The mitochondrial electron transport chain (ETC) serves as the main site of cellular energy production and a major source of reactive oxygen species (ROS) generation, which can contribute to the lipid peroxidation associated with ferroptosis. However, the critical roles of mitochondria in ferroptosis are still being debated, and the consequences for cell survival vary depending on different ferroptosis inducers or mitochondrial modulators. In the neuroblastoma clonal cells SH-SY5Y, we demonstrated that inhibition of mitochondrial Complex II by 2-thenoyltrifluoroacetone (TTFA) markedly suppressed RSL3-induced ferroptotic lipid peroxidation and cell death. RSL3, a known inhibitor of glutathione peroxidase 4 (GPX4), significantly increased the mitochondrial membrane potential and superoxide production while reducing ATP-linked oxygen consumption. Co-treatment with TTFA effectively attenuated RSL3-induced mitochondrial hyperpolarization, lowered mitochondrial ROS generation, and restored respiratory activities - particularly enhanced ATP-linked oxygen consumption and reduced proton leak. Consistently, TTFA restored ATP production suppressed by RSL3. In contrast, inhibition of Complex I by rotenone did not suppress superoxide production and lipid peroxidation induced by RSL3, although it provided some protection against RSL3-mediated cytotoxicity. These findings suggest that inhibition of Complex II confers protection against ferroptosis by maintaining mitochondrial redox balance and protecting mitochondrial energy metabolism. In addition, our results uncover a novel mitochondrial mechanism underlying RSL3-induced oxidative stress and ferroptosis that can be modulated through targeted regulation of the ETC.

Background/Objectives: The concept of the “smoker’s paradox” in prior research posits that smoking could potentially offer neuroprotective effects in cases of acute carbon monoxide (CO) poisoning. This study aimed to determine the validity of this hypothesis by minimizing selection bias and confounding variables in a comparison of neurocognitive outcomes between smokers and non-smokers following acute CO poisoning. Methods: A total of 1150 patients were included in this retrospective study. Propensity Score Matching (PSM) was used to control for variables such as age, initial Glasgow Coma Scale (GCS) score, co-morbidities, and HBO₂ therapy application. Neurocognitive outcomes were assessed and compared between smokers and non-smokers. Results: In the initial analysis, 1150 patients were divided into non-smoking (61.7%) and smoking (38.3%) groups. Before PSM, smokers had a lower rate of poor outcomes (12.1% vs. 6.8%, p = 0.004). However, baseline differences emerged, with non-smokers being older with longer CO exposure, while smokers had more males and higher rates of intentional CO poisoning and drug ingestion. Smokers had a 0.56 times lower relative risk of poor outcomes compared to non-smokers (95% CI: 0.38–0.84, p = 0.004). After meticulous 1:1 PSM with 15 covariates, 317 patient pairs were matched, creating balanced cohorts. Neurocognitive outcomes at 1 month post-CO exposure showed no significant differences between matched non-smoking and smoking groups (9.8% vs. 7.9%, p = 0.461). Post-PSM, the relative risk for poor outcomes remained approximately 0.81 times lower in smokers compared to non-smokers, but with no statistical significance [0.81 (95% CI: 0.49–1.33, p = 0.402)]. Conclusions: Our findings do not support the idea of a protective effect from smoking in the context of acute CO poisoning. After accounting for potential confounders through PSM, we found that smoking status was not significantly associated with more favorable neurocognitive outcomes.

Background/Objectives: Carbon monoxide (CO) poisoning remains a major cause of poisoning-related morbidity, and delayed neuropsychiatric sequelae (DNS) are important long-term complications. This study evaluated the association between the COGAS score and operationally defined 6-month DNS after acute CO poisoning. Methods: Overall, 272 patients with acute CO poisoning were included in this single-center observational cohort study. The primary outcome was operationally defined as 6-month DNS based on changes in the Global Deterioration Scale (GDS). Logistic regression analyses were performed to evaluate the association between the COGAS score and operationally defined 6-month DNS. Conventional and Firth penalized logistic regression models were used. Results: Among 272 patients, 14 (5.1%) met the criteria for operationally defined 6-month DNS. Each 1-point increase in the COGAS score was associated with higher odds of operationally defined 6-month DNS in univariable analysis (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.30–3.65; p = 0.003) and in the fully adjusted model including initial GDS, troponin I, and CO exposure duration (OR, 2.19; 95% CI, 1.14–4.35; p = 0.020). Conclusions: Higher COGAS scores were associated with operationally defined 6-month DNS after acute CO poisoning. The COGAS score may provide prognostic information, but further validation in larger cohorts is needed.