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Molecular and biochemical alterations in tubular epithelial cells of patients with isolated methylmalonic aciduria


Ruppert, T; Schumann, A; Gröne, H J; Okun, J G; Kölker, S; Morath, M A; Sauer, S W (2015). Molecular and biochemical alterations in tubular epithelial cells of patients with isolated methylmalonic aciduria. Human Molecular Genetics, 24(24):7049-7059.

Abstract

Methylmalonic acidurias (MMAurias) are a group of inherited disorders in the catabolism of branched-chain amino acids, odd-chain fatty acids and cholesterol caused by complete or partial deficiency of methylmalonyl-CoA mutase (mut0 and mut- subtype respectively) and by defects in the metabolism of its cofactor 5′-deoxyadenosylcobalamin (cblA, cblB or cblD variant 2 type). A long-term complication found in patients with mut0 and cblB variant is chronic tubulointerstitial nephritis. The underlying pathomechanism has remained unknown. We established an in vitro model of tubular epithelial cells from patient urine (hTEC; 9 controls, 5 mut0, 1 cblB). In all human tubular epithelial cell (hTEC) lines we found specific tubular markers (AQP1, UMOD, AQP2). Patient cells showed disturbance of energy metabolism in glycolysis, mitochondrial respiratory chain and Krebs cycle in concert with increased reactive oxygen species (ROS) formation. Electron micrographs indicated increased autophagosome production and endoplasmic reticulum stress, which was supported by positive acridine orange staining and elevated levels of LC3 II, P62 and pIRE1. Screening mTOR signaling revealed a release of inhibition of autophagy. Patient hTEC produced and secreted elevated amounts of the pro-inflammatory cytokine IL8, which was highly correlated with the acridine orange staining. Summarizing, hTEC of MMAuria patients are characterized by disturbed energy metabolism and ROS production that lead to increased autophagy and IL8 secretion

Abstract

Methylmalonic acidurias (MMAurias) are a group of inherited disorders in the catabolism of branched-chain amino acids, odd-chain fatty acids and cholesterol caused by complete or partial deficiency of methylmalonyl-CoA mutase (mut0 and mut- subtype respectively) and by defects in the metabolism of its cofactor 5′-deoxyadenosylcobalamin (cblA, cblB or cblD variant 2 type). A long-term complication found in patients with mut0 and cblB variant is chronic tubulointerstitial nephritis. The underlying pathomechanism has remained unknown. We established an in vitro model of tubular epithelial cells from patient urine (hTEC; 9 controls, 5 mut0, 1 cblB). In all human tubular epithelial cell (hTEC) lines we found specific tubular markers (AQP1, UMOD, AQP2). Patient cells showed disturbance of energy metabolism in glycolysis, mitochondrial respiratory chain and Krebs cycle in concert with increased reactive oxygen species (ROS) formation. Electron micrographs indicated increased autophagosome production and endoplasmic reticulum stress, which was supported by positive acridine orange staining and elevated levels of LC3 II, P62 and pIRE1. Screening mTOR signaling revealed a release of inhibition of autophagy. Patient hTEC produced and secreted elevated amounts of the pro-inflammatory cytokine IL8, which was highly correlated with the acridine orange staining. Summarizing, hTEC of MMAuria patients are characterized by disturbed energy metabolism and ROS production that lead to increased autophagy and IL8 secretion

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Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:29 September 2015
Deposited On:05 Oct 2018 16:58
Last Modified:15 Dec 2018 01:00
Publisher:Oxford University Press
ISSN:0964-6906
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/hmg/ddv405
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicenceoxford101093hmgddv405 (Library Catalogue)
PubMed ID:26420839

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