Disruption Of Redox Status Research Articles

Downregulation of the SREBP pathways and disruption of redox status by 25-hydroxycholesterol predispose cells to ferroptosis.

Enzymatically formed side-chain oxysterols function as signaling molecules regulating cholesterol homeostasis and act as intermediates in the biosynthesis of bile acids. In addition to these physiological functions, an imbalance in oxysterol homeostasis has been implicated in pathophysiology. Cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25-OHC), also formed by autoxidation, are associated with amyotrophic lateral sclerosis. However, the effects of 25-OHC on cell viability in glial cells remain unclear. This study demonstrates that 25-OHC induces ferroptosis, an iron-dependent programmed cell death, in mouse Schwann IMS32cells. Mechanistically, 25-OHC suppressed the expression of selenoprotein glutathione peroxidase 4 (GPX4) at both the transcriptional and translational levels by inhibiting the processing of sterol regulatory element-binding proteins (SREBPs). In addition, 25-OHC upregulated the expression of NADH-cytochrome b5 reductase 1 (CYB5R1) and NADPH-cytochrome P450 reductase (POR), enzymes that promote lipid peroxidation. We further found that 25-OHC increases the expression of glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) and decreases glutathione levels. Importantly, non-cytotoxic concentrations of 25-OHC enhanced cellular sensitivity to ferroptosis inducers by downregulating GPX4 expression. These findings reveal a multifaceted approach whereby 25-OHC induces ferroptosis through SREBP pathway suppression and redox imbalance in mouse Schwann IMS32cells.

Idh2 deficiency accelerates renal dysfunction in aged mice

The free radical or oxidative stress theory of aging postulates that senescence is due to an accumulation of cellular oxidative damage, caused largely by reactive oxygen species (ROS) that are produced as by-products of normal metabolic processes in mitochondria. The oxidative stress may arise as a result of either increased ROS production or decreased ability to detoxify ROS. The availability of the mitochondrial NADPH pool is critical for the maintenance of the mitochondrial antioxidant system. The major enzyme responsible for generating mitochondrial NADPH is mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2). Depletion of IDH2 in mice (idh2-/-) shortens life span and accelerates the degeneration of multiple age-sensitive traits, such as hair grayness, skin pathology, and eye pathology. Among the various internal organs tested in this study, IDH2 depletion-induced acceleration of senescence was uniquely observed in the kidney. Renal function and structure were greatly deteriorated in 24-month-old idh2-/- mice compared with wild-type. In addition, disruption of redox status, which promotes oxidative damage and apoptosis, was more pronounced in idh2-/- mice. These data support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice, and thus support the oxidative stress theory of aging.

Heat Pretreatment Alleviates UV‐B Toxicity in the CyanobacteriumAnabaena doliolum: A Proteomic Analysis of Cross Tolerance

This study offers proteomic elucidation of heat pretreatment-induced alleviation of UV-B toxicity in Anabaena doliolum. Heat-pretreated cells exposed to UV-B showed improved activity of PSI, PSII, whole chain, (14)C fixation, ATP and NADPH contents compared to UV-B alone. Proteomic analysis using two-dimensional gel electrophoresis (2-DE), MALDI-TOF MS/MS and reverse transcription polymerase chain reaction (RT-PCR) of UV-B and heat pretreatment followed by UV-B-treated cells exhibited significant and reproducible alterations in nine proteins homologous to phycocyanin-alpha-chain (PC-alpha-chain), phycoerythrocyanin-alpha-chain (PEC-alpha-chain), hypothetical protein alr0882, phycobilisome core component (PBS-CC), iron superoxide dismutase (Fe-SOD), fructose-1,6-bisphosphate aldolase (FBA), nucleoside diphosphate kinase (NDPK), phosphoribulokinase (PRK) and ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCo) large chain. Except the PEC-alpha-chain, hypothetical protein alr0882 and PBS-CC, all other proteins showed upregulation at low doses of UV-B (U2) and significant downregulation at higher doses of UV-B (U5). The disruption of redox status, signaling, pentose phosphate pathway and Calvin cycle appears to be due to the downregulation of Fe-SOD, NDPK, FBA, PRK and RuBisCo thereby leading to the death of Anabaena. In contrast to this, the upregulation of all the above proteins in heat-pretreated cells, harboring different heat shock proteins (HSPs) like 60, 26 and 16.6, followed by UV-B treatment than only the UV-B-treated ones suggests a protective role of HSPs in mitigating UV-B toxicity.