Truncating PKHD1 and PKD2 mutations alter energy metabolism
Autor: | Sylvie Mrug, Victor M. Darley-Usmar, P. Darwin Bell, Phillip Chumley, Stephen Barnes, Bradley K. Yoder, Anil K. Challa, Taylor F. Berryhill, Balu K. Chacko, Landon Wilson, Robert A. Kesterson, Juling Zhou, John M. Parant, Michal Mrug |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Physiology Energy metabolism Receptors Cell Surface 03 medical and health sciences 0302 clinical medicine Genome editing CRISPR Humans Clustered Regularly Interspaced Short Palindromic Repeats Cell Proliferation Polycystin-1 Gene Editing Chemistry Gene targeting Cell biology 030104 developmental biology Glucose HEK293 Cells 030220 oncology & carcinogenesis Mutation Energy Metabolism Extracellular acidification Protein Kinases Protein Kinase D2 Research Article |
Zdroj: | American journal of physiology. Renal physiology. 316(3) |
ISSN: | 1522-1466 |
Popis: | Deficiency in polycystin 1 triggers specific changes in energy metabolism. To determine whether defects in other human cystoproteins have similar effects, we studied extracellular acidification and glucose metabolism in human embryonic kidney (HEK-293) cell lines with polycystic kidney and hepatic disease 1 ( PKHD1) and polycystic kidney disease (PKD) 2 ( PKD2) truncating defects along multiple sites of truncating mutations found in patients with autosomal recessive and dominant PKDs. While neither the PKHD1 or PKD2 gene mutations nor their position enhanced cell proliferation rate in our cell line models, truncating mutations in these genes progressively increased overall extracellular acidification over time ( P < 0.001 for PKHD1 and PKD2 mutations). PKHD1 mutations increased nonglycolytic acidification rate (1.19 vs. 1.03, P = 0.002), consistent with an increase in tricarboxylic acid cycle activity or breakdown of intracellular glycogen. In addition, they increased basal and ATP-linked oxygen consumption rates [7.59 vs. 5.42 ( P = 0.015) and 4.55 vs. 2.98 ( P = 0.004)]. The PKHD1 and PKD2 mutations also altered mitochondrial morphology, resembling the effects of polycystin 1 deficiency. Together, these data suggest that defects in major PKD genes trigger changes in mitochondrial energy metabolism. After validation in in vivo models, these initial observations would indicate potential benefits of targeting energy metabolism in the treatment of PKDs. |
Databáze: | OpenAIRE |
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