Samm50 downregulation-driven mitochondrial dysfunction triggers ferroptosis and contributes to ketamine-induced neurotoxicity and cognitive impairment.

Abstract

Ketamine abuse is associated with persistent cognitive deficits and neurotoxicity, though the underlying mechanisms remain incompletely understood. While mitochondrial dysfunction and ferroptosis have been separately implicated, their causal relationship and the key molecular link in ketamine-induced hippocampal damage are unclear. Using a mouse model of ketamine-induced cognitive impairment and an HT22 hippocampal neuronal cell line, we found that ketamine significantly downregulated Samm50, a key protein maintaining mitochondrial outer membrane integrity, in both the hippocampus and HT22 cells. This downregulation was accompanied by reduced mitochondrial membrane potential (MMP) and ATP levels, and elevated reactive oxygen species (ROS). Concurrently, ketamine upregulated transferrin receptor TFR1, led to Fe²⁺/Fe³⁺ accumulation, increased malondialdehyde (MDA) and lipid peroxidation (LPO), and decreased the ferroptosis regulators GPX4 and SLC7A11. In vitro, ferroptosis inhibitors Fer-1 and deferoxamine (DFO) reversed ketamine-induced cell death, Fe²⁺ overload, LPO, and MMP loss, but Fer-1 failed to restore ATP or Samm50 expression. MitoQ rescued ATP, MMP, and ROS. Strikingly, Samm50 overexpression not only restored mitochondrial function (ATP, MMP, ROS) but also upregulated GPX4 and SLC7A11, thereby ameliorating ferroptosis. Collectively, ketamine induces hippocampal neurotoxicity and cognitive impairment via a two-step mechanism: it first downregulates Samm50, leading to primary mitochondrial dysfunction (energy failure and oxidative stress); this mitochondrial impairment then triggers ferroptosis through iron accumulation and suppression of GPX4/SLC7A11. Samm50 downregulation serves as a critical upstream event linking mitochondrial dysfunction to ferroptosis, representing a novel therapeutic target for ketamine-induced neuropsychiatric toxicity.

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