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Background Skeletal muscle aging is associated with oxidative stress and mitochondrial dysfunction. Peroxiredoxins (PRDXs), particularly PRDX3 and PRDX5, are antioxidant enzymes that are uniquely localized to mitochondria. While PRDX3 has been reported to play a role in maintaining mitochondrial function in muscle, the specific function of PRDX5 in muscle remains unclear. This study investigated the role of PRDX5 in mitochondrial function, myonuclear distribution and muscle aging. Methods Myoblasts were isolated from wild‐type (WT), Prdx3−/−, Prdx5−/− and Prdx3−/−; Prdx5−/− mice crossed with mitochondria reporter (mt‐GFP) mice. Nuclear and mitochondrial positioning were evaluated using confocal and super‐resolution lattice structured illumination microscopy (SIM). Mitochondrial function was assessed by Seahorse oxygen consumption rates (OCR) assays. In vivo analyses included grip strength, treadmill performance and histological evaluation following venom‐induced muscle injury. Results During myogenesis, Prdx5−/− and Prdx3−/−; Prdx5−/− myotubes exhibited impairments in nuclear spreading, characterized by clustered nuclei, unlike the even distribution observed in WT and Prdx3−/− myotubes (44.4% and 44.9% vs. 17.1% and 21.9%, respectively; p < 0.001). Mitochondrial ATP production was significantly reduced in Prdx3−/−, Prdx5−/− and Prdx3−/−; Prdx5−/− myotubes (p < 0.05). The expression of Rhot1 and Trak1, key regulators of mitochondrial transport, was significantly decreased in Prdx5−/− and Prdx3−/−; Prdx5−/− myotubes (p < 0.01). Knockdown of Rhot1 or Trak1 in WT myotubes led to myonuclear clustering similar to that observed in Prdx5‐deficient myotubes, supporting that PRDX5 facilitates mitochondrial transport and nuclear positioning, at least in part, through transcriptional regulation of genes including Rhot1 and Trak1. In vivo, 48‐week‐old Prdx5−/− mice exhibited mitochondrial dysfunction and myonuclear clustering in myofibers, with reduced treadmill performance (p < 0.05). Muscle regeneration was impaired in Prdx5−/− mice, with decreased expression of regeneration and mitochondrial transport markers and increased nuclear clustering in regenerating myofibers (p < 0.05). Prdx3−/−; Prdx5−/− double‐knockout mice displayed accelerated muscle aging, including decreased muscle mass and strength, and elevated expression of E3 ligases Atrogin1 and MuRF1 as early as 10 weeks of age (p < 0.05). These mice also exhibited increased mitochondrial H2O2 production, which upregulated the expression of Atrogin1 and MuRF1 (p < 0.05). Conclusions Our findings reveal a previously unidentified role of PRDX5 in coordinating mitochondrial function and nuclear positioning during myogenesis and muscle regeneration. The combined deficiency of PRDX3 and PRDX5 accelerates muscle aging by exacerbating oxidative stress and mitochondrial dysfunction, suggesting that enhancing their activity may be a promising therapeutic strategy to prevent sarcopenia and age‐related muscle degeneration.

Cryopreservation of bull sperm, crucial for breeding and assisted reproduction, often reduces sperm quality due to oxidative stress. This study examines how oxidative stress during cryopreservation affects peroxiredoxin 5 (PRDX5) and peroxiredoxin 6 (PRDX6) proteins, leading to their translocation and oligomerization in bull sperm. Increased reactive oxygen species (ROS) and nitric oxide (NO) levels were linked to reduced mitochondrial potential, higher DNA fragmentation, and increased membrane fluidity, prompting PRDX5 to move intracellularly and PRDX6 to the cell membrane. Under cryopreservation, these proteins formed high molecular weight oligomers, that may shift from peroxidase to chaperone roles. Their interaction with Toll-like receptor 4 (TLR4) may be key to their intracellular transport. On the other hand, the presence of PRDX5 and PRDX6 in exosomal vesicles suggested a potential mechanism for their transport into sperm cells. Using Imaging Flow Cytometry and various PAGE techniques, the study detected PRDX5 and PRDX6 in different sperm locations and analyzed their oligomer formation. These findings highlight the adaptive roles of PRDX5 and PRDX6 in protecting sperm cells, offering insights that could improve cryopreservation protocols in animal breeding and human reproductive medicine, and advance our understanding of the oxidative stress response in sperm cells.

Circadian clocks provide a temporal structure to processes from gene expression to behavior in organisms from all phyla. Most clocks are synchronized to the environment by alternations of light and dark. However, many organisms experience only muted daily environmental cycles due to their lightless spatial niches (e.g., caves or soil). This has led to speculation that they may dispense with the daily clock. However, recent reports contradict this notion, showing various behavioral and molecular rhythms in Caenorhabditis elegans and in blind cave fish. Based on the ecology of nematodes, we applied low-amplitude temperature cycles to synchronize populations of animals through development. This entrainment regime reveals rhythms on multiple levels: in olfactory cued behavior, in RNA and protein abundance, and in the oxidation state of a broadly conserved peroxiredoxin protein. Our work links the nematode clock with that of other clock model systems; it also emphasizes the importance of daily rhythms in sensory functions that are likely to impact on organism fitness and population structure.

Thiol-based redox regulation is central to adjusting chloroplast functions under varying light conditions. A redox cascade via the ferredoxin-thioredoxin reductase (FTR)/thioredoxin (Trx) pathway has been well recognized to mediate the light-responsive reductive control of target proteins; however, the molecular basis for reoxidizing its targets in the dark remains unidentified. Here, we report a mechanism of oxidative thiol modulation in chloroplasts. We biochemically characterized a chloroplast stroma-localized atypical Trx from Arabidopsis, designated as Trx-like2 (TrxL2). TrxL2 had redox-active properties with an unusually less negative redox potential. By an affinity chromatography-based method, TrxL2 was shown to interact with a range of chloroplast redox-regulated proteins. The direct discrimination of thiol status indicated that TrxL2 can efficiently oxidize, but not reduce, these proteins. A notable exception was found in 2-Cys peroxiredoxin (2CP); TrxL2 was able to reduce 2CP with high efficiency. We achieved a complete in vitro reconstitution of the TrxL2/2CP redox cascade for oxidizing redox-regulated proteins and draining reducing power to hydrogen peroxide (H₂O₂). We further addressed the physiological relevance of this system by analyzing protein-oxidation dynamics. In Arabidopsis plants, a decreased level of 2CP led to the impairment of the reoxidation of redox-regulated proteins during light–dark transitions. A delayed response of protein reoxidation was concomitant with the prolonged accumulation of reducing power in TrxL2. These results suggest an in vivo function of the TrxL2/2CP redox cascade for driving oxidative thiol modulation in chloroplasts.

Ferroptosis is a non-apoptotic, iron-dependent oxidative form of cell death that is specifically induced by erastin in RAS mutant cancer cells. Ferroptotic cell death is the result of membrane lipid peroxide damage caused by the accumulation of hydroxyl radicals derived from H 2 O 2 by the Fenton reaction. Peroxidases are key cellular antioxidant enzymes that block such damaging processes. Few studies have examined the roles of long non-coding RNAs (lncRNAs) in the regulation of cellular oxidative stress, especially in ferroptosis. Here, we demonstrated that erastin upregulated the lncRNA GABPB1-AS1, which downregulated GABPB1 protein levels by blocking GABPB1 translation, leading to the downregulation of the gene encoding Peroxiredoxin-5 (PRDX5) peroxidase and the eventual suppression of the cellular antioxidant capacity. Such effects critically inhibited the cellular antioxidant capacity and cell viability. Additionally, high expression levels of GABPB1 were correlated with poor prognosis of hepatocellular carcinoma (HCC) Patients, while high GABPB1-AS1 levels in HCC patients correlated with improved overall survival. Collectively, these data demonstrate a mechanistic link between GABPB1 and its antisense lncRNA GABPB1-AS1 in erastin-induced ferroptosis and establish GABPB1 and GABPB1-AS1 as attractive therapeutic targets for HCC.

We studied the expression of peroxiredoxin genes ( PRDX1 , PRDX2 , PRDX3 , and PRDX6 ) in human erythroleukemia K652, human breast carcinoma MCF-7, and human ovarian carcinoma SKOV-3 cells during cisplatin resistance development. It was found that drug resistance formation was accompanied by a significant increase in the expression of PRDX1 , PRDX2 , PRDX3 , PRDX6 genes in all cancer cell strains, which confirms the important contribution of redox-dependent mechanisms into the development of cisplatin resistance of cancer cells.

Cyanobacteria are model organisms for photosynthesis and are attractive for biotechnology applications. To aid investigation of genotype-phenotype relationships in cyanobacteria, we develop an inducible CRISPRi gene repression library in Synechocystis sp. PCC 6803, where we aim to target all genes for repression. We track the growth of all library members in multiple conditions and estimate gene fitness. The library reveals several clones with increased growth rates, and these have a common upregulation of genes related to cyclic electron flow. We challenge the library with 0.1 M L-lactate and find that repression of peroxiredoxin bcp2 increases growth rate by 49%. Transforming the library into an L-lactate-secreting Synechocystis strain and sorting top lactate producers enriches clones with sgRNAs targeting nutrient assimilation, central carbon metabolism, and cyclic electron flow. In many examples, productivity can be enhanced by repression of essential genes, which are difficult to access by transposon insertion. Developing cyanobacteria as CO2-neutral cell factories relies on the knowledge of the regulation mechanisms for growth and metabolism. Here, the authors develop an inducible CRISPRi gene repression library in Synechocystis sp. PCC 6803 and screens genes potentially affecting growth and L-lactate tolerance and production.

Reactive oxygen species exacerbate nonalcoholic steatohepatitis (NASH) by oxidizing macromolecules; yet how they promote NASH remains poorly understood. Here, we show that peroxidase activity of global hepatic peroxiredoxin (PRDX) is significantly decreased in NASH, and palmitic acid (PA) binds to PRDX1 and inhibits its peroxidase activity. Using three genetic models, we demonstrate that hepatic PRDX1 protects against NASH in male mice. Mechanistically, PRDX1 suppresses STAT signaling and protects mitochondrial function by scavenging hydrogen peroxide, and mitigating the oxidation of protein tyrosine phosphatases and lipid peroxidation. We further identify rosmarinic acid (RA) as a potent agonist of PRDX1. As revealed by the complex crystal structure, RA binds to PRDX1 and stabilizes its peroxidatic cysteine. RA alleviates NASH through specifically activating PRDX1’s peroxidase activity. Thus, beyond revealing the molecular mechanism underlying PA promoting oxidative stress and NASH, our study suggests that boosting PRDX1’s peroxidase activity is a promising intervention for treating NASH. Oxidative stress is closely linked with nonalcoholic steatohepatitis (NASH). Here, the authors show that palmitic acid stimulates NASH by inhibiting PRDX1 to increase oxidative stress, while rosmarinic acid improves NASH by activating PRDX1 to reduce oxidative stress.

Brain cells that die after stroke release intracellular proteins into their environment. Akihiko Yoshimura and his colleagues demonstrate that peroxiredoxin proteins released from dying cells induce inflammatory cytokine expression and drive brain damage after stroke. Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. The extracellular release of Prxs in the ischemic core occurred 12 h after stroke onset, and neutralization of extracellular Prxs with antibodies suppressed inflammatory cytokine expression and infarct volume growth. In contrast, high mobility group box 1 (HMGB1), a well-known damage-associated molecular pattern molecule, was released before Prx and had a limited role in post-ischemic macrophage activation. We thus propose that extracellular Prxs are previously unknown danger signals in the ischemic brain and that its blocking agents are potent neuroprotective tools.

While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage‐induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage‐induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor. Synopsis Genetic screens, proteomics, and metabolomics are performed to investigate the crosstalk between metabolism and the DNA damage response. Integrative analyses identify Peroxiredoxin‐1 (PRDX1) as a DNA damage surveillance factor. Systematic approaches following DNA damage induction by etoposide reveal the aspects of metabolism that are crucial for maintaining genome integrity. Loss of electron transport chain enzymes is synthetically viable with etoposide, and some of these enzymes are partially located on chromatin 24 h after etoposide release. The metabolic enzyme PRDX1 contributes to DNA repair and translocates to the nucleus where it reduces DNA damage‐induced nuclear ROS. Loss of PRDX1 lowers aspartate availability and perturbs de novo nucleotide synthesis, which induces replication stress and limits the DNA repair capacities of the cells. Graphical Abstract Genetic screens, proteomics, and metabolomics are performed to investigate the crosstalk between metabolism and the DNA damage response. Integrative analyses identify Peroxiredoxin‐1 (PRDX1) as a DNA damage surveillance factor.