A mutation in the Na-K-2Cl cotransporter-1 leads to changes in cellular metabolism.

Omer S, Koumangoye R, Delpire E
J Cell Physiol. 2020 235 (10): 7239-7250

PMID: 32039487 · PMCID: PMC7416433 · DOI:10.1002/jcp.29623

The Na-K-Cl cotransporter-1 (NKCC1), by mediating the electroneutral transport of Na , K , and Cl plays an important role in cell volume regulation, epithelial transport, and the control of neuronal excitability. Recently, we reported the first known human mutation in SLC12A2, the gene encoding NKCC1. The 17-year old patient suffers from multiorgan failure. Laboratory tests conducted on muscle and liver biopsies of the patient showed abnormal increase in mitochondrial DNA copy number and increased glycogen levels, indicating the possibility that the transporter may play a role in energy metabolism. Here, we show that fibroblasts isolated from the patient demonstrate a significant increase in mitochondrial respiration, compared to fibroblasts isolated from healthy individuals. Similarly, Madin Darby canine kidney (MDCK) cells transfected with enhanced green fluorescent protein (EGFP)-tagged mutant NKCC1 DNA demonstrated increased mitochondrial respiration when compared to MDCK cells expressing EGFP-tagged wild-type (WT) cotransporter. Direct inhibition of the cotransporter through addition of bumetanide did not change the rate of basal respiration, but led to increased maximal mitochondrial respiration. Fibroblasts extracted from NKCC1 and NKCC1 mice also demonstrated a significant elevation in mitochondrial respiration, compared to fibroblasts isolated from their WT littermates. Expression of the mutant protein was associated with an increase in hydrogen peroxide and peroxidase activity and a decrease in messenger RNA transcript levels for protein involved in the unfolded protein response. These data reveal that cells expressing the mutant cotransporter demonstrate increased mitochondrial respiration and behave like they are experiencing a state of starvation.

© 2020 Wiley Periodicals, Inc.

MeSH Terms (22)

Adolescent Animals Cell Line DNA, Mitochondrial Dogs Energy Metabolism Female Fibroblasts Glycolysis Humans Madin Darby Canine Kidney Cells Mice Mice, Inbred C57BL Mice, Mutant Strains Microscopy, Electron, Transmission Mitochondria Multiple Organ Failure Mutant Proteins Mutation Recombinant Fusion Proteins Sequence Deletion Solute Carrier Family 12, Member 2

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