Figure 3.

Electrical remodeling induced by metabolic reprogramming in diseased pulmonary vasculature. Down-regulation of voltage-gated potassium (K_v) channels prevents K⁺ efflux, leading to a high concentration of K⁺ in the cytosol. The resulting membrane depolarization triggers the opening of L-type calcium channels, which allows for Ca²⁺ influx. Calcium suppresses GSK-3, thus preventing inhibition of HK-II. HK-II then freely inhibits the voltage-dependent anion channel (VDAC) of the mitochondrial permeability transition pore (MPTP), causing mitochondrial hyperpolarization and preventing the release of pro-apoptotic factors through the MPTP. Ca²⁺ also promotes NFAT entry into the cell. NFAT further inhibits K_v channels, creating a feedback loop and augmenting the above responses.