bims-mistre 2026-05-17 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–05–17
twenty-two papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity.
Oxidative stress as a converging mechanism of aging and neurodegeneration: From molecular pathways to therapeutic targets.
Sex differences in mitochondrial function in aging mouse skeletal muscle.
Human whole-blood NAD+ levels do not vary with age or lifestyle interventions.
Exploring Mitochondrial Dysfunction and Protective Therapeutic Approaches to Counteract Its Role in Alzheimer's Disease Progression.
Nicotinamide mononucleotide (NMN) improves the ovarian microenvironment associated with oocyte quality by increasing estrogen signaling, reprogramming ovarian metabolism, reducing oxidative stress, and inhibiting apoptosis in the spotted scat (Scatophagus argus).
Skin Aging and Mitochondrial Dysfunction: Structural Changes, Mechanistic Insights, and Therapeutic Perspectives.
Dietary Polyphenols in Aging: A Systems-Level Perspective on Mitochondrial Quality Control and Microbiome Interactions.
Molecular pathways, tissue-specific roles, and therapeutic opportunities in mitochondrial resilience-based strategies for insulin resistance.
Update: Is exercise-induced oxidative stress a friend or foe?
Dynamic changes in mitochondrial function in brain cortex synaptosomes during aging.
Ergothioneine as a potential geroprotector: Targeting molecular hallmarks of ageing and age-related diseases.
ROS: their roles in diminished ovarian reserve.
Pyrroloquinoline quinone and imidazopyrroloquinoline intake diminish mortality risk during midlife and improve muscular dysfunctions with age in mice.
Glucocorticoid excess disrupts NAD+ homeostasis in male and female mice.
Diagnostic accuracy of fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15) for predicting insulin resistance using triglyceride-glucose Index, HOMA-C-Peptide, and C-peptide-to-glucose ratio in type 2 diabetes: A systematic review and bivariate diagnostic test accuracy meta-analysis.
The mitochondria-synapse axis in Alzheimer's disease: Lost coordination in early stages.
N-acetylcysteine, Acetyl-L-carnitine, and Citicoline: A Potential Synergism in Neurological and Psychiatric Disorders.
Mitochondrial ROS Production at Complexes I and III in Human Myocardium and Skeletal Muscle: A Distinct Pattern Compared with Rat Tissue.
170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.
Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.
Potential causal role of mitochondrial biological effects in COVID-19: Evidence from Mendelian randomization study.

Bioessays. 2026 May;48(5): e70146

Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity.

Yi Sheng, Zachary Markovich, Sung Min Han, Rui Xiao.

  Mitochondria are vital not only for energy production but also for regulating signaling pathways that influence aging. While mitochondrial dysfunction contributes to age-related decline, emerging evidence shows that mild, regulated mitochondrial stress can paradoxically promote longevity. This review highlights recent advances in mitochondrial biology and aging across species. We explore the dual role of reactive oxygen species (ROS) as both damaging agents and signaling molecules that activate adaptive stress responses. Key pathways such as the mitochondrial unfolded protein response (UPRMT) and integrated stress response (ISR) are discussed, including their tissue-specific as well as non-cell-autonomous effects on aging. Additionally, we examine the impact of mitochondrial protein import/export, dynamics (fission, fusion, mitophagy, biogenesis), and quality control in aging. Finally, we address challenges in understanding context-dependent mitochondrial responses and mitonuclear communication. Together, these insights position mitochondria as central regulators of aging and highlight their potential as therapeutic targets to enhance health span and longevity.

Keywords:  aging; integrated stress response; mitochondria ROS; mitochondrial dynamics; mitochondrial unfolded protein response

DOI:  https://doi.org/10.1002/bies.70146
Narra J. 2026 Apr;6(1): e3042

Oxidative stress as a converging mechanism of aging and neurodegeneration: From molecular pathways to therapeutic targets.

Meutia A Faradilla, Karina S Anastasya, Deasyka Yastani, Yohana Yohana, Endrico X Tungka, Suweino Suweino.

  Aging is the primary risk factor for major neurodegenerative disorders, yet the precise molecular links between biological aging and progressive neuronal loss remain complex. Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses, has emerged as a central converging mechanism driving both processes. This review aims to synthesize current evidence demonstrating how chronic redox imbalance drives cellular senescence and neuronal vulnerability through mitochondrial dysfunction, lipid peroxidation, and oxidative protein damage. These insights underscore how sustained oxidative insults promote the misfolding and aggregation of disease-defining proteins, including amyloid-beta in Alzheimer's disease and α-synuclein in Parkinson's disease, thereby amplifying neuroinflammation, synaptic dysfunction, and bioenergetic failure. Furthermore, antioxidant-based therapeutic strategies are critically reassessed, highlighting a paradigm shift from non-specific radical scavenging toward targeted modulation of endogenous defense systems, particularly NRF2 signaling and mitochondria-directed antioxidants. By integrating molecular mechanisms with translational perspectives, this review integrates molecular, cellular, and translational evidence to explain how oxidative stress links biological aging to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.

Keywords:  Oxidative stress; aging; mitochondria; neurodegeneration; reactive oxygen species

DOI:  https://doi.org/10.52225/narra.v6i1.3042
Front Aging. 2026 ;7 1824237

Sex differences in mitochondrial function in aging mouse skeletal muscle.

Angelina Holcom, Ashley Liao, Kaitlyn G Holden, Anne M Bronikowski, Ashley E Webb.

