","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/mp.2011.131","volume":"18","author":"J Yang","year":"2013","unstructured":"Yang, J. et al. Potential metabolite markers of schizophrenia. Mol Psychiatry 18, 67\u201378 (2013).","journal-title":"Mol Psychiatry"},{"key":"15414_CR39","doi-asserted-by":"publisher","first-page":"5554","DOI":"10.1093\/nar\/gkq305","volume":"38","author":"T Uchiumi","year":"2010","unstructured":"Uchiumi, T. et al. ERAL1 is associated with mitochondrial ribosome and elimination of ERAL1 leads to mitochondrial dysfunction and growth retardation. Nucleic Acids Res 38, 5554\u20135568 (2010).","journal-title":"Nucleic Acids Res"},{"key":"15414_CR40","doi-asserted-by":"crossref","first-page":"10333","DOI":"10.1523\/JNEUROSCI.22-23-10333.2002","volume":"22","author":"M Marin-Husstege","year":"2002","unstructured":"Marin-Husstege, M., Muggironi, M., Liu, A. & Casaccia-Bonnefil, P. Histone deacetylase activity is necessary for oligodendrocyte lineage progression. J Neurosci 22, 10333\u201310345 (2002).","journal-title":"J Neurosci"},{"key":"15414_CR41","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1016\/S0021-9258(18)91286-X","volume":"239","author":"LA Fahien","year":"1964","unstructured":"Fahien, L. A. & Cohen, P. P. A Kinetic Study of Carbamyl Phosphate Synthetase. J Biol Chem 239, 1925\u20131934 (1964).","journal-title":"J Biol Chem"},{"key":"15414_CR42","doi-asserted-by":"publisher","first-page":"1762","DOI":"10.1172\/JCI114360","volume":"84","author":"JT Lee","year":"1989","unstructured":"Lee, J. T. & Nussbaum, R. L. An arginine to glutamine mutation in residue 109 of human ornithine transcarbamylase completely abolishes enzymatic activity in Cos1 cells. J Clin Invest 84, 1762\u20131766, d (1989).","journal-title":"J Clin Invest"},{"key":"15414_CR43","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1139\/y59-099","volume":"37","author":"EG Bligh","year":"1959","unstructured":"Bligh, E. G. & Dyer, W. J. A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37, 911\u2013917 (1959).","journal-title":"Can J Biochem Physiol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15414-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15414-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15414-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,27]],"date-time":"2023-08-27T22:53:09Z","timestamp":1693176789000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15414-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,9]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["15414"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-15414-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,9]]},"assertion":[{"value":"15 June 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 October 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"15131"}}