The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria

• Verfasst von: Schumann, Anke [VerfasserIn]
• Verfasst von: Brutsche, Marion [VerfasserIn]
• Verfasst von: Havermans, Monique [VerfasserIn]
• Verfasst von: Grünert, Sarah C. [VerfasserIn]
• Verfasst von: Kölker, Stefan [VerfasserIn]
• Verfasst von: Groß, Olaf [VerfasserIn]
• Verfasst von: Hannibal, Luciana [VerfasserIn]
• Verfasst von: Spiekerkoetter, Ute [VerfasserIn]
• Titel: The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria
• Verf.angabe: Anke Schumann, Marion Brutsche, Monique Havermans, Sarah C. Grünert, Stefan Kölker, Olaf Groß, Luciana Hannibal & Ute Spiekerkoetter
• E-Jahr: 2023
• Jahr: 11 May 2023
• Umfang: 15 S.
• Fussnoten: Gesehen am 28.06.2023
• Titel Quelle: Enthalten in: Scientific reports
• Ort Quelle: [London] : Macmillan Publishers Limited, part of Springer Nature, 2011
• Jahr Quelle: 2023
• Band/Heft Quelle: 13(2023) vom: Mai, Artikel-ID 7677, Seite 1-15
• ISSN Quelle: 2045-2322
• DOI: doi:10.1038/s41598-023-34373-8
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Diseases
• Sach-SW: Medical research
• Sach-SW: Molecular medicine
• K10plus-PPN: 1851170057

Abstract

Methylmalonic aciduria (MMA-uria) is caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). MUT deficiency hampers energy generation from specific amino acids, odd-chain fatty acids and cholesterol. Chronic kidney disease (CKD) is a well-known long-term complication. We exposed human renal epithelial cells from healthy controls and MMA-uria patients to different culture conditions (normal treatment (NT), high protein (HP) and isoleucine/valine (I/V)) to test the effect of metabolic stressors on renal mitochondrial energy metabolism. Creatinine levels were increased and antioxidant stress defense was severely comprised in MMA-uria cells. Alterations in mitochondrial homeostasis were observed. Changes in tricarboxylic acid cycle metabolites and impaired energy generation from fatty acid oxidation were detected. Methylcitrate as potentially toxic, disease-specific metabolite was increased by HP and I/V load. Mitophagy was disabled in MMA-uria cells, while autophagy was highly active particularly under HP and I/V conditions. Mitochondrial dynamics were shifted towards fission. Sirtuin1, a stress-resistance protein, was down-regulated by HP and I/V exposure in MMA-uria cells. Taken together, both interventions aggravated metabolic fingerprints observed in MMA-uria cells at baseline. The results point to protein toxicity in MMA-uria and lead to a better understanding, how the accumulating, potentially toxic organic acids might trigger CKD.