   Introduction: Sex differences in lifespan and age-associated phenotypes are pervasive across species, yet the mechanisms remain poorly understood. Mitochondrial dysfunction is a major hallmark of aging, but whether skeletal muscle mitochondria age along sex specific trajectories remains incompletely defined.
Methods: Here, we profiled mitochondrial bioenergetics and DNA integrity in flexor digitorum brevis (FDB) muscle from young (3-4 months) and aged (20-24 months) male and female C57BL/6 mice. We quantified cellular respiration in intact myofibers, measured mitochondrial DNA (mtDNA) copy number, and assessed expression of genes involved in mitochondrial dynamics, electron transport chain (ETC) function, and mtDNA maintenance.
Results: Cellular respiration differed by sex at baseline and changed with age in a sex-dependent manner. Aged females exhibited a lower basal and ATP-linked respiration than aged males. In contrast, spare respiratory capacity increased in aged females relative to aged males, consistent with age- and sex-specific remodeling of the bioenergetic reserve. mtDNA copy number increased with age in both sexes, with a greater increase in mtDNA content in aged males. Gene-expression analyses revealed age- and/or sex-dependent changes, including lower Pink1 expression in females compared to males, an age-related increase in the mtDNA maintenance gene Polg2 only in males, though most genes were not significantly different. As an exploratory systemic readout, we additionally assessed DNA damage responsiveness in whole-blood leukocytes using the alkaline comet assay following oxidative challenge; young females exhibited greater induced DNA damage than young males.
Discussion: Together, these data define sex- and age-associated mitochondrial remodeling in FDB and provide an initial assessment of sex-dependent inducible DNA damage responses in blood, underscoring the importance of sex as a biological variable in studies of aging.

Keywords:  alkaline comet assay; flexor digitorum brevis (FDB); mitochondria bioenergetics; mitochondrial DNA copy number; sex differences; skeletal muscle aging

DOI:  https://doi.org/10.3389/fragi.2026.1824237
Nat Metab. 2026 May 14.

Human whole-blood NAD+ levels do not vary with age or lifestyle interventions.

Maria M Trętowicz, Angelique M L Scantlebery, Bauke V Schomakers, Kaan D Eroğlu, Michel van Weeghel, Vera Spek, Kasper T Vinten, Luc Legon, Evrim Coskun, Fernando Millan-Domingo, Gloria Olaso-Gonzalez, Maria Carmen Gomez-Cabrera, Silvia Montoro-García, Clara Noguera-Navarro, André B P van Kuilenburg, Sofia Moco, Juliette C van Hattum, Harald T Jørstad, Mohammed Benali, Jantine van der Helder, Esmee J M Biersteker, Maheswary Muniandy, Kirsi H Pietiläinen, Eija Pirinen, P Eline Slagboom, Marian Beekman, Joris Deelen, Rubén Zapata-Pérez, Peter J M Weijs, Michael Tieland, Georges E Janssens, Riekelt H Houtkooper.

Nicotinamide adenine dinucleotide (NAD+) levels in blood and tissues are widely proposed to decline with age, yet evidence in human blood is inconsistent. Using a rigorously validated ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry system that accounts for real-world analytical variability, we quantify NAD+ across seven independent human cohorts. We find that whole-blood NAD+ levels remain remarkably stable with age and across lifestyle interventions, but change in response to nicotinamide riboside supplementation, as expected. Our results challenge the utility of blood NAD+ levels as a biomarker of ageing or lifestyle factors.

DOI: https://doi.org/10.1038/s42255-026-01537-5
Curr Neuropharmacol. 2026 May 08.

Exploring Mitochondrial Dysfunction and Protective Therapeutic Approaches to Counteract Its Role in Alzheimer's Disease Progression.

Sanjana Gupta, P Mohamed Nihal, Talha Jawaid, Astik Manju Ashesh, Manish R Bhise, Manoj Rawat, Sathiyanarayanan Lohidasan, Pranay Wal, Ajay Kumar, Dileep Kumar, Amin Gasmi.

  Alzheimer's disease (AD) is the primary cause of dementia, characterized by a progres-sive decrease in mental abilities and the accumulation of amyloid-beta (Aβ) peptides in the brain. The combination of these peptides leads to the development of neuritic plaques and neurofibrillary tangles that disrupt neural communication and eventually lead to the loss of neurons. One of the fac-tors that are involved in the development of AD is mitochondrial dysfunction. Disrupted function-ing of mitochondria leads to the production of less energy by the cells, increased oxidative stress, and accelerates the neurodegeneration process. Neurons that carry out their mitochondrial functions normally are required to keep the balance of calcium, in a reasonable energy production, and in the survival of the cells. Mitophagy, which guarantees the clearing of damaged mitochondria, is im-paired in AD. Cholinesterase blockers and NMDA receptor blockers are currently used as treat-ments, but these are not aimed at the underlying pathophysiology of the condition. New treatment approaches that are aimed at enhancing mitochondrial health, in contrast, are viable at providing a potential to decelerate or alter mitochondrial AD progression. The goals of these approaches include enhancement of the mitophagy process, alleviation of oxidative stress, and preservation of mito-chondrial health, which may disrupt major pathological events such as Aβ aggregation and tau hy-perphosphorylation. By concentrating on the replacement of mitochondria, scientists are moving in the right direction to develop therapies that will not only help control the symptoms but also cure the disease.

Keywords:  Alzheimer’s disease; antioxidants; calcium dyshomeostasis; mitochondrial dysfunction; mitochondrial targeted therapies; mitophagy; neurodegeneration; neuroprotection; oxidative stress.

DOI:  https://doi.org/10.2174/011570159X419571260226033536
Theriogenology. 2026 May 05. pii: S0093-691X(26)00170-6. [Epub ahead of print]262 117980

Nicotinamide mononucleotide (NMN) improves the ovarian microenvironment associated with oocyte quality by increasing estrogen signaling, reprogramming ovarian metabolism, reducing oxidative stress, and inhibiting apoptosis in the spotted scat (Scatophagus argus).

Jie Luo, Siqin Wang, Xinghua Lin, Tuo Wang, Jinli Li, Dongneng Jiang, Tianli Wu, Siping Deng.

  Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD+), has been shown to improve oocyte quality in mammals. A healthy ovarian microenvironment is essential for oocyte quality and reproductive success in teleost fish. To investigate the effects of NMN on ovarian microenvironment parameters associated with oocyte quality in the spotted scat (Scatophagus argus), the levels of serum glucose, insulin, total cholesterol, triglycerides, 17β-estradiol (E2), and ovarian NAD+ were analyzed following an intraperitoneal (IP) injection of NMN. Ovarian transcriptomic profiling was also conducted using RNA sequencing. The expression of genes related to steroidogenesis, apoptosis, and oxidative stress after NMN supplementation was analyzed by qRT-PCR. In vitro, ATP content, glutathione (GSH) levels, reactive oxygen species (ROS) accumulation, and mitochondrial membrane potential (ΔΨm) were quantified in follicles after NMN incubation. The results showed that NMN injection significantly increased ovarian NAD + levels and serum E2 concentrations. NMN improved glucose and lipid metabolism, as evidenced by elevated insulin levels and reduced serum glucose, total cholesterol, and triglycerides. KEGG enrichment analysis revealed significant enrichment of pathways related to metabolism, the stress response, and apoptosis. qRT-PCR demonstrated the upregulation of steroidogenesis-related genes (cyp17a1, hsd3b1, 20β-hsd, cyp19a1a, mmp2, and foxl2), antioxidant genes (gpx1a, gpx1b, and slc7a11), and the anti-apoptotic gene bcl2, along with downregulation of pro-apoptotic genes (bax and caspase3). NMN incubation reduced ROS accumulation and increased GSH levels, accompanied by enhanced mitochondrial function, as reflected by increased ΔΨm and ATP production. Collectively, these results suggest that NMN improves the ovarian microenvironment associated with oocyte quality in spotted scat by enhancing NAD+ availability, which subsequently promotes estrogen signaling, reprogrammed ovarian metabolism, mitigates oxidative stress, and inhibits apoptosis.

Keywords:  Estrogen signaling; Nicotinamide mononucleotide; Ovarian metabolism; Ovarian microenvironment; Oxidative stress; Scatophagus argus

DOI:  https://doi.org/10.1016/j.theriogenology.2026.117980
Oxid Med Cell Longev. 2026 ;2026(1): e5140711

Skin Aging and Mitochondrial Dysfunction: Structural Changes, Mechanistic Insights, and Therapeutic Perspectives.

Nathália Cardoso de Afonso Bonotto, Elize Musachio, Giulliano Danezi Felin, Giancarllo Danezi Felin, Carla Helena Augustin Schwanke, Ivana Beatrice Mânica da Cruz, Fernanda Barbisan.

  This narrative review discusses the relationship between structural changes in the skin and mitochondrial function during aging and evaluates emerging therapeutic interventions targeting mitochondrial dysfunction. An analysis of 49 scientific articles published between 2015 and 2025 was conducted using descriptors including "skin aging," "mitochondrial dysfunction," "oxidative stress," and "cutaneous senescence," and articles were retrieved from PubMed, Scopus, and ScienceDirect. Additional research was conducted using terms related to therapeutic interventions, including "mitochondrial therapies AND skin aging OR cutaneous aging." Original research articles were included based on thematic relevance, recency, and scientific rigor. The reviewed studies suggest that oxidative stress, mainly from mitochondrial metabolism, is a primary cause of skin cell senescence. Mitochondrial dysfunction emerges as a central mechanistic hub linking oxidative stress, mitochondrial genome instability, chronic low-grade inflammation (inflammaging), and the senescence-associated secretory phenotype (SASP) to age-related structural and functional skin alterations. Mitochondria maintain skin homeostasis through cell proliferation, differentiation, and genetic material synthesis. With advancing age, mitochondrial DNA copy number declines significantly, while reactive oxygen species production increases, thereby compromising cellular energy metabolism. Emerging mitochondrial-targeted therapeutic strategies, including nicotinamide adenine dinucleotide (NAD+) precursors, coenzyme Q10 supplementation, senolytics, and modulators of mitochondrial quality control, show promising effects on skin aging parameters in preclinical and early clinical studies. However, current evidence is based on small clinical trials with short follow-up periods, and long-term safety data remain limited. Therefore, while mitochondria are not the sole source of oxidants, growing evidence indicates that oxidative stress-driven mitochondrial dysfunction represents a priority pathogenic mechanism in skin aging. The clinical translation of mitochondrial-targeted therapies represents an innovative opportunity for anti-aging strategies, although the validation of standardized biomarkers and longitudinal safety investigations remains critical for clinical implementation.

Keywords:  mitochondrial dysfunction; oxidative stress; skin aging; therapeutic approach

DOI:  https://doi.org/10.1155/omcl/5140711
Int J Mol Sci. 2026 Apr 28. pii: 3930. [Epub ahead of print]27(9):

Dietary Polyphenols in Aging: A Systems-Level Perspective on Mitochondrial Quality Control and Microbiome Interactions.

Adnan Yılmaz, Hae-Jin Park, Eun-Mi Ahn, Jaehoon Bae.

  Aging is a multifactorial biological process characterized by progressive functional decline and increased susceptibility to chronic diseases. Targeting the molecular mechanisms underlying aging has therefore emerged as an important strategy for promoting healthy aging. Natural polyphenols, widely present in fruits, vegetables, tea, and medical and aromatic plants, have attracted considerable attention due to their geroprotective properties. This review examines current evidence on the ability of major dietary polyphenols, including resveratrol, epigallocatechin gallate (EGCG), curcumin, and quercetin, to modulate the hallmarks of aging, with particular emphasis on mitochondrial quality control as a central regulatory mechanism. Evidence indicates that polyphenols regulate key signaling pathways involved in aging biology, including AMP-activated protein kinase (AMPK), sirtuins (SIRT), mechanistic target of rapamycin (mTOR), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor-κB (NF-κB). Through coordinated modulation of these pathways, polyphenols influence mitochondrial biogenesis, mitophagy, redox homeostasis, cellular senescence, and chronic inflammation. In addition, interactions between dietary polyphenols and the gut microbiome generate bioactive metabolites, such as urolithin A, which further contribute to mitochondrial regulation. Overall, polyphenols represent promising modulators of aging-associated pathways and may support strategies aimed at improving healthspan and reducing age-related disease risk.

Keywords:  AMPK; Nrf2; SIRT1; aging; cellular senescence; gut microbiome; inflammaging; mitochondrial quality control; mitophagy; polyphenols

DOI:  https://doi.org/10.3390/ijms27093930
Front Clin Diabetes Healthc. 2026 ;7 1790182

Molecular pathways, tissue-specific roles, and therapeutic opportunities in mitochondrial resilience-based strategies for insulin resistance.

Yousef M Almoghrabi, Basmah M Eldakhakhny, Ghada Ajabnoor, Faisal Alandejani, Ahmad Jamal, Dareen Alyousfi, Ahmad M Alzahrani, Mostafa A Elsamanoudy, Taghreed Shamrani, Ayman Z Elsamanoudy.

  Insulin resistance (IR) is characterized by impaired insulin signaling in skeletal muscle, liver, and adipose tissue. Increasing evidence indicates mitochondrial dysfunction as a key factor contributing to IR. Mitochondrial resilience refers to the mitochondria's ability to adapt to metabolic stress by regulating biogenesis, dynamics, mitophagy, and redox homeostasis. Linking mitochondrial resilience with insulin signaling could be essential for maintaining metabolic health. This review aims to map and synthesize the existing literature on the relationship between mitochondrial resilience and insulin resistance, focusing on cellular and molecular mechanisms, tissue-specific roles, metabolic consequences, and translational evidence from both animal and human studies. This scoping review adhered to PRISMA-ScR guidelines and included comprehensive searches of PubMed, Scopus, Web of Science, Embase, and Google Scholar. It included experimental and observational studies, original articles, systematic reviews, and meta-analyses, while excluding non-English publications and animal studies without clinical relevance. A total of 7, 012 records were identified; after removing duplicates, screening, and assessing eligibility, 184 studies were included. The evidence shows that impaired mitochondrial biogenesis, defective mitochondrial dynamics, reduced mitophagy, and oxidative stress disturb insulin signaling and promote metabolic inflexibility. Conversely, enhancing mitochondrial resilience increases mitochondrial quantity and function. Lifestyle modification strategies and pharmacological intervention target these pathways to improve mitochondrial resilience. Importantly, understanding inter-individual differences in mitochondrial adaptive capacity may support the development of personalized therapeutic and nutritional strategies aimed at improving insulin sensitivity and metabolic outcomes. In conclusion, mitochondrial resilience provides a comprehensive framework connecting mitochondrial quality to insulin signaling and metabolic health. Focusing on mitochondrial resilience is a promising, mechanism-based strategy for preventing and managing insulin resistance and its related comorbidities.

Keywords:  insulin resistance; lifestyle interventions; metabolic health; mitochondrial biogenesis; mitochondrial dysfunction; mitochondrial resilience; mitophagy; oxidative stress

DOI:  https://doi.org/10.3389/fcdhc.2026.1790182
Sports Med Health Sci. 2026 May;8(3): 229-239

Update: Is exercise-induced oxidative stress a friend or foe?

Scott K Powers, Mari Carmen Gomez-Cabrera.

  Free radicals (radicals) are highly reactive atoms or molecules that contain one or more unpaired electrons in their outermost shell. The first evidence that muscular exercise increases radical production and promotes oxidative damage to tissues was reported almost five decades ago. Following this milestone discovery, many studies have corroborated the finding that exercise increases the production of radicals and other reactive oxygen species (ROS) resulting in oxidative damage to macromolecules in muscles and other tissues. Although exercise-induced ROS production is associated with oxidative damage in many tissues, growing evidence reveals that ROS produced in contracting muscles act as signaling molecules to promote healthy exercise-induced adaptations in skeletal muscles and other tissues. These adaptive responses include increased mitochondrial volume, improved antioxidant capacity, and expression of cytoprotective proteins. Therefore, a key question emerges: "Is exercise-induced ROS production a friend or foe?" This review provides a state-of-the-art discussion of both the positive and negative effects of exercise-induced ROS production by examining the consequences of both oxidative damage to cellular macromolecules and the redox signaling-induced adaptations that occur in muscle fibers. To address the question of whether exercise-induced ROS production is a friend or foe we conclude with a risk/benefit analysis of the biological effects of exercise-induced production of ROS.

Keywords:  Fatigue; Oxidants; Radicals; Reactive oxygen species; Skeletal muscle

DOI:  https://doi.org/10.1016/j.smhs.2026.03.006
J Bioenerg Biomembr. 2026 May 09.

Dynamic changes in mitochondrial function in brain cortex synaptosomes during aging.

Paulina Lombardi, Analía G Karadayian, Juan Ignacio Guerra, Silvia Lores-Arnaiz.

  Alterations in mitochondrial function and in reactive oxygen species generation have been associated with physiological aging. In this study, mice aged 3, 10, 20, and 24 months were utilized to investigate the changes in mitochondrial function and reactive oxygen species (ROS) at synapses. Mitochondrial membrane potential was 21% decreased in 20 months-old animals, while it increased (24%) at advanced age (24 months), compared with young mice. Coupling efficiency and ATP synthesis decreased in synaptosomes from 24-months old mice. Regarding mitochondrial respiratory complex activity, reductions in complex II-III and IV activity were observed (42% and 47%, respectively) at 10 months of age. A significant increase in complex I-III activity (48%) was found at 20 months, with no changes in complexes II-III or complex IV enzymatic activities. Likewise, complex II-III activity showed an increase (100%) at 24 months, while complex I-III significantly decreased (37%). An age-related increase in superoxide generation was observed, consistent with impaired respiratory chain function. Interestingly, H2O2 production rates were 43% decreased in 20-months old mice, compared to young animals. This study presents evidence that the aging process leads to changes in mitochondrial function in brain cortex synaptosomes, which become significantly impaired at the age of 20 months. Even though at more advanced ages, compensatory mechanisms might appear to counteract the impact of mitochondrial dysfunction and oxidative damage, mitochondrial bioenergetics seems to be severely compromised.

Keywords:  aging; bioenergetics; cerebral cortex; respiratory complexes; synaptosomes

DOI:  https://doi.org/10.1007/s10863-026-10087-0
Ageing Res Rev. 2026 May 08. pii: S1568-1637(26)00150-9. [Epub ahead of print]119 103158

Ergothioneine as a potential geroprotector: Targeting molecular hallmarks of ageing and age-related diseases.

Pengfei Zhao, Ying Qi.

  Hypothesized to be a diet-derived 'longevity vitamin', Ergothioneine (ET) is increasingly recognized for its potential to modulate cellular homeostasis and support healthy ageing in preclinical models. This systematic review, encompassing evidence from 2005 to 2025, investigates ET's unique pharmacokinetics mediated by the OCTN1 (SLC22A4) transporter, which ensures its selective accumulation in tissues susceptible to age-related oxidative decline. Beyond its role as a secondary antioxidant buffer, we critically evaluate ET's ability to target molecular hallmarks of ageing, specifically focusing on telomere maintenance, mitochondrial integrity, and the NRF2-mediated cytoprotective response. Utilizing network pharmacology, this review deciphers the multi-target regulatory landscape of ET in mitigating neurodegeneration, cardiovascular remodeling, and metabolic dysfunction. Furthermore, we address clinical gaps by discussing ET's potential utility as a candidate biomarker of biological aging and emphasizing the necessity of precision nutrition strategies incorporating SLC22A4/SLC22A15 genetic stratification. By synthesizing mechanistic insights and longitudinal human data, we highlight ET as an emerging candidate with geroprotective potential that warrants rigorous clinical evaluation for extending healthspan.

Keywords:  Anti-inflammatory; Antioxidant; Ergothioneine; Medicine food homology; Therapeutic potential; Toxicology

DOI:  https://doi.org/10.1016/j.arr.2026.103158
Front Endocrinol (Lausanne). 2026 ;17 1823452

ROS: their roles in diminished ovarian reserve.

Xin Chen, Danzhuo Liu.

  Diminished Ovarian Reserve (DOR) is a core pathological condition leading to reduced female fertility, characterized by decreased follicular quantity and diminished oocyte quality in the ovaries, which significantly impacts natural pregnancy and assisted reproductive technology outcomes. Despite its complex etiology, recent studies have demonstrated that reactive oxygen species (ROS)-mediated oxidative stress (OS) serves as a common pathological hub, integrating multiple pathogenic factors, including aging, metabolic abnormalities, environmental exposure, and iatrogenic damage, throughout the process of DOR development. This article systematically reviews the key mechanisms of ROS in DOR and the corresponding intervention strategies. At the level of pathological mechanisms, ROS drive ovarian reserve depletion through a multilevel, networked mechanism. Based on mechanistic understanding, intervention strategies focus on mitochondrial-targeted antioxidants. This article provides a systematic framework for an in-depth understanding of the central role of ROS in DOR and the development of mechanism-driven intervention strategies.

Keywords:  ROS; antioxidant therapy; dor; follicular development; os

DOI:  https://doi.org/10.3389/fendo.2026.1823452
Food Funct. 2026 May 13.

Pyrroloquinoline quinone and imidazopyrroloquinoline intake diminish mortality risk during midlife and improve muscular dysfunctions with age in mice.

Keiko Odera, Yuka Tanaka, Kazuto Ikemoto, Masanori Tamakoshi, Ryoya Takahashi.

Pyrroloquinoline quinone (PQQ) and its derivative imidazopyrroloquinoline (IPQ) are nutritionally important vitamin-like compounds that exert various physiological effects, including cell-growth promotion, neuroprotection, and mitochondriogenesis stimulation. This study investigated the potential of PQQ and IPQ as geroprotectors that promote healthy longevity, addressing the general lack of lifespan aging intervention experiments in mammals. We conducted lifelong and midlife experiments with 0.02% (w/w) PQQ and 0.02% (w/w) IPQ supplementation in the senescence-accelerated mouse P8 strain that is characterized by a short lifespan. In lifelong experiments, the survival days at the 75th percentile was prolonged by 73% and 36% in the PQQ and IPQ groups, respectively, compared with that in the control. In addition, significant delays in the appearance of aging and age-related muscular dysfunction were observed. Intake of PQQ and IPQ diets from midlife improved muscular function that had declined with age. IPQ intake reduced lipid accumulation in adipose tissue and the liver. To the best of our knowledge, this is the first study to demonstrate that PQQ and IPQ supplementation, whether initiated in the early or middle age, is effective in ameliorating age-related alterations, such as muscular function, and diminishes mortality risk during midlife in mice.

DOI: https://doi.org/10.1039/d6fo00788k
J Endocrinol. 2026 May 11. pii: JOE-26-0011. [Epub ahead of print]

Glucocorticoid excess disrupts NAD+ homeostasis in male and female mice.

Samuel R Heaselgrave, Silke Heising, Minghao Deng, Stuart A Morgan, David M Carthwright, Christian Ludwig, Raissa N Rodrigues, Peter Aldiss, Jonas T Treebak, Kostas Tsintzas, Gareth G Lavery, Craig L Doig.

  Glucocorticoid excess induces a plethora of metabolic disturbances including obesity, muscle atrophy, hepatic steatosis, and increased energy expenditure, hallmark features of Cushing's syndrome. Despite understanding of these outcomes, it remains unclear how glucocorticoid excess affects the metabolically critical nicotinamide adenine dinucleotide (NAD+) and related metabolites and transcripts, including redox cofactors, intermediates, and biosynthetic enzymes. Furthermore, the therapeutic potential of NAD+ precursor supplementation in this context is unknown. Here, we investigated tissue- and sex-specific effects of sustained corticosterone treatment on NAD+ and its related metabolites and transcripts in skeletal muscle and liver of male and female mice and assessed the efficacy of nicotinamide riboside (NR) supplementation in preventing glucocorticoid-induced metabolic dysfunction. Using LC-MS and gene expression analyses, we demonstrate that glucocorticoid excess increases NAD+ and NAAD levels in skeletal muscle, alongside modest changes in salvage pathway gene expression in males and females. However, NADP+ was increased in males only. In the liver, glucocorticoid treatment decreased NADPH and increased the NADP+/NADPH ratio in males and females, with widespread downregulation of biosynthetic enzymes despite stable NAD+ levels. NR supplementation failed to prevent classical features of glucocorticoid excess, including increased body weight, muscle atrophy, adiposity, hepatic triglyceride accumulation, and elevated energy expenditure. These findings reveal novel effects of glucocorticoid excess on NAD+ and related metabolites and transcripts but also question the importance of NAD+ in glucocorticoid-induced metabolic dysfunction. Consequently, while NAD+ pathways are impacted by glucocorticoid excess, our data show no therapeutic benefit of NR supplementation under the conditions tested and do not support its efficacy in this model of glucocorticoid excess.

Keywords:  Glucocorticoid excess; de novo biosynthesis; nicotinamide adenine dinucleotide; nicotinamide riboside

DOI:  https://doi.org/10.1530/JOE-26-0011
Diabetes Res Clin Pract. 2026 May 12. pii: S0168-8227(26)00238-X. [Epub ahead of print] 113318

Diagnostic accuracy of fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15) for predicting insulin resistance using triglyceride-glucose Index, HOMA-C-Peptide, and C-peptide-to-glucose ratio in type 2 diabetes: A systematic review and bivariate diagnostic test accuracy meta-analysis.

Mustakin, Mansyur Arief, Nurahmi, Liong Boy Kurniawan.

  Fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15) are metabolokines associated with insulin resistance in type 2 diabetes, but their pooled diagnostic performance has not been systematically established. We conducted a PRISMA-DTA-compliant systematic review and bivariate diagnostic test accuracy meta-analysis to evaluate the accuracy of FGF-21 and GDF-15, individually and in combination, for predicting insulin resistance using the triglyceride-glucose (TyG) index, HOMA-C-peptide, and C-peptide-to-glucose ratio as reference standards. Six databases were searched from January 2015 to March 2025. Fifteen studies involving 14,832 participants were included. Against TyG, FGF-21 showed pooled sensitivity of 82.4% and specificity of 78.9% (AUC 0.88), while GDF-15 demonstrated slightly higher sensitivity of 85.6% and specificity of 82.1% (AUC 0.91). Combined FGF-21 and GDF-15 testing achieved the best overall performance, with sensitivity of 88.9%, specificity of 86.4%, and AUC of 0.94. TyG was the most discriminating reference standard across both biomarkers. These findings support the potential utility of FGF-21 and GDF-15, particularly in combination, as adjunctive laboratory biomarkers for insulin resistance risk stratification in type 2 diabetes.

Keywords:  Diagnostic test accuracy; Fibroblast growth factor-21; Growth differentiation factor-15; Insulin resistance; Triglyceride-glucose index; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.diabres.2026.113318
Ageing Res Rev. 2026 May 07. pii: S1568-1637(26)00160-1. [Epub ahead of print]119 103168

The mitochondria-synapse axis in Alzheimer's disease: Lost coordination in early stages.

Priyanshu Sharma, Navneet Kaur, Nandini Vasal, Kusum Solanki, Aditya Sunkaria.

  Synaptic dysfunction emerges early in Alzheimer's disease, often years before the appearance of clinical symptoms, and is among the most reliable predictors of subsequent cognitive decline. Despite its importance, the cellular events that trigger this early synaptic vulnerability remain poorly defined. Growing evidence points to a critical failure at the interface between neuronal energy metabolism and synaptic signalling, commonly referred to as the mitochondria-synapse axis, suggesting that its disruption may occur well before the accumulation of classical amyloid and tau pathology. In this Review, we combine findings from human neuronal models, multi-omics analyses, and in vivo studies to show how amyloid-β oligomers (Aβ oligomers) induce subtle yet consequential defects in mitochondrial trafficking, calcium handling, redox homeostasis, and local ATP supply. Together, these changes undermine the precise coordination between mitochondrial metabolism and calcium-dependent signalling that is essential for synaptic plasticity. As a result, affected neural circuits lose the capacity to meet the energetic demands of sustained information processing. We propose that this early uncoupling of energy availability from synaptic demand represents a leading contributor to neuronal vulnerability rather than a secondary consequence of protein aggregation, based on converging evidence from iPSC-derived cortical neurons, human neuronal cultures, and transgenic mouse models, with human in vivo validation still emerging. Finally, we highlight emerging therapeutic strategies aimed at restoring mitochondrial quality control, axonal transport, and metabolic communication. By re-aligning bioenergetic support with synaptic function, such approaches may open a critical window for intervention before irreversible circuit degeneration takes hold.

Keywords:  Alzheimer’s disease; Aβ oligomers; Mitochondria-synapse axis; Mitochondrial dynamics; Neuroenergetics; Synaptic dysfunction

DOI:  https://doi.org/10.1016/j.arr.2026.103168
Curr Neuropharmacol. 2026 May 09.

N-acetylcysteine, Acetyl-L-carnitine, and Citicoline: A Potential Synergism in Neurological and Psychiatric Disorders.

Marika Alborghetti, Matteo Caridi, Giada Mascio, Valeria Bruno, Giuseppe Battaglia.

  The cellular oxidative balance is finely regulated by glutathione (GSH) levels and its reduced form. N-acetylcysteine (NAC) is an antioxidant agent that reduces disulphide bonds, scavenges reactive oxygen species (ROS), and serves as a precursor for GSH biosynthesis. Moreover, NAC can modulate glutamatergic transmission in the central nervous system (CNS), stimulating the system xc- activity and thus enhancing the endogenous activation of metabotropic glutamate receptors type 2 and 3 presinaptically, which restrains the excessive release of glutamate. Acetyl-Lcarnitine (ALC) is an acetylated form of L-carnitine and plays a key role in cellular energy metabolism. NAC and ALC show great neuroprotective potential, owing to their ability to counteract oxidative stress, modulate the glutamatergic system and neurotransmission, and maintain mitochondrial bioenergy and membrane integrity, acting synergistically. Several preclinical and clinical studies suggest that NAC and ALC may have effects in different psychiatric and neurological disorders, including mood disorders, schizophrenia, substance use disorder, chronic pain, and neurodegenerative diseases. The combination of the two products together with citicoline could also be beneficial when cognitive fatigue or cognitive impairment are clinical manifestations. These agents act on complementary pathways-redox regulation, mitochondrial support, and membrane integrity-potentially enhancing each other's neuroprotective effects. The purpose of this review is to explore the fields (psychiatric, neurological, and also rheumatological), in which the combination of these compounds may benefit patient management, starting with preclinical evidence and focusing on clinical trials conducted over the years.

Keywords:  ALC; Acetyl-L-carnitine; N-acetylcysteine; NAC; chronic pain; citicoline; cognitive decline.; drug use disorder; mood disorder; neurodegenerative disease; neurological disorders; psychiatric disorders; stroke

DOI:  https://doi.org/10.2174/011570159X403105251105014447
Cells. 2026 May 01. pii: 830. [Epub ahead of print]15(9):

Mitochondrial ROS Production at Complexes I and III in Human Myocardium and Skeletal Muscle: A Distinct Pattern Compared with Rat Tissue.

Ivan Mihanovic, Jasna Marinovic, Cristijan Bulat, Bruno Luksic, Zlatko Marovic, Marko Ljubkovic.

  Mitochondrial reactive oxygen species (ROS) play a central role in cardiac ischemia/reperfusion injury, heart failure, and arrhythmogenesis, while also serving essential signaling functions under physiological conditions. Among the eleven identified mitochondrial ROS-producing sites, complexes I and III are considered the major contributors, particularly under conditions of impaired electron flow. However, much of the existing knowledge comes from rodent models or cultured cells and is often assumed to apply to humans. Here, ROS production from complexes I and III was measured directly in human myocardial and skeletal muscle biopsies and compared with corresponding rat tissues under identical experimental conditions. Hydrogen peroxide generation was quantified using Amplex UltraRed, with simultaneous monitoring of mitochondrial respiration using a Clark-type oxygen electrode. Across all examined mechanisms-reverse and forward electron transport at complex I and the ubiquinol oxidation site of complex III, rat tissues produced more ROS than human tissues, consistent with their higher respiratory rates. However, the dominant ROS-producing sites differed: in rats, complex III was the primary source, whereas in human tissues the highest ROS production occurred during reverse electron transport at complex I. When normalized to respiration, human tissues showed relatively greater ROS generation at complex I but markedly lower production at complex III. These direct measurements of mitochondrial ROS production in human myocardium provide new insight into cardiac redox physiology and may explain the limited clinical translation of cardioprotective strategies targeting mitochondrial ROS production, such as interventions aimed at modulating reperfusion injury or preconditioning.

Keywords:  complex I; complex III; human myocardium; mitochondrial ROS hierarchy; mitochondrial reactive oxygen species; skeletal muscle

DOI:  https://doi.org/10.3390/cells15090830
J Clin Pharmacol. 2026 May;66(5): e70209

170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.

Volkmar Weissig.

  One hundred and sixty-eight years lie between the first description of mitochondria as "pale roundish granules" and their eventual recognition as the "chief executive organelle" of the cell. Booming mitochondrial research during the last three decades has revealed that being the "powerhouse of the cell" is just one of many fundamental roles mitochondria play for cellular life. Mitochondria are at the crossroads of complex metabolic pathways; they regulate cellular signaling and innate immunity, and they determine whether a cell should divide, differentiate, or die. Human disorders caused by malfunctioning mitochondria have been described starting at the beginning of the 1960s, nowadays, it seems widely accepted that there are hardly any human diseases anymore that are not associated with dysfunctioning mitochondria. Even the process of aging seems to be controlled by this powerful organelle. This review is written for Pharmacologists, Physicians, and Healthcare Providers who are not familiar with mitochondrial biology and with the tremendous insights gained during the last three decades into the vital roles this cell organelle plays for life and death. It is aimed at raising awareness of still underappreciated mitochondrial diseases, which represent the largest group of inborn errors of metabolism.

Keywords:  aging; apoptosis; cellular signaling; drug development; energy metabolism; immunity; mitochondria; mitochondrial diseases

DOI:  https://doi.org/10.1002/jcph.70209
Am J Physiol Cell Physiol. 2026 May 13.

Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.

Klaudia Sztolsztener, Thulasi Mahendran, David A Hood.

  Protein homeostasis is critical for mitochondrial function and is maintained by proteases and chaperones that respond to stress and mediate adaptive changes such as the mitochondrial unfolded protein response (UPRmt), the integrated stress response (ISR) and antioxidant signaling. However, the mechanisms by which stressors regulate these retrograde responses remains uncharacterized in muscle. Thus, we examined the effect of mitochondrial stressors on the activation of these pathways in myoblasts and differentiated myotubes. Cells were exposed to either 1) CDDO, a LonP1 protease inhibitor, 2) GTPP, an HSP90 chaperone inhibitor, 3) CCCP, an energetic uncoupler, or 4) MB-10, an inhibitor of protein import, and responses were compared to those induced by acute contractile activity (ACA). LonP1 inhibition activated ATF4 and Nrf2 signaling, increased mitochondrial chaperones, and resulted in protein aggregation without elevating reactive oxygen species (ROS). In contrast, blocking HSP90 led to increases in mitochondrial ROS and activation of CHOP, indicating protein homeostasis-related stress with limited antioxidant signaling. ACA elicited responses similar to the inhibition of LonP1, including the activation of ATF4 and Nrf2, increased UPRmt markers, and a redox balance. Although CCCP and MB-10 both impaired protein import, they activated distinct downstream responses. CCCP resulted in ISR activation, while MB-10 induced Nrf2-mediated antioxidant responses. Together, these findings show that the type of mitochondrial stress determines the direction of the retrograde signaling pathways between protein homeostasis and redox signaling in muscle cells, and they provide insights on how muscle coordinates signaling pathways as part of mitochondrial adaptations to contractile activity.

Keywords:  integrated stress response; mitochondrial biogenesis; mitochondrial proteostasis; mitochondrial unfolded protein response; muscle contractile activity

DOI:  https://doi.org/10.1152/ajpcell.00167.2026
Medicine (Baltimore). 2026 May 08. 105(19): e48654

Potential causal role of mitochondrial biological effects in COVID-19: Evidence from Mendelian randomization study.

Jiaxin Li, Hongbo Ding, Sumin Zuo, Yi Wang, Ying Guo, Senlin Niu, Zhe-An Shen, Yongan Xu.

  Potential mitochondrial biomarkers play an important role in probing COVID-19 physiopathology. We aimed to investigate the causal effects of 82 mitochondrial biomarkers on COVID-19 in a population-based public database. Based on the IEU Open genome-wide association studies database and the genome-wide association studies Catalog database, the significant single-nucleotide polymorphisms of mitochondrial and COVID-19 were extracted as instrumental variables. The inverse variance weighting (IVW) method and the Bayesian weighting method in the two-sample Mendelian randomization (MR) method were used for the main causal analysis. Sensitivity tests were performed using the MR-Egger regression test, the MR-PRESSO test for multiple residuals and outliers, the Cochran Q statistic, and the leave-one-out method, and directionality tests were performed using the MR-Steiger method. The protective factors of COVID-19 were determined by IVW method and Bayesian weighting method: Apoptosis-inducing factor 1, mitochondrial (PIVW = 9.6 × 10-5; PBWMR = 4.2 × 10-2) and risk factors: 39S ribosomal protein L33, mitochondrial (PIVW = 2.8 × 10-3; PBWMR = 1.9 × 10-3) and 39S ribosomal protein L52, mitochondrial (PIVW = 2.0 × 10-2; PBWMR = 7.3 × 10-3) and Mitochondrial ubiquitin ligase activator of NF-κB-1 (PIVW = 2.7 × 10-2; PBWMR = 4.8 × 10-2). In the sensitivity test, we did not find heterogeneity, pleiotropic and reverse causality. In this study, we identified 4 potential biomarkers of mitochondrial dysfunction associated with COVID-19, providing new insights into the realization of COVID-19 precision medicine and potential mechanisms.

Keywords:  Biomarker; COVID-19; Genome-wide association study; Mendelian randomization analysis; Mitochondria

DOI:  https://doi.org/10.1097/MD.0000000000048654