Mitochondrial Dysregulation Secondary to Endoplasmic Reticulum Stress in Autosomal Dominant Tubulointerstitial Kidney Disease - UMOD (ADTKD-UMOD)

Kemter, Elisabeth; Fröhlich, Thomas; Arnold, Georg J.; Wolf, Eckhard und Wanke, Rüdiger (2017): Mitochondrial Dysregulation Secondary to Endoplasmic Reticulum Stress in Autosomal Dominant Tubulointerstitial Kidney Disease - UMOD (ADTKD-UMOD). In: Scientific Reports, Bd. 7, 42970: S. 1-13

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 eIF2 alpha (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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Tiermedizin ; Chemie und Pharmazie > Department Biochemie
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 2045-2322
• Sprache: Englisch