bims-mistre 2026-03-29 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–03–29
thirty papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows.
Next-Generation Dietary Antioxidants in Women's Reproductive Health: Mechanisms, Reproductive Outcomes, and Therapeutic Potential.
Astaxanthin protects heart mitochondria from damage caused by chronic alcohol intoxication.
Veronicastrum sibiricum (L.) Pennell extract alleviates inflammation‑induced muscle atrophy through NLRP3 inflammasome regulation and mitochondrial function restoration.
Effect of (-)-Epicatechin on Mitochondrial Homeostasis in Skeletal Muscle of Female Obese Rats.
Maternal Immune Activation Leads to Mitochondrial Dysfunction and a Social Deficit in Offspring That Is Reversed by Nicotinamide Riboside.
New Insights into Potential Anti-Aging Effects of a Dietary Supplement from Chlorella Growth Factor and γ-PGA in Aged SAMP8 Mice.
Overview of Aging, Skin Health, Estrogen, Menopause and HRT.
Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases.
Restoring Mitochondrial Homeostasis: Therapeutic Strategies for Metabolic Dysfunction-Associated Fatty Liver Disease.
Epigallocatechin gallate mitigates oxidative stress-induced transient senescence and injury by preserving mitochondrial integrity and restoring redox-inflammatory homeostasis in murine macrophages.
In vitro effects of Taurine on Taxol-induced mitochondrial dysfunction.
Mitochondrial NADP(H) integrates redox and metabolism.
Effect of caloric restriction on organ-specific biological aging in a randomized clinical trial.
Rosmarinic Acid Targets AKR1B1 to Ameliorate Atherosclerosis via Vascular Endothelial Cell Energy Metabolism Regulation.
Renin-angiotensin system blockade attenuates brain mitochondrial dysfunction, oxidative stress, and neuroinflammation associated with hypertension, metabolic disorders, and aging.
Oxidative Stress in Diabetic Cardiomyopathy: Molecular Mechanisms and Emerging Therapeutic Targets.
Multi-omics liquid biopsy identifies mitochondrial dysfunction in geographic atrophy and supports the longevity-associated metabolite α-ketoglutarate as a therapeutic strategy.
Estrogen, Epigenetics, and Cardiometabolic Health: Mechanisms and Therapeutic Strategies in Postmenopausal Women.
Age at natural menopause, reproductive lifespan and Alzheimer's disease in females: is APOE ε4 the missing link?
Antiaging Properties of the Klotho Protein.
Curcuminoid supplementation for vasomotor symptoms in postmenopausal women: a pilot, randomized, double-blind, placebo-controlled proof-of-concept trial.
Cognition in menopausal women.
Integrative Insights Into Mitochondrial Dysfunction and Organelle Crosstalk in Diabetic Kidney Disease.
Modulation of Microbiome-Mitochondria Axis as a Novel Approach for Treatment of Obesity: A Scoping Review.
Therapeutic potential of dihydronicotinamide riboside (NRH) on obesity and glucose intolerance in mice.
Immunohistochemical Markers of Mitochondrial Electron Transport Chain Instability in Human Brain Regions: A Study of Aging and Alzheimer's Disease.
Disorders in lipid metabolism, oxidative stress, and antioxidants in patients with amnestic mild cognitive impairment without major depression.
Association of leukocyte mitochondrial DNA copy number and inflammation with mortality among older adults.
Humanin as an evolutionarily tuned mitochondrial peptide: Insights from mammalian oxidative stress diversity.

Biomolecules. 2026 03 16. pii: 445. [Epub ahead of print]16(3):

Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows.

Snježana Kaštelan, Antonela Gverović Antunica, Suzana Konjevoda, Zora Tomić, Ana Sarić, Marjan Kulaš, Lorena Kulaš, Emina Kujundžić Begović, Samir Čanović, Petra Kovačević, Mira Ivanković.

  Mitochondrial reactive oxygen species (mtROS) play a dual role in retinal physiology, acting as essential redox signalling mediators under homeostatic conditions but driving oxidative damage and neurodegeneration once regulatory thresholds are exceeded. Owing to the exceptionally high energetic demands of retinal neurons and supporting cells, even subtle perturbations in mitochondrial redox balance can precipitate progressive retinal dysfunction. Increasing evidence indicates that retinal neurodegenerative diseases, including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), and inherited optic neuropathies, are characterised not by uniform oxidative stress, but by disease- and stage-specific mtROS signatures shaped by mitochondrial quality control capacity. This review synthesises current insights into the sources, regulation, and signalling functions of mtROS in the retina, with particular emphasis on threshold-dependent redox transitions, reverse electron transport, and the progressive failure of mitochondrial quality control mechanisms, including mitophagy, mitochondrial dynamics, and redox-responsive transcriptional networks. The limitations of non-selective antioxidant strategies are critically examined, highlighting why indiscriminate ROS suppression has yielded limited clinical benefit. In contrast, emerging therapeutic approaches aimed at recalibrating mitochondrial redox homeostasis, rather than abolishing physiological signalling, are discussed in the context of disease stage, metabolic state, and mitochondrial competence. By integrating redox biology with mitochondrial quality control and precision medicine concepts, this review proposes a unifying framework in which retinal neurodegeneration is governed by regulated mtROS signalling and the progressive exhaustion of mitochondrial resilience. This model defines critical therapeutic windows for mitochondria-targeted intervention and provides a framework for biomarker-guided patient stratification.

Keywords:  mitochondria-targeted intervention; mitochondrial quality control; mitochondrial reactive oxygen species (mtROS); mitophagy; precision medicine; redox signalling; retinal ganglion cells; retinal neurodegeneration; reverse electron transport

DOI:  https://doi.org/10.3390/biom16030445
Antioxidants (Basel). 2026 Mar 03. pii: 319. [Epub ahead of print]15(3):

Next-Generation Dietary Antioxidants in Women's Reproductive Health: Mechanisms, Reproductive Outcomes, and Therapeutic Potential.

Md Ataur Rahman, Maroua Jalouli, Mohammed Al-Zharani, Abdel Halim Harrath.

  Oxidative stress has emerged as a key factor regulating female fertility, reproductive aging, and the development of various gynecologic and pregnancy-associated diseases. While physiological concentrations of reactive oxygen species play a fundamental role in many aspects of normal reproduction such as folliculogenesis, oocyte maturation, implantation, and placental development, abnormal or chronic oxidative stress impairs redox homeostasis and promotes mitochondrial dysfunction, inflammation, DNA damage, and cellular senescence. Recent research interest has shifted toward next-generation dietary antioxidants, including bioactive polyphenols, carotenoids, micronutrients, and nutraceutical combinations with improved bioavailability and molecular targets. These compounds go beyond classical free-radical scavenging activity and modulate a network of redox-sensitive signaling pathways involved in autophagy, apoptosis, endocrine regulation, and immunological balance. In this review, we integrate current mechanistic advances into a cohesive framework that illustrates the regulation of key cellular processes affecting female reproductive physiology by next-generation dietary antioxidants. We also critically evaluate experimental, translational, and clinical data supporting their role in promoting reproductive outcomes, including oocyte quality, ovarian reserve, pregnancy success, and mitigation of age-related reproductive decline. We highlight their potential in the therapeutic intervention of oxidative stress-related conditions such as infertility, polycystic ovary syndrome, endometriosis, early ovarian insufficiency, and menopause-associated disorders. Finally, we discuss the current challenges associated with dosage optimization, bioavailability, long-term safety, and interindividual variability. We conclude by highlighting next-generation dietary antioxidants as a promising, widely available, and non-invasive approach to improve women's reproductive health and promote fertility throughout their lifespan.

Keywords:  dietary antioxidants; female fertility; mitochondrial function; oxidative stress; redox signaling; reproductive aging

DOI:  https://doi.org/10.3390/antiox15030319
Biomed Khim. 2026 Feb;72(1): 28-41

Astaxanthin protects heart mitochondria from damage caused by chronic alcohol intoxication.

O V Krestinina, I V Odinokova, A I Zvyagina, R R Sotnikov, L D Sotnikova, Yu L Baburina.

  The natural antioxidant astaxanthin (AST) demonstrates the cardioprotective effect on cardiac mitochondria in rats subjected to chronic alcohol intoxication. Particularly, AST restored cardiac mitochondrial respiratory activity and Ca2+ capacity of rats exposed to chronic alcohol intoxication; it also had a positive impact on the balance of functionally important processes of mitochondrial fission/fusion, as well as mitophagy. In addition, AST prevented alcohol-induced morphological damage to cardiac tissue. Overall, the results demonstrate that AST promotes normalization of cardiac mitochondrial function, protecting these organelles from degenerative changes caused by alcohol intoxication and improving cardiac energy metabolism. Thus, AST helps to compensate the cardiac mitochondrial damage caused by chronic alcohol intake by restoring their functional activity and stress resistance.

Keywords:  astaxanthin; cardiac mitochondria; chronic alcohol intoxication; mitochondrial dysfunction; mitochondrial fission/fusion; mitophagy

DOI:  https://doi.org/10.18097/PBMCR1617
Mol Med Rep. 2026 May;pii: 147. [Epub ahead of print]33(5):

Veronicastrum sibiricum (L.) Pennell extract alleviates inflammation‑induced muscle atrophy through NLRP3 inflammasome regulation and mitochondrial function restoration.

Eunhye Lee, Minjeong Kwon, Ju-Ock Nam.

  Inflammation‑induced sarcopenia pathophysiology is associated with the NLR family pyrin domain containing 3 (NLRP3) inflammasome, and the concomitant mitochondrial dysfunction is a notable symptom that requires control. The Veronicastrum genus has anti‑inflammatory and antioxidant effects; however, to the best of our knowledge, the specific mechanism associated with the seed activities and the effects on muscle have not been elucidated. Therefore, the present study aimed to evaluate how Veronicastrum sibiricum (L.) Pennell seed extract (VSE) can improve muscle strength under conditions of inflammation‑induced muscle atrophy. The sepsis‑induced sarcopenia model was used to elucidate the muscle atrophy‑attenuating effects of VSE in vitro and in vivo. The mechanism of action of VSE was revealed in vitro by assessing the expression of associated factors at the mRNA and protein levels. Mice were administered lipopolysaccharide (LPS) intraperitoneally in vivo to mimic the disease state of sepsis. H&E staining was carried out to examine the cross‑section of muscle tissues. ELISAs were carried out to investigate cytokine expression in mouse serum. Significant muscle atrophy was observed under the LPS‑induced inflammatory state, whereas VSE decreased the expression levels of the muscle atrophy markers muscle‑specific RING finger protein 1 and muscle atrophy F‑box protein. Furthermore, VSE reduced the expression levels of factors involved in the NLRP3 inflammasome, such as NLRP3, GSDMD, cleaved‑GSDMD, caspase‑1 and cleaved‑caspase‑1. Additionally, the present study revealed that VSE improved mitochondrial function.

Keywords:  NLRP3; inflammasome; inflammation‑induced muscle atrophy; mtROS; sepsis; translocation

DOI:  https://doi.org/10.3892/mmr.2026.13857
Molecules. 2026 Mar 22. pii: 1050. [Epub ahead of print]31(6):

Effect of (-)-Epicatechin on Mitochondrial Homeostasis in Skeletal Muscle of Female Obese Rats.

Elena de la C Herrera-Cogco, Socorro Herrera-Meza, Yuridia Martínez-Meza, Javier Pérez-Durán, Guillermo Ceballos, Enrique Méndez-Bolaina, Nayelli Nájera.

   BACKGROUND: Main risk factors associated with the development of sarcopenia (coexistence of muscle mass loss and dysfunction) are a sedentary lifestyle coupled with obesity. Associated mitochondrial dysfunction leads to energy deficits and perturbations in the balance between protein synthesis and degradation, thereby triggering muscle dysfunction or atrophy. Aside from exercise, which is challenging to implement and maintain, particularly in women, treatments for diminishing sarcopenia are scarce. The objective of the present study was to evaluate the effect of the flavanol (-)-epicatechin (EC) in a hypercaloric diet-induced obese female rat model. Muscle strength and endurance, as well as relative mitochondrial DNA content in skeletal muscle, were assessed.
METHODS: Female rats were fed a hypercaloric diet to induce obesity, as evidenced by increases in body weight, Lee index, and lipid profile alterations, and by abdominal fat accumulation, and to promote a sarcopenic phenotype. Functional tests of grip strength and mobility (treadmill) were performed. Mitochondrial relative content was evaluated by measuring the ratio of mtDNA/nuclear DNA, and the expression of genes related to mitochondrial biogenesis (Pgc1-α, Tfam), fusion (Mfn1 and Opa1), fission (Drp1 and Fis1), and mitophagy (Pink1 and Pkn), and function; citrate synthase and Ucp3 were also evaluated.
RESULTS: A significant decrease in mobility and strength was observed in obese female rats, accompanied by reduced mitochondrial numbers, activity, and dynamics, but not by changes in muscle size or weight. Treatment with EC induced mitochondrial biogenesis and positive changes in mitochondrial dynamics (fission and fusion) and activity, as measured indirectly by changes in citrate synthase and Ucp3 expression.
DISCUSSION: Results reinforce the potential of EC as a modulator of mitochondrial function in dysfunctional conditions associated with obesity, thereby attenuating the mechanisms underlying sarcopenia.

Keywords:  epicatechin; females; obesity; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3390/molecules31061050
Nutrients. 2026 Mar 11. pii: 889. [Epub ahead of print]18(6):

Maternal Immune Activation Leads to Mitochondrial Dysfunction and a Social Deficit in Offspring That Is Reversed by Nicotinamide Riboside.

Arkadiy A Bazhin, Ekaterina S Solodnikova, Daniel A San Miguel, Robert Dantzer, Yezaz A Ghouri, Jennifer J Donegan, Elena Goun.

  Background: Maternal immune activation (MIA) during pregnancy is a known risk factor for several neurodevelopmental and psychiatric disorders, including schizophrenia. In rodent models, MIA is commonly induced using polyinosinic/polycytidylic acid (Poly(I/C)), a viral mimetic that activates Toll-like receptor 3 (TLR3) signaling and elicits an inflammatory response in both the dam and the fetuses. MIA results in various behavioral abnormalities in offspring, including deficits in social interaction. Recent studies have shown that MIA decreases the ability to maintain mitochondrial membrane potential (ΔΨm), the electrical component of the electrochemical gradient required for ATP production and alters mitochondrial protein expression in brain tissue isolated from adult offspring. Methods: In the present study, we monitor ΔΨm non-invasively in vivo using a previously published bioluminescence probe in juvenile and adult MIA offspring. We then investigated gene expression in the medial prefrontal cortex of MIA offspring by analyzing a previously published RNA sequencing dataset in combination with MitoCarta3.0, a comprehensive inventory of genes involved in mitochondrial function. Finally, we tested the hypothesis that this mitochondrial dysfunction contributes to the behavioral deficits observed in MIA offspring. Results: We have observed impaired ΔΨm maintenance in juvenile MIA offspring that persists into adulthood. Also, we found that MIA alters the expression of many genes associated with mitochondrial energy production. We demonstrated that nicotinamide riboside, a precursor to NAD+ known to restore ΔΨm, significantly attenuates MIA-induced social interaction deficits. Conclusions: Together, these findings highlight mitochondrial function as a promising therapeutic target for symptoms associated with schizophrenia and support the potential for drug discovery aimed at enhancing mitochondrial health.

Keywords:  maternal immune activation; mitochondria; nicotinamide riboside; prefrontal cortex; social interaction

DOI:  https://doi.org/10.3390/nu18060889
Biology (Basel). 2026 Mar 20. pii: 503. [Epub ahead of print]15(6):

New Insights into Potential Anti-Aging Effects of a Dietary Supplement from Chlorella Growth Factor and γ-PGA in Aged SAMP8 Mice.

Ming-Yu Chou, Shih-An Yang, Po-Hsien Li, Tzu-Chien Kao, Shih-Yi Wang, Po-Hsun Cheng, Ching-Hsin Chi, Shu-Fen Cheng, Yue-Ching Wong, Ming-Fu Wang.

  Aging is closely associated with oxidative stress, which contributes to functional decline and increased vulnerability to neurodegenerative diseases. Natural antioxidants, such as Chlorella Growth Factor (CGF) and γ-polyglutamic acid (γ-PGA), possess antioxidant and anti-aging properties; however, their combined effects remain unknown. This study investigated the potential synergistic effects of CGF and γ-PGA supplementation in senescence-accelerated mouse-prone 8 (SAMP8) mice, a model characterized by early cognitive decline, locomotor deficits, and elevated oxidative DNA damage. Three-month-old male SAMP8 mice (n = 40) were divided into four groups: control, CGF (49.2 mg/kg BW/day), γ-PGA (20.5 mg/kg BW/day), and combined CGF + γ-PGA (69.7 mg/kg BW/day), and were treated for 13 weeks. Behavioral and physiological assessments included locomotor activity, aging index, and cognitive function (passive and active avoidance tests). Biochemical analysis focused on brain 8-hydroxy-2'-deoxyguanosine (8-OHDG) as a biomarker of oxidative DNA damage. Supplementation with CGF and γ-PGA, particularly in combination, significantly improved locomotor activity, aging scores, and cognitive functions. Notably, the combined treatment yielded the greatest reduction in brain 8-OHDG levels. These findings indicate that CGF and γ-PGA, when administered together, exert enhanced protective effects against functional and molecular aging. In conclusion, long-term supplementation with CGF and γ-PGA protects against aging-related decline in SAMP8 mice. This study highlights the potential of CGF and γ-PGA as safe, natural candidates for the development of functional foods or nutraceuticals aimed at promoting healthy aging and reducing oxidative stress-associated disorders.

Keywords:  SAMP8; anti-aging; chlorella growth factor; γ-PGA

DOI:  https://doi.org/10.3390/biology15060503
Life (Basel). 2026 Mar 02. pii: 401. [Epub ahead of print]16(3):

Overview of Aging, Skin Health, Estrogen, Menopause and HRT.

Edwin D Lephart, Zoe D Draelos.

  While skin aging is inevitable, healthy habits, sun protection, skincare, and medical interventions can slow visible skin changes; estrogen is also crucial. In 2002, the Women's Health Initiative (WHI) results contributed to the subsequent trend toward fear and avoidance of hormone replacement therapy (HRT). Since 2002, the WHI results have been re-evaluated and caused the US FDA to announce "the removal of the misleading FDA warnings on HRT", stating that "estrogen is a key hormone for women's health where every single part of a woman's body depends on estrogen to operate at its best-including the brain, bones, heart, and muscles". This overview explores this transformation of scientific information/perspective on HRT via (a) aging and skin health; (b) the importance and changes in estrogen in women with a focus on dermal parameters; (c) provides a brief review of the WHI result, impact, and current status of this report; (d) explores the "timing hypothesis" for HRT interventions; and (e) proposes that HRT might be considered not only for symptomatic women but also for esthetic treatment in perimenopause and menopause patients. The latest reviews support a recent large-scale systematic review and meta-analysis on skin parameters, which suggests that HRT may have a place in esthetic treatment. However, beyond esthetic benefits, the positive implications of HRT on several other health parameters in women during aging are briefly presented. Of course, hormonal and numerous other treatments require a review of the risks/benefits and their discussion among the patient and medical professionals to determine the most effective interventions for treating hormone-related skin changes, but this shift in perspective warrants further investigation and validation.

Keywords:  HTR; MHT; aging; estrogen; menopause; perimenopause; skin

DOI:  https://doi.org/10.3390/life16030401
Biomedicines. 2026 Mar 16. pii: 682. [Epub ahead of print]14(3):

Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases.

Salvatore Nesci.

  Neurodegenerative diseases share a mitochondrial-immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q (CoQ) junction: catalytic defects, misassembly, or reverse electron transport over-reduce the CoQ pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII2, CIII2-CIVn, or CI-CIII2-CIVn) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and Huntington's models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes.

Keywords:  inflammation; mitochondrial dysfunction; oxidative stress; respiratory complexes

DOI:  https://doi.org/10.3390/biomedicines14030682
Int J Mol Sci. 2026 Mar 12. pii: 2599. [Epub ahead of print]27(6):

Restoring Mitochondrial Homeostasis: Therapeutic Strategies for Metabolic Dysfunction-Associated Fatty Liver Disease.

José S Morgado, Ivo F Machado, Anabela P Rolo, Carlos M Palmeira.

  Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disorder worldwide, driven by metabolic dysfunction, excessive lipid accumulation, and progressive hepatocellular injury. A growing body of evidence identifies mitochondrial impairment as a central contributor to MAFLD pathogenesis and disease progression. Reduced oxidative capacity, elevated reactive oxygen species, and accumulation of dysfunctional mitochondria collectively exacerbate steatosis, inflammation, and metabolic inflexibility. In recent years, therapeutic strategies aimed at restoring mitochondrial homeostasis have gained considerable attention, with particular focus on agents capable of inducing mitochondrial biogenesis through pathways involving PGC-1α, AMPK, SIRT1, and mTOR. This review synthesizes current knowledge on mitochondrial dysfunction in MAFLD and highlights emerging compounds that ameliorate disease phenotypes by enhancing mitochondrial biogenesis. By examining their mechanisms of action and preclinical efficacy, we underscore the therapeutic potential of targeting mitochondrial quality-control pathways, mainly mitochondrial biogenesis, as a promising avenue for mitigating MAFLD progression.

Keywords:  MAFLD; biogenesis; dynamics; mitochondria; mitophagy

DOI:  https://doi.org/10.3390/ijms27062599
Biogerontology. 2026 Mar 22. pii: 73. [Epub ahead of print]27(2):

Epigallocatechin gallate mitigates oxidative stress-induced transient senescence and injury by preserving mitochondrial integrity and restoring redox-inflammatory homeostasis in murine macrophages.

Ravi Kumar, Abhishek Goel, Rohit Sharma, Yogendra Padwad.

  Macrophages serve as major defenders against pathogens, playing a crucial role in the initiation and modulation of immune responses. Age-related decline in macrophage functions is attributed to a complex network of cellular senescence and immunosenescence. The onset of cellular senescence is often a consequence of sustained oxidative stress, which is worsened by immunosenescence. Green tea catechin, epigallocatechin gallate (EGCG), has emerged as a promising candidate for promoting healthy aging by reducing cellular senescence and enhancing cytoprotective responses. However, its effectiveness in preventing oxidative stress-induced senescence and dysfunction in immune cells, particularly macrophages, remains less characterized. The present study explored the anti-senescence and cytoprotective effects of EGCG in the wake of oxidative stress-induced premature senescence in RAW 264.7 macrophages. Oxidative stress was induced in cells using repeated exposure to hydrogen peroxide (H2O2), followed by subsequent analyses of the degree of senescence, injury-induced apoptosis, inflammatory activity, mitochondrial stability, and alterations in macrophage functions. Senescence-associated markers p16, p21, and senescence-associated β-galactosidase were significantly up-regulated in response to prolonged oxidative stress, along with a concomitant rise in apoptosis, likely driven by oxidative damage. These alterations were accompanied by diminished phagocytosis, increased mitochondrial superoxide levels, depolarization of mitochondrial membrane potential, and augmented inflammatory responses driven by enhanced activation of nuclear factor-κB. Co-treatment with EGCG significantly mitigated these detrimental effects, reversing senescence-associated alterations and restoring both redox equilibrium and macrophage functionality. This study highlights the cytoprotective potential of EGCG in maintaining macrophage functional integrity under conditions of oxidative stress-induced senescence and cellular injury.

Keywords:  Apoptosis; EGCG; Macrophage; Oxidative Stress; Phagocytosis; Senescence

DOI:  https://doi.org/10.1007/s10522-026-10419-y
Proc SPIE Int Soc Opt Eng. 2026 Jan;pii: 1385609. [Epub ahead of print]13856

In vitro effects of Taurine on Taxol-induced mitochondrial dysfunction.

Rozhin Penjweini, Katie A Link, Jasmine Su, Dan L Sackett, Jay R Knutson.

  Mitochondria are intricately involved with essential functions in normal and cancer cells and, as such, mitochondria are a natural target for chemotherapeutic drugs. We previously showed that Taxol, even at low doses, adversely effects mitochondrial energetics, function, and intracellular migration patterns. We observed (by multiple optical means) suppression of oxidative phosphorylation (OXPHOS) and decreased adenosine triphosphate (ATP) production, increased reactive oxygen species (ROS) generation (both immediately and integrated over time), increased mitotic fraction, and the release of LDH and cytochrome c in Taxol-treated cells. Moreover, we observed more random (less ordered) motion of the mitochondria as well as altered mitochondrial morphology and lessened association with microtubules. Recently, several in vitro and in vivo studies have demonstrated the beneficial effects of taurine (a very abundant non-protein amino acid in most tissues, particularly in the heart, retina, brain and muscles) in maintaining mitochondrial functions. Intracellular concentrations of taurine in tissues range from 5-50 mM, but most culture conditions have little or no taurine. In this study, we show how taurine supplementation alters the impact of Taxol treatment in a variety of cell lines with varying glycolytic profiles. A549 (non-small cell lung epithelial cancer cell line), A549-ρ 0 (mitochondrial DNA-depleted derivative of A549), BEAS-2B (a non-cancer cell line derived from normal bronