期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1867, 期 4, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2020.166062
关键词
Complex I deficiency; Leigh syndrome; Metabolic network modeling; Cholesterol biosynthesis; NAD(P)H; Ndufs4(-/-) mice
资金
- Netherlands Organization for Scientific Research NWO Centers for Systems Biology Research initiative [CSBR09/013V]
- Prinses Beatrix Spierfonds [W.OR16-19]
- Radboud University Medical Center [RIMLS 017-010a]
The failure of the mitochondrial oxidative phosphorylation system is associated with disease symptoms, for which there is currently no approved drug treatment. Research has shown that fibrates can regulate cholesterol metabolism, improve cell growth and motor function, and prolong survival time.
The majority of cellular energy is produced by the mitochondrial oxidative phosphorylation (OXPHOS) system. Failure of the first OXPHOS enzyme complex, NADH:ubiquinone oxidoreductase or complex I (CI), is associated with multiple signs and symptoms presenting at variable ages of onset. There is no approved drug treatment yet to slow or reverse the progression of CI-deficient disorders. Here, we present a comprehensive human metabolic network model of genetically characterized CI-deficient patient-derived fibroblasts. Model calculations predicted that increased cholesterol production, export, and utilization can counterbalance the surplus of reducing equivalents in patient-derived fibroblasts, as these pathways consume considerable amounts of NAD(P)H. We show that fibrates attenuated increased NAD(P)H levels and improved CI-deficient fibroblast growth by stimulating the production of cholesterol via enhancement of its cellular efflux. In CI-deficient (Ndufs4(-/)(-)) mice, fibrate treatment resulted in prolonged survival and improved motor function, which was accompanied by an increased cholesterol efflux from peritoneal macrophages. Our results shine a new light on the use of compen-satory biological pathways in mitochondrial dysfunction, which may lead to novel therapeutic interventions for mitochondrial diseases for which currently no cure exists.
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