The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria
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
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Notes
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Scientific reports. - 13, 1 (2023) , 7677, ISSN: 2045-2322
- Event
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Veröffentlichung
- (where)
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Freiburg
- (who)
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Universität
- (when)
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2023
- Creator
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Schumann, Anke
Brutsche, Marion
Havermans, Monique
Grünert, Sarah
Kölker, Stefan
Groß, Olaf
Hannibal, Luciana
Spiekerkötter, Ute
- DOI
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10.1038/s41598-023-34373-8
- URN
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urn:nbn:de:bsz:25-freidok-2364536
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 10:50 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Schumann, Anke
- Brutsche, Marion
- Havermans, Monique
- Grünert, Sarah
- Kölker, Stefan
- Groß, Olaf
- Hannibal, Luciana
- Spiekerkötter, Ute
- Universität
Time of origin
- 2023
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