Sodium disrupts mitochondrial energy metabolism to execute NECSO.

ABSTRACT: Na⁺ influx is a critical pathological event in various conditions such as ischemia, hyperosmotic stress, and organ failure. Although persistent activation of the transient receptor potential cation channel subfamily M member 4 (TRPM4) by chemical agonist Necrocide 1 (NC1) triggers necrosis by sodium overload (NECSO), the underlying mechanism remains to be elucidated. Here, we demonstrate that Na⁺ influx promotes necrosis by suppressing mitochondrial energy production. TRPM4-mediated Na⁺ entry elevates mitochondrial Na⁺ and reduces mitochondrial Ca²⁺ via NCLX, inhibiting oxidative phosphorylation and the Trichloroacetic acid (TCA) cycle, leading to severe energy depletion. This results in Na/K-ATPase inactivation, loss of ion gradients, cellular swelling and lysis. Our

SUBMITTER: Qiao Y 

PROVIDER: S-EPMC12804697 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature