ArticleBiochimica et biophysica acta
Increased reactive oxygen species production during reductive stress: The roles of mitochondrial glutathione and thioredoxin reductases.
Article in Biochimica et biophysica acta. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed, 200 citations in OpenAlex.
- Exercise-Induced Reductive Stress Is a Protective Mechanism against Oxidative Stress in Peripheral Blood Mononuclear Cells.Oxidative medicine and cellular longevity · 2018Trial
- A Phase II Randomized Placebo-Controlled Trial of Oral N-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress In Vivo.Cancer prevention research (Philadelphia, Pa.) · 2017Trial
- The Reductive Stress Nexus: Integrated Pathways of Metabolic Dysregulation, Senescence and Blood-Brain Barrier Failure in Neurodegenerative Disease and Brain Aging.Cell biochemistry and biophysics · 2026Review
- Mechanism of action of synaptic mitochondrial damage in delayed cognitive recovery.Neural regeneration research · 2026Article
- The Positive Roles for Reactive Oxygen Species in Human Reproduction; Implications for the Therapeutic Application of Antioxidants.Antioxidants (Basel, Switzerland) · 2026Review
- KLF9 Aggravates Doxorubicin-Induced Cardiotoxicity by Regulating the ROS/p53 Signalling Pathway.Cardiovascular toxicology · 2026Article
- Hope for a heart's lonesome hunt: metabolic roadblocks and cardiac electrical instability in long-chain fatty acid oxidation deficiency.American journal of physiology. Heart and circulatory physiology · 2026Article
- Reversible phase dynamics of PsAF5 regulate mitophagy to balance redox levels inScience advances · 2026Article
- Integrating simulated and experimental data to identify mitochondrial bioenergetic defects in Parkinson's Disease models.PloS one · 2026Article
- Bioelectronics forNanotheranostics · 2026Review
- Oxidative stress and ferroptosis in diabetic cardiomyopathy: mechanistic interplay and therapeutic implications.Apoptosis : an international journal on programmed cell death · 2025Review
- Research advances in inflammation and oxidative stress in varicocele-induced male infertility: a narrative review.Asian journal of andrology · 2025Review
- The Role of Reductive Stress in the Pathogenesis of Endocrine-Related Metabolic Diseases and Cancer.International journal of molecular sciences · 2025Review
- Oxphos targeting ofFrontiers in oncology · 2025Article
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- Towards the Development of Novel, Point-of-Care Assays for Monitoring Different Forms of Antioxidant Activity: The RoXstaAntioxidants (Basel, Switzerland) · 2024Article
- Effects of Melatonin on Exercise-Induced Oxidative Stress in Adults with Obesity Undergoing a Multidisciplinary Body Weight Reduction Program.Journal of clinical medicine · 2024Article
- Glutathione-Dependent Pathways in Cancer Cells.International journal of molecular sciences · 2024Review
- Genome-scale model ofMicrobiology spectrum · 2024Article
33 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Both extremes of redox balance are known to cause cardiac injury, with mounting evidence revealing that the injury induced by both oxidative and reductive stress is oxidative in nature. During reductive stress, when electron acceptors are expected to be mostly reduced, some redox proteins can donate electrons to O2 instead, which increases reactive oxygen species (ROS) production. However, the high level of reducing equivalents also concomitantly enhances ROS scavenging systems involving redox couples such as NADPH/NADP+ and GSH/GSSG. Here our objective was to explore how reductive stress paradoxically increases net mitochondrial ROS production despite the concomitant enhancement of ROS scavenging systems. Using recombinant enzymes and isolated permeabilized cardiac mitochondria, we show that two normally antioxidant matrix NADPH reductases, glutathione reductase and thioredoxin reductase, generate H2O2 by leaking electrons from their reduced flavoprotein to O2 when electron flow is impaired by inhibitors or because of limited availability of their natural electron acceptors, GSSG and oxidized thioredoxin. The spillover of H2O2 under these conditions depends on H2O2 reduction by peroxiredoxin activity, which may regulate redox signaling in response to endogenous or exogenous factors. These findings may explain how ROS production during reductive stress overwhelms ROS scavenging capability, generating the net mitochondrial ROS spillover causing oxidative injury. These enzymes could potentially be targeted to increase cancer cell death or modulate H2O2-induced redox signaling to protect the heart against ischemia/reperfusion damage.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.