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A mutation in the Na-K-2Cl cotransporter-1 leads to changes in cellular
Omer S, Koumangoye R, Delpire E
Submitted Externally on 2/12/2020
Journal of cellular physiology, REFERENCES
Volume : Pages
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 NKCC1WT/DFX and NKCC1DFX/DFX 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.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
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