title: Mitochondrial Dysregulation Secondary to Endoplasmic Reticulum Stress in Autosomal Dominant Tubulointerstitial Kidney Disease - UMOD (ADTKD-UMOD).
abstract: 'Autosomal dominant tubulointerstitial kidney disease - UMOD' (ADTKD-UMOD) is caused by impaired maturation and secretion of mutant uromodulin (UMOD) in thick ascending limb of Henle loop (TAL) cells, resulting in endoplasmic reticulum (ER) stress and unfolded protein response (UPR). To gain insight into pathophysiology, we analysed proteome profiles of TAL-enriched outer renal medulla samples from ADTKD-UMOD and control mice by quantitative LC-MS/MS. In total, 212 differentially abundant proteins were identified. Numerous ER proteins, including BiP (HSPA5), phosphorylated eIF2α (EIF2S1), ATF4, ATF6 and CHOP (DDIT3), were increased abundant, consistent with UPR. The abundance of hypoxia-inducible proteins with stress survival functions, i.e. HYOU1, TXNDC5 and ERO1L, was also increased. TAL cells in ADTKD-UMOD showed a decreased proportion of mitochondria and reduced abundance of multiple mitochondrial proteins, associated with disturbed post-translational processing and activation of the mitochondrial transcription factor NRF1. Impaired fission of organelles, as suggested by reduced abundance of FIS1, may be another reason for disturbed biogenesis of mitochondria and peroxisomes. Reduced amounts of numerous proteins of the OXPHOS and citrate cycle pathways, and activation of the LKB1-AMPK-pathway, a sensor pathway of cellular energy deficits, suggest impaired energy homeostasis. In conclusion, our study revealed secondary mitochondrial dysfunction in ADTKD-UMOD.
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fröhlich
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany.
authors.forename: Georg J
authors.initials: GJ
authors.lastname: Arnold
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany.|Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, D-80539 Munich, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Wanke
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004734:Energy Metabolism; D007679:Kidney Medulla / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology*; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020543:Proteome / Q000032:analysis; D056811:Unfolded Protein Response; D058949:Uromodulin / Q000235:genetics* / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C561064:FIS1 protein, mouse; C000717248:Hspa5 protein, mouse; D024101:Mitochondrial Proteins; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D020543:Proteome; D058949:Uromodulin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases