The endoplasmic reticulum is the cellular factory where newly made proteins are folded, modified, and quality-checked before they move on to their final destinations. Because protein folding is chemically demanding and exquisitely sensitive to the cellular environment, the ER is among the first organelles to falter when a cell is under oxidative assault. When misfolded proteins accumulate, the ER activates a rescue program known as the unfolded protein response, orchestrated by sensor proteins including PERK, IRE1α, and ATF6, together with the chaperone GRP78. If the stress is mild, this response restores balance. If it is prolonged or severe, the response turns lethal, ramping up the transcription factor ATF4 and its downstream partner CHOP, a protein that pushes stressed cells toward apoptosis.

Nicotine, the addictive alkaloid in tobacco, is a potent pro-oxidant that generates reactive oxygen species and depletes cellular antioxidant defenses. Earlier studies had implicated nicotine in testicular damage, showing reduced gametogenesis, altered steroidogenesis, and increased apoptosis in animal models, and had even linked nicotine exposure to ER stress in tissues such as the placenta and airway smooth muscle. What remained unclear was whether the ER stress pathway was a genuine mechanistic driver of nicotine-induced sperm dysfunction in the testis, and whether antioxidants could intervene at that specific signaling node rather than merely mopping up free radicals.

To answer these questions, the researchers worked with 48 two-month-old male Wistar albino rats, dividing them into six experimental groups: an untreated control, a nicotine-exposed group, three groups receiving nicotine together with melatonin, coenzyme Q10, or both compounds, and a group receiving the two antioxidants without nicotine. The design allowed the team to disentangle the toxic effects of nicotine from the protective effects of each supplement, and to test whether the combination offered any advantage over either compound alone. Sperm quality was assessed using standard andrological measures, while testicular tissue was examined for oxidative stress markers, ER stress gene expression, histopathology, and the immunohistochemical localization of key stress proteins.

The results were striking. Nicotine exposure significantly impaired sperm motility and membrane integrity while increasing abnormal sperm morphology, sperm mortality, and apoptosis, with all of these changes reaching high statistical significance. Biochemically, the nicotine-exposed testes showed elevated lipid peroxidation, a hallmark of oxidative damage to cellular membranes, alongside a collapse of antioxidant defenses, including reduced levels of glutathione, glutathione peroxidase, and catalase. In other words, nicotine created a double hit: it flooded the tissue with reactive oxygen species while simultaneously stripping away the enzymes and molecules that would normally neutralize them.

The critical new finding concerned the ER. In the nicotine group, the expression of a battery of ER stress-associated genes was markedly upregulated, including ATF4, ATF6, CHOP, GRP78, IRE1α, and PERK, the full cast of the canonical unfolded protein response. Immunohistochemistry confirmed increased CHOP immunoreactivity in the tissue, indicating that the pro-apoptotic arm of the ER stress response was not merely transcribed but translated into accumulated protein. This pattern suggests that nicotine pushes testicular cells past the adaptive phase of ER stress and into the maladaptive, death-signaling phase, providing a mechanistic bridge between oxidative damage and the observed sperm apoptosis.

Antioxidant treatment changed the picture substantially. Melatonin, the pineal hormone best known for regulating circadian rhythm but also a versatile direct and indirect antioxidant, and coenzyme Q10, an essential component of the mitochondrial electron transport chain and a lipid-soluble radical scavenger, each partially restored sperm quality and antioxidant capacity when given alongside nicotine. At the molecular level, the supplements significantly downregulated the ER stress gene panel, tamping down the expression of ATF4, ATF6, CHOP, GRP78, IRE1α, and PERK, and reducing CHOP immunoreactivity in the tissue. Histopathological analysis showed corresponding protection of testicular architecture, preserving the seminiferous environment in which sperm develop.

One detail of the data may prove particularly interesting to researchers. Coenzyme Q10 selectively enhanced XBP-1 immunoreactivity, a marker associated with the IRE1α branch of the unfolded protein response. Because the IRE1α–XBP-1 arm is generally considered adaptive, promoting protein folding capacity and cellular survival rather than death, this selective effect hints that coenzyme Q10 may not simply suppress ER stress wholesale but may help re-balance the response toward its protective branch. Melatonin, meanwhile, has previously been shown to modulate ER stress in contexts ranging from arsenite-induced neurotoxicity to fulminant hepatitis and testicular injury from bisphenol A and phthalates, and the new findings extend that mechanistic portfolio to nicotine-driven reproductive damage.

The authors are careful about scope. This is a rat study, with controlled dosing and a defined exposure window, and the leap from rodent testes to human male fertility is neither automatic nor trivial. The supplements produced partial rather than complete protection, which itself is informative: nicotine inflicts damage through multiple converging pathways, including vascular effects, hormonal disruption, and direct genotoxicity, so no single antioxidant can be expected to erase the harm. Data from the study are available upon reasonable request, and the work was supported by the Scientific Research Projects Coordination Unit of Hatay Mustafa Kemal University, with ethics approval from the institution’s Local Animal Ethics Committee.

Even with those caveats, the study carries real weight for a public health conversation that often treats smoking-related fertility damage as an afterthought. It identifies a specific, druggable signaling axis, the oxidative stress–ER stress–CHOP cascade, as a mediator of nicotine’s assault on sperm, and it demonstrates that two inexpensive, widely available compounds can intervene at that axis in a living animal. For the millions of smokers whose fertility may be quietly eroding, the message is not that a supplement can undo the damage of smoking, but that the biology of that damage is now understood well enough to be targeted, and that the surest intervention remains removing the toxin itself. Translational studies in human populations will be needed before melatonin or coenzyme Q10 can be recommended clinically, but as a proof of mechanism, this work sharpens the picture of how tobacco smoke reaches deep into the cellular machinery of reproduction.

Subject of Research: Nicotine-induced oxidative stress and endoplasmic reticulum stress signaling in rat testis and its attenuation by melatonin and coenzyme Q10

Article Title: Targeting the Nicotine-driven Maladaptive ER Stress Axis: Protective Roles of Melatonin and Coenzyme Q10 in Rat Testis

Article References: Eraslan Sakar, A., Yildiz, C., Coskun, N., Sengul, S. A., Akcakavak, F. K., Kutlu, T., Sayan, M., & Karabulut, D. (2026). Targeting the Nicotine-driven Maladaptive ER Stress Axis: Protective Roles of Melatonin and Coenzyme Q10 in Rat Testis. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02235-z

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02235-z

Keywords: nicotine, endoplasmic reticulum stress, melatonin, coenzyme Q10, sperm quality, male fertility, oxidative stress, testis, apoptosis, unfolded protein response, CHOP, rat model

The stakes are higher than the word platelet might suggest. As people age, their platelets become hyperreactive, aggregating more readily and contributing to the elevated risk of heart attacks and strokes in older adults. Megakaryocytes sit at the origin of that problem. These enormous cells, which can contain up to 64 copies of the genome, undergo a metabolically demanding maturation program before shedding platelets into the bloodstream. Aging impairs their proliferation, differentiation, and quality-control machinery through both intrinsic cellular defects and changes in the bone marrow environment. Yet the precise molecular drivers of megakaryocyte decline during natural aging have remained poorly defined, and no targeted nutritional intervention had been shown to reverse it.

The research team, led by investigators affiliated with the Sun Yat-sen University Health System, took an unusually rigorous approach for a nutrition study. Rather than relying on accelerated genetic aging models, they used naturally aged male C57BL/6J mice, dividing 84 animals into cohorts starting at 1, 9, 15, 19, 21, and 23 months of age. Each cohort received either a control diet or the same diet supplemented with CoQ10 at 550 milligrams per kilogram of chow for 12 weeks, a dose the authors calculate as roughly equivalent to 300 milligrams per day for a 60-kilogram adult. The mice were then analyzed at 4, 12, 18, 22, 24, and 26 months of age, spanning nearly the entire murine lifespan.

The systemic effects of the supplement were clear and age-dependent. CoQ10-treated mice showed reduced levels of reactive oxygen species and malondialdehyde, a marker of lipid peroxidation, along with increased total antioxidant capacity and higher activity of the antioxidant enzymes superoxide dismutase, catalase, and glutathione. Chronic inflammation, the smoldering fire that accompanies aging, also receded: plasma concentrations of the inflammatory cytokines IL-6, TNF-alpha, and IL-1beta were significantly lower in supplemented animals, with IL-1beta dropping as early as 12 months. Circulating klotho, a protein whose decline is closely associated with aging, was modestly preserved, reaching statistical significance at 24 months. Notably, blood levels of ubiquinol and ubiquinone, the two forms of CoQ10, rose most clearly in mice older than 22 months, suggesting the biological effects of supplementation become most pronounced in advanced age, when endogenous CoQ10 availability has waned.

Within the bone marrow, the changes were striking. Colony-forming assays revealed that megakaryocytes from CoQ10-fed mice proliferated more vigorously, forming larger and more numerous colonies at 12, 16, and 18 months. Flow cytometry showed increased proportions of cells expressing the maturation markers CD41 and CD61, and ploidy analysis revealed a shift toward highly polyploid 16N, 32N, and 64N megakaryocytes, the fully mature end-stage cells most capable of platelet production, whereas control animals accumulated predominantly 8N cells. Apoptosis among megakaryocytes, which rises with age, was significantly reduced in the supplemented groups at 22, 24, and 26 months.

The mechanistic thread connecting these improvements was autophagy, the conserved intracellular recycling process by which cells digest damaged proteins and organelles. Autophagic activity declines with age across many tissues, and in the megakaryocytes of naturally aged mice the researchers observed exactly that pattern: the ratio of lipidated LC3-II to LC3-I, a standard readout of autophagosome formation, fell progressively, while the cargo receptor p62 accumulated. Twelve weeks of CoQ10 reversed both markers at nearly every age examined. Because LC3 and p62 were measured under steady-state conditions in the animal experiments, the authors are careful to note that these data indicate altered autophagic activity but do not by themselves prove enhanced autophagic flux in vivo.

To find the molecular link, the team turned to unbiased quantitative proteomics using Astral DIA mass spectrometry on megakaryocytes isolated from 24-month-old mice. Among the proteins upregulated by CoQ10, one stood out: COPS3, a core subunit of the COP9 signalosome, an evolutionarily conserved complex that regulates protein stability by deneddylating Cullin-RING ubiquitin ligases. In fact, the proteomic data showed that COPS3 was the most highly represented protein within the biological process of protein deneddylation, and several other COP9 subunits rose in parallel. Western blotting across the age series confirmed that COPS3 expression declines gradually with age and that CoQ10 supplementation significantly restores it, particularly at 24 months. Because the COP9 signalosome governs ubiquitin signaling, which is intricately intertwined with autophagy regulation, COPS3 offered a plausible bridge between the supplement and the cellular cleaning crew.

Cell-culture experiments in senescent MEG-01 human megakaryocytic cells, driven into senescence with hydrogen peroxide, put the hypothesis to the test. CoQ10 treatment raised COPS3 levels and shifted the autophagy markers in the direction of enhanced flux, and these effects persisted even when autophagy was pharmacologically blocked with LY294002. Critically, when the researchers silenced COPS3 with siRNA, the CoQ10-induced increase in the LC3-II/LC3-I ratio, the reduction in p62, and the improvements in maturation-marker expression and polyploidization were all partially attenuated. A bafilomycin A1 turnover assay, which blocks lysosomal degradation and thereby reveals how much LC3-II is actually being delivered to lysosomes, provided direct evidence that CoQ10 enhances autophagic flux rather than merely causing autophagosomes to pile up. The incomplete rescue after COPS3 knockdown tells an honest story: COPS3 is a functional contributor to CoQ10’s effects, but not their sole mediator, and gain-of-function and rescue experiments remain to be done.

The downstream consequence for platelet biology is perhaps the most clinically tantalizing finding. Collagen-induced platelet aggregation, which rises with age and peaks before declining at the very oldest ages, was significantly suppressed in CoQ10-fed mice from 18 through 26 months. Activation markers CD62P and JON/A, an antibody that reports the active conformation of the integrin alphaIIb-beta3, were similarly reduced. Importantly, these benefits came without apparent costs: platelet counts, reticulated platelet percentages, and tail-bleeding times were unchanged, suggesting the supplement tames platelet hyperreactivity without crippling primary hemostasis. The authors caution, however, that tail-bleeding time is a crude measure of hemostasis and that these results should not be read as evidence that CoQ10 prevents thrombosis in older adults.

The study is candid about its limits. The mechanistic cell work used an induced senescence model rather than primary megakaryocytes, the in vitro CoQ10 concentration of 100 micromolar exceeds what oral supplementation typically achieves in blood, only a single dietary dose was tested, and only male mice were studied, leaving open whether females respond similarly. How CoQ10, a molecule best known for shuttling electrons inside mitochondria, signals to the nucleus to raise COPS3 expression remains unresolved, though prior work showing that CoQ10 modulates Nrf2 and NF-kappaB-dependent transcription offers plausible routes. Even with those caveats, the convergence of a lifespan-scale dietary intervention, proteomic discovery, genetic knockdown, and flux assays makes a compelling case that CoQ10 supports proteostatic resilience in aging megakaryocytes through a COPS3-autophagy axis. For a supplement often dismissed as scientifically soft, that is a remarkably concrete mechanism, and it points toward nutritional strategies for the platelet dysfunction of aging that now deserve proper clinical scrutiny.

Subject of Research: Effects of dietary coenzyme Q10 on age-related megakaryocyte dysfunction via COPS3-mediated autophagy activation

Article Title: Dietary CoQ10 Ameliorates Age‐Related Megakaryocyte Dysfunction via COPS3‐Mediated Activation of Autophagy

Article References: Xu, Y., Mao, Y.-H., Song, F., He, F., Wu, Y., Wang, C., Wang, M., Xie, S., Ni, H., & Yang, Y. (2026). Dietary CoQ10 Ameliorates Age‐Related Megakaryocyte Dysfunction via COPS3 ‐Mediated Activation of Autophagy. Aging Cell, 25(10), Article e70726. https://doi.org/10.1111/acel.70726

Image Credits: AI Generated

DOI: 10.1111/acel.70726

Keywords: coenzyme Q10, megakaryocytes, autophagy, COPS3, COP9 signalosome, aging, platelets, oxidative stress, inflammaging, bone marrow, proteomics, Aging Cell

The logic behind CoQ10 supplementation is seductively straightforward. The molecule is an essential cofactor in the mitochondrial electron transport chain, shuttling electrons between complexes I and III during oxidative phosphorylation, the process that generates the bulk of cellular ATP. It also functions as a powerful lipid-phase antioxidant, quenching the free radicals that attack cell membranes. Because strenuous exercise dramatically increases oxygen flux through working muscles, it simultaneously increases the production of reactive oxygen species. Exercise-induced oxidative stress has been proposed as a mechanistic link between heavy training loads, membrane injury, impaired recovery, and inconsistent performance responses. Supplementing with the antioxidant cofactor that sits at the crossroads of energy production and radical defense therefore seemed like an obvious win for athletes, even as individual randomized trials kept returning contradictory results.

To resolve that contradiction, the Chinese research team conducted a prospectively registered systematic review, searching PubMed, Web of Science, Embase, and EBSCOhost from database inception to April 2026, with the protocol registered in PROSPERO under identifier CRD420261370320. They included randomized parallel-group and crossover trials evaluating oral CoQ10 in athletes or athlete-relevant trained individuals. The final tally was twenty-four studies encompassing 613 participants for the systematic review, with fifteen studies and 330 participants contributing to at least one quantitative synthesis. Because several studies contributed more than one eligible estimate, the unit of quantitative reporting was the effect size or comparison, and random-effects models were used throughout the meta-analysis.

The headline result concerns malondialdehyde, or MDA, a widely used biomarker of lipid peroxidation that serves as a chemical fingerprint of oxidative damage to cell membranes. The primary pooled analysis for MDA included seven effect sizes drawn from five studies and was not statistically significant, with a standardized mean difference of negative 0.96 and a 95 percent confidence interval spanning from negative 2.07 to positive 0.15. In other words, the point estimate suggested a substantial reduction in oxidative damage, but the uncertainty was so wide that the result could not be distinguished from chance. A sensitivity analysis tightened the interval to negative 0.93 with a confidence interval of negative 1.65 to negative 0.22, favoring CoQ10, yet the authors emphasize that this signal remained fragile, burdened by residual heterogeneity with an I-squared statistic of 73 percent, small sample sizes, and methodological limitations in the underlying trials.

The physiological picture was even more definitive. The representative pooled performance outcome, maximal oxygen uptake or VO2max, included eight effect sizes from seven studies and was essentially neutral, with a standardized mean difference of 0.03 and a confidence interval of negative 0.32 to positive 0.39. The I-squared statistic of 0.0 percent indicates remarkable consistency across trials, but the consistency points to a null effect rather than a benefit. Supplementary pooled analyses were likewise neutral for blood pressure, creatine kinase, interleukin-6, total antioxidant capacity, tumor necrosis factor-alpha, and anaerobic threshold. For a supplement whose promotional materials promise everything from faster recovery to enhanced endurance capacity, the absence of any measurable effect on inflammation, muscle damage, cardiovascular parameters, or aerobic fitness represents a comprehensive null result.

Perhaps the most damning statistic in the entire analysis concerns the quality of the evidence itself. Using the revised Cochrane risk-of-bias tool, the authors judged overall risk of bias as raising some concerns in twenty-three of the twenty-four included studies, or 95.8 percent, with one study judged at high risk, or 4.2 percent. Not a single trial emerged unscathed. This matters because biased trials tend to inflate effect estimates, which means the modest signals that did emerge may themselves be overestimates. The finding echoes a persistent problem in sports nutrition research, where small samples, short durations, and commercial entanglements frequently undermine the reliability of individual studies, leaving meta-analysts to extract signal from noise.

There is, however, a nuanced thread running through the narrative synthesis. The authors observed more coherent, context-dependent signals in studies conducted under conditions of marked oxidative or recovery stress, such as elite swimmers combining supplementation with pre-cooling strategies, or athletes undergoing intensive training camps. This pattern fits with a broader understanding of exercise physiology: reactive oxygen species are not simply damaging byproducts but also serve as signaling molecules that trigger adaptive responses, including endogenous antioxidant enzyme upregulation and mitochondrial biogenesis. Blunting oxidative stress indiscriminately during moderate training might even interfere with adaptation, whereas athletes under extreme oxidative loads could plausibly benefit from additional antioxidant capacity. The review cannot confirm this hypothesis, but it offers a framework for designing better-targeted future trials.

The biochemistry of CoQ10 also helps explain why results have been so inconsistent. The molecule is highly lipophilic and poorly absorbed, and plasma response to oral ingestion varies substantially between formulations, with ubiquinol, the reduced form, generally achieving higher circulating concentrations than ubiquinone. Studies have shown that supplementation does reliably enrich plasma and blood cells, yet raising blood levels does not guarantee that the coenzyme reaches the mitochondria of working muscle in sufficient quantities to alter electron transport flux or membrane protection. A recent companion study cited in the review found that CoQ10 supplementation raised plasma levels without improving mitochondrial function in older adults, underscoring the gap between what blood tests measure and what muscle cells actually experience.

For the global supplement market, where CoQ10 products are frequently marketed to endurance athletes and fitness enthusiasts, the implications are uncomfortable. The new analysis aligns with earlier systematic reviews, including a 2024 GRADE-assessed dose-response meta-analysis and a 2025 review in the British Journal of Nutrition that found limited and inconsistent effects on exercise performance despite reliable increases in blood concentrations. The consistent pattern across independent teams, databases, and decades of trials, stretching back to studies of trained cyclists and cross-country skiers in the 1990s, suggests that the null findings are not an artifact of any single analysis but a genuine property of the intervention in healthy, well-trained populations.

The authors stop short of declaring CoQ10 useless, and their caution is warranted. The potentially favorable MDA signal in the sensitivity analysis, the hints of benefit under extreme oxidative stress, and the heterogeneity of study designs all leave room for refined hypotheses, perhaps involving specific populations, dosing regimens, or combinations with other interventions. But for the average athlete contemplating a daily capsule in pursuit of a competitive edge, the message from this comprehensive synthesis is clear: the best available evidence shows no meaningful improvement in aerobic capacity, muscle damage markers, inflammation, blood pressure, or antioxidant status. Until higher-quality trials demonstrate otherwise, the molecule that powers mitochondria appears unable to power personal bests.

Subject of Research: Effects of coenzyme Q10 supplementation on exercise-induced oxidative stress and physiological outcomes in athletes

Article Title: The effects of coenzyme Q10 supplementation on exercise-induced oxidative stress and related physiological outcomes in athletes: a systematic review and meta-analysis

Article References: Lu, S., Zhong, W., & Wang, H. (2026). The effects of coenzyme Q10 supplementation on exercise-induced oxidative stress and related physiological outcomes in athletes: a systematic review and meta-analysis. 3 Biotech, 16(10), Article 445. https://doi.org/10.1007/s13205-026-05076-4

Image Credits: AI Generated

DOI: 10.1007/s13205-026-05076-4

Keywords: coenzyme Q10, athletes, oxidative stress, malondialdehyde, VO2max, meta-analysis, systematic review, sports nutrition, mitochondria, exercise physiology, dietary supplements, recovery