Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis.

Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer's disease and Parkinson's disease. Inhibition of cystine/glutamate antiporter could lead to mitochondrial fragmentation, mitochondrial calcium ([Ca2+]m) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm), and ferroptotic cell death. The observation that mitochondrial dysfunction is a characteristic of ferroptosis makes preservation of mitochondrial function a potential therapeutic option for diseases associated with ferroptotic cell death. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of Ca2+ into the mitochondrial matrix. Therefore, we have hypothesized that negative modulation of MCU complex may confer protection against ferroptosis. Here we evaluated whether the known negative modulators of MCU complex, ruthenium red (RR), its derivative Ru265, mitoxantrone (MX), and MCU-i4 can prevent mitochondrial dysfunction and ferroptotic cell death. These compounds mediated protection in HT22 cells, in human dopaminergic neurons and mouse primary cortical neurons against ferroptotic cell death. Depletion of MICU1, a [Ca2+]m gatekeeper, demonstrated that MICU is protective against ferroptosis. Taken together, our results reveal that negative modulation of MCU complex represents a therapeutic option to prevent degenerative conditions, in which ferroptosis is central to the progression of these pathologies.

Effects of Coronary Artery Bypass Grafting Surgery on Olfactory and Taste Functions.

BACKGROUND: Olfactory and taste sensations have a high impact on the quality of life. Impaired olfactory and taste functions may have a negative effect on physical and mental well-being, personal hygiene, and nutritional satisfaction, leading to the occurrence of depressive symptoms and impaired quality of life. Therefore, the recovery period of patients with disturbed olfactory and taste functions may be prolonged, and return to active life may be delayed. We designed this study to determine whether on-pump and off-pump coronary artery bypass grafting (CABG) surgeries have any effects on olfactory and taste functions and compare these functions between the surgical groups. METHODS: A total of 60 patients, who underwent elective isolated first-time CABG, were included in this study. Patients were divided into two groups as Off-Pump and On-Pump CABG groups with 30 patients in each group. In addition to patients' primary clinical and laboratory data, olfactory and taste functions were evaluated pre- and postoperatively in both groups separately, and then these functions were compared between the groups. Olfactory functions were evaluated by the Brief Smell Identification Test, while taste functions by the Burghart Taste test. RESULTS: Olfactory functions significantly were disrupted in the postoperative period in patients undergoing on-pump CABG (P value < .05), while these functions significantly were not affected in patients undergoing off-pump CABG (P value > .05). During the preoperative period, advanced age and smoking were detected to be independent predictors of impaired olfactory function for the study population. During the postoperative period, smoking, amount of postoperative bleeding and serum low-density lipoprotein (LDL) level were found to be independent predictors of impaired olfactory function for just the On-Pump CABG Group. In both groups, no significant deterioration in taste functions occurred during the postoperative period (P value > .05). CONCLUSION: Our study demonstrated that olfactory function was impaired in patients, who underwent on-pump CABG in the postoperative period, and significant impairment in taste function was present in neither off-pump nor on-pump CABG patients. However, the results of our study should be supported by more comprehensive, prospective, randomized controlled trials with more extensive patient series and by further tests.