Format

Send to

Choose Destination
Am J Physiol Renal Physiol. 2019 Mar 1;316(3):F414-F425. doi: 10.1152/ajprenal.00167.2018. Epub 2018 Dec 19.

Truncating PKHD1 and PKD2 mutations alter energy metabolism.

Author information

1
Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
2
Department of Psychology, University of Alabama at Birmingham , Birmingham, Alabama.
3
Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham , Birmingham, Alabama.
4
Department of Pharmacology and Toxicology, University of Alabama at Birmingham , Birmingham, Alabama.
5
Department of Genetics, University of Alabama at Birmingham , Birmingham, Alabama.
6
Department of Pathology, University of Alabama at Birmingham , Birmingham, Alabama.
7
Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Alabama.
8
Department of Veterans Affairs Medical Center , Birmingham, Alabama.

Abstract

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.

KEYWORDS:

CRISPR; Cas9 nucleases; ECAR; OCR; gene editing; gene targeting

PMID:
30566001
PMCID:
PMC6442375
[Available on 2020-03-01]
DOI:
10.1152/ajprenal.00167.2018

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center