{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T14:40:57Z","timestamp":1791816057279,"version":"4.3.4"},"reference-count":29,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,5,2]],"date-time":"2021-05-02T00:00:00Z","timestamp":1619913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2017R1D1AB03035061"],"award-info":[{"award-number":["2017R1D1AB03035061"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chungnam National University Hospital Research Fund","award":["to K.W.L."],"award-info":[{"award-number":["to K.W.L."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent studies have implicated mitochondrial disruption in podocyte dysfunction, which is a characteristic feature of primary and diabetic glomerular diseases. However, the mechanisms by which primary mitochondrial dysfunction in podocytes affects glomerular renal diseases are currently unknown. To investigate the role of mitochondrial oxidative phosphorylation (OxPhos) in podocyte dysfunction, glomerular function was examined in mice carrying a loss of function mutation of the gene encoding CR6-interacting factor-1 (CRIF1), which is essential for intramitochondrial production and the subsequent insertion of OxPhos polypeptides into the inner mitochondrial membrane. Homozygotic deficiency of CRIF1 in podocytes resulted in profound and progressive albuminuria from 3 weeks of age; the CRIF1-deficient mice also developed glomerular and tubulointerstitial lesions by 10 weeks of age. Furthermore, marked glomerular sclerosis and interstitial fibrosis were observed in homozygous CRIF1-deficient mice at 20 weeks of age. In cultured mouse podocytes, loss of CRIF1 resulted in OxPhos dysfunction and marked loss or abnormal aggregation of F-actin. These findings indicate that the OxPhos status determines the integrity of podocytes and their ability to maintain a tight barrier and control albuminuria. Analyses of the glomerular function of the podocyte-specific primary OxPhos dysfunction model mice demonstrate a link between podocyte mitochondrial dysfunction, progressive glomerular sclerosis, and tubulointerstitial diseases.<\/jats:p>","DOI":"10.3390\/ijms22094827","type":"journal-article","created":{"date-parts":[[2021,5,2]],"date-time":"2021-05-02T08:05:21Z","timestamp":1619942721000},"page":"4827","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Mitochondrial Dysfunction in Podocytes Caused by CRIF1 Deficiency Leads to Progressive Albuminuria and Glomerular Sclerosis in Mice"],"prefix":"10.3390","volume":"22","author":[{"given":"Ki Ryang","family":"Na","sequence":"first","affiliation":[{"name":"Department of Nephrology, Chungnam National University School of Medicine, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Young","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chungnam National University School of Medicine, Daejeon 35015, Korea"},{"name":"Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Ah","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chungnam National University School of Medicine, Daejeon 35015, Korea"},{"name":"Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4193-2034","authenticated-orcid":false,"given":"Yoon-Kyung","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Daejeon St. Mary\u2019s Hospital, Catholic University of Korea, Daejeon 34572, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3874-864X","authenticated-orcid":false,"given":"Kwang-Sun","family":"Suh","sequence":"additional","affiliation":[{"name":"Department of Pathology, Chungnam National University School of Medicine, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang Wook","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chungnam National University School of Medicine, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2870-3958","authenticated-orcid":false,"given":"Dae Eun","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chungnam National University School of Medicine, Daejeon 35015, Korea"},{"name":"Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.beem.2012.05.003","article-title":"Cellular and molecular mechanisms of mitochondrial function","volume":"26","author":"Osellame","year":"2012","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/nrm2959","article-title":"Mitochondrial protein import: From proteomics to functional mechanisms","volume":"11","author":"Schmidt","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/sj.ki.5000207","article-title":"Mitochondrial dysfunction in focal segmental glomerulosclerosis of puromycin aminonucleoside nephrosis","volume":"69","author":"Hagiwara","year":"2006","journal-title":"Kidney Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1111\/j.1523-1755.2000.00356.x","article-title":"Focal segmental glomerulosclerosis associated with mitochondrial cytopathy","volume":"58","author":"Doleris","year":"2000","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nrneph.2015.214","article-title":"Mitochondrial dysfunction in inherited renal disease and acute kidney injury","volume":"12","author":"Emma","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3389\/fmed.2018.00221","article-title":"Proteinuric Kidney Diseases: A Podocyte\u2019s Slit Diaphragm and Cytoskeleton Approach","volume":"5","author":"Yu","year":"2018","journal-title":"Front. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"F398","DOI":"10.1152\/ajprenal.00136.2015","article-title":"Podocyte endocytosis in the regulation of the glomerular filtration barrier","volume":"309","author":"Inoue","year":"2015","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/j.kint.2016.01.012","article-title":"Podocyte injury and its consequences","volume":"89","author":"Nagata","year":"2016","journal-title":"Kidney Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/nrneph.2018.9","article-title":"Mitochondrial dysfunction in diabetic kidney disease","volume":"14","author":"Forbes","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1196\/annals.1433.018","article-title":"Oxidative stress and advanced glycation in diabetic nephropathy","volume":"1126","author":"Coughlan","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1046\/j.1523-1755.2001.0590041236.x","article-title":"Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation","volume":"59","author":"Hotta","year":"2001","journal-title":"Kidney Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3166","DOI":"10.1681\/ASN.2017020143","article-title":"The Evolving Complexity of the Podocyte Cytoskeleton","volume":"28","author":"Schell","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cmet.2012.06.012","article-title":"CRIF1 is essential for the synthesis and insertion of oxidative phosphorylation polypeptides in the mammalian mitochondrial membrane","volume":"16","author":"Kim","year":"2012","journal-title":"Cell Metab."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ryu, M.J., Kim, S.J., Kim, Y.K., Choi, M.J., Tadi, S., Lee, M.H., Lee, S.E., Chung, H.K., Jung, S.B., and Kim, H.J. (2013). Crif1 deficiency reduces adipose OXPHOS capacity and triggers inflammation and insulin resistance in mice. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003356"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/sj.emboj.7601986","article-title":"Crif1 is a novel transcriptional coactivator of STAT3","volume":"27","author":"Kwon","year":"2008","journal-title":"EMBO J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1002\/gene.10164","article-title":"Podocyte-specific expression of cre recombinase in transgenic mice","volume":"35","author":"Moeller","year":"2003","journal-title":"Genesis"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Bian, X., Fang, L., He, W., Dai, C., and Yang, J. (2013). Aristolochic acid causes albuminuria by promoting mitochondrial DNA damage and dysfunction in podocyte. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0083408"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1038\/sj.ki.5001965","article-title":"Puromycin aminonucleoside induces oxidant-dependent DNA damage in podocytes in vitro and in vivo","volume":"70","author":"Marshall","year":"2006","journal-title":"Kidney Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1097\/01.ASN.0000019772.17954.F8","article-title":"Mitochondrial DNA mutations in focal segmental glomerulosclerosis lesions","volume":"13","author":"Yamagata","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1016\/j.ajpath.2011.01.029","article-title":"Mitochondrial dysfunction mediates aldosterone-induced podocyte damage: A therapeutic target of PPARgamma","volume":"178","author":"Zhu","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/82826","article-title":"Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes","volume":"26","author":"Inoue","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/nrneph.2017.107","article-title":"Mitochondrial energetics in the kidney","volume":"13","author":"Bhargava","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1007\/s10024-005-0058-z","article-title":"Focal segmental glomerulosclerosis associated with mitochondrial cytopathy: Report of two cases with special emphasis on podocytes","volume":"8","author":"Gucer","year":"2005","journal-title":"Pediatr. Dev. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"F520","DOI":"10.1152\/ajprenal.00570.2012","article-title":"Mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury","volume":"305","author":"Su","year":"2013","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4203","DOI":"10.1167\/iovs.07-1364","article-title":"Mitochondrial DNA oxidative damage triggering mitochondrial dysfunction and apoptosis in high glucose-induced HRECs","volume":"49","author":"Xie","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.cmet.2012.01.009","article-title":"Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells","volume":"15","author":"Wang","year":"2012","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1038\/sj.ki.5000195","article-title":"The parathyroid hormone-related protein system and diabetic nephropathy outcome in streptozotocin-induced diabetes","volume":"69","author":"Izquierdo","year":"2006","journal-title":"Kidney Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1006\/excr.1997.3739","article-title":"Rearrangements of the cytoskeleton and cell contacts induce process formation during differentiation of conditionally immortalized mouse podocyte cell lines","volume":"236","author":"Mundel","year":"1997","journal-title":"Exp. Cell Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1681\/ASN.V13186","article-title":"Reactive oxygen species alter gene expression in podocytes: Induction of granulocyte macrophage-colony-stimulating factor","volume":"13","author":"Greiber","year":"2002","journal-title":"J. Am. Soc. 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