Acute renal proximal tubule alterations during induced metabolic crises in a mouse model of glutaric aciduria type 1

Bastian Thies, Catherine Meyer-Schwesinger, Jessica Lamp, Michaela Schweizer, David M. Koeller, Kurt Ullrich, Thomas Braulke, Chris Mühlhausen

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


The metabolic disorder glutaric aciduria type 1 (GA1) is caused by deficiency of the mitochondrial glutaryl-CoA dehydrogenase (GCDH), leading to accumulation of the pathologic metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in blood, urine and tissues. Affected patients are prone to metabolic crises developing during catabolic conditions, with an irreversible destruction of striatal neurons and a subsequent dystonic-dyskinetic movement disorder. The pathogenetic mechanisms mediated by GA and 3OHGA have not been fully characterized. Recently, we have shown that GA and 3OHGA are translocated through membranes via sodium-dependent dicarboxylate cotransporter (NaC) 3, and organic anion transporters (OATs) 1 and 4. Here, we show that induced metabolic crises in Gcdh-/- mice lead to an altered renal expression pattern of NaC3 and OATs, and the subsequent intracellular GA and 3OHGA accumulation. Furthermore, OAT1 transporters are mislocalized to the apical membrane during metabolic crises accompanied by a pronounced thinning of proximal tubule brush border membranes. Moreover, mitochondrial swelling and increased excretion of low molecular weight proteins indicate functional tubulopathy. As the data clearly demonstrate renal proximal tubule alterations in this GA1 mouse model during induced metabolic crises, we propose careful evaluation of renal function in GA1 patients, particularly during acute crises. Further studies are needed to investigate if these findings can be confirmed in humans, especially in the long-term outcome of affected patients.

Original languageEnglish (US)
Pages (from-to)1463-1472
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number10
StatePublished - Oct 2013


  • Acute tubular injury
  • Dicarboxylate transporter
  • Glutaric aciduria type 1
  • Metabolic disease
  • Transporter expression

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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