Therapeutic potential for KCC2-targeted neurological diseases.

Patients with neurological diseases, such as schizophrenia, tend to show low K-Cl co-transporter 2 (KCC2) levels in the brain. The cause of these diseases has been associated with stress and neuroinflammation. However, since the pathogenesis of these diseases is not yet fully investigated, drug therapy is still limited to symptomatic therapy.

Mitochondrial dysfunction promotes aquaporin expression that controls hydrogen peroxide permeability and ferroptosis.

Most anti-cancer agents and radiotherapy exert their therapeutic effects via the production of free radicals. Ferroptosis is a recently described cell death process that is accompanied by iron-dependent lipid peroxidation. Hydrogen peroxide (HO) has been reported to induce cell death.

Lipid peroxidation increases hydrogen peroxide permeability leading to cell death in cancer cell lines that lack mtDNA.

4-Hydroxynonenal (HNE) is an important product of plasma membrane lipid peroxidation, which is a cause of cell and tissue injury. Mitochondrial DNA (mtDNA)-depleted ρ cells were established using human cervical cancer and oral squamous cell carcinoma cell lines. We investigated the effect of reactive oxygen species in ρ cells, especially the mechanism of hydrogen peroxide (H O )-mediated cell death.

Clinically relevant radioresistant cells exhibit resistance to HO by decreasing internal HO and lipid peroxidation.

Radiation therapy is one of the choices to treat malignant tumors. In radiation therapy, existence of radiation-resistant cell is a major problem to overcome. We established clinically relevant radioresistant cells that had been obtained by exposing to 2 Gy/day X-rays for more than 30 days.

Data on the aquaporin gene expression differences among ρ, clinically relevant radioresistant, and the parental cells of human cervical cancer and human tongue squamous cell carcinoma.

We present data about mitochondrial DNA (mtDNA) copy number and aquaporin (AQP) gene expression in clinically radioresistant (CRR), ρ, and their parental cells from human cervical cancer and human tongue squamous cell carcinoma. In both ρ and CRR cells, the mtDNA copy number was lower than for the parental strain. In addition, the obtained data suggest an association between the gene expression levels of AQP (1, 3, 8, and 9) and the difference in hydrogen peroxide (HO) sensitivity between ρ and CRR cells.

Sensitivity of mitochondrial DNA depleted ρ0 cells to HO depends on the plasma membrane status.

To clarify the relationship between mitochondrial DNA (mtDNA)-depleted ρ0 cells and the cellular sensitivity to hydrogen peroxide (HO), we established HeLa and SAS ρ0 cell lines and investigated their survival rate in HO, radical scavenging enzymes, plasma membrane potential status, and chronological change in intracellular HO amount under the existence of extracellular hydrogen peroxide compared with the parental cells. The results revealed that ρ0 cells had higher sensitivity to HO than their parental cells, even though the catalase activity of ρ0 cells was up-regulated, and the membrane potential of the ρ0 cells was lower than their parental cells. Furthermore, the internal HO amount significantly increased only in ρ0 cells after 50 μM HO treatment for 1 h.