Induction of ferroptosis and mitochondrial dysfunction by oxidative stress in PC12 cells

Abstract

Neurodegenerative diseases (NDD) are typically associated with neuron loss in nervous system areas. Interventions with related death mechanisms may ameliorate NDD progression. Oxidative stress plays an important role in NDD cell death routines. However, tert-butylhydroperoxide (t-BHP), a widely used oxidative stress stimulus, induces neural cell death through a mechanism that remains elusive. In our study, the ferroptosis marker events occurred after co-treatment with 100 μM t-BHP for 1 h, all of which were reversed in the presence of the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine, implying the occurrence of ferroptosis. Moreover, mitochondrial dysfunction accompanied by a decreased in membrane potential and ATP production, increased mitochondrial ROS generation. Furthermore, this mitochondrial dysfunction could be reversed by Fer-1. In addition, JNK1/2 and ERK1/2 were activated upstream of the ferroptosis and mitochondrial dysfunction. In summary, these data suggest that ferroptosis, coupled with mitochondrial dysfunction, was involved in t-BHP-induced PC12 death. JNK1/2 and ERK1/2 played important roles in t-BHP-induced cell death. Overall, this study might provide clues to the oxidative stress-based strategies for cell protection in NDD.

Ferroptosis Is Regulated by Mitochondria in Neurodegenerative Diseases

“…Recent studies have suggested that mitochondrial damage may be the final step of ferroptosis-related oxida-tive cell death in neurodegenerative diseases [156]. In a study of neurodegenerative diseases using PC12 cells, tert-butyl hydroperoxide (t-BHP) was reported to induce ferroptosis, which was accompanied by a decrease in mitochondrial membrane potential and ATP production as well as an increase in mitochondrial ROS [156].…”

“…Recent studies have suggested that mitochondrial damage may be the final step of ferroptosis-related oxida-tive cell death in neurodegenerative diseases [156]. In a study of neurodegenerative diseases using PC12 cells, tert-butyl hydroperoxide (t-BHP) was reported to induce ferroptosis, which was accompanied by a decrease in mitochondrial membrane potential and ATP production as well as an increase in mitochondrial ROS [156]. Previous studies have demonstrated that the separation of IRP-1 from IRE is ATP-dependent, so the depletion of ATP leads to enhanced IRP-1 and IRE binding activity, which in turn causes TFR upregulation and a subsequent increase in iron content [157].…”

Oxidative stress: role of physical exercise and antioxidant nutraceuticals in adulthood and aging

“…Exogenous antioxidants have generated growing interest in preventing or reducing oxidative stress, in decreasing muscle soreness and physical stress, and in ameliorating sport performance [ 7 ]. The exogenous antioxidants act in addition to the endogenous ones, and the most known are tocopherols (vitamin E), ascorbic acid (vitamin C), carotenoids (β-carotene), ubiquinone and polyphenols [ 58 , 59 ].…”

Neuronal-specific function of hTim8a in Complex IV assembly provides insight into the molecular mechanism underlying Mohr-Tranebjærg syndrome

“…Given that both apoptosis and ferroptosis are associated with ROS accumulation, we also examined whether loss of hTim8a increased vulnerability to this iron-dependent, lipid peroxidation-mediated form of regulated cell death (Dixon et al, 2012;Simon et al, 2000;Wu et al, 2018). Treatment with specific ferroptosis inducers, including: (i) Erastin, an SLC7A11 inhibitor; (ii) (1S,3R)-RSL3, which inhibits glutathione peroxidase 4 and (iii) buthionine sulfoximine (BSO), which depletes glutathione (GSH), did not enhance cell death of hTim8a MUT SH-SY5Y cells (Figure 6E).…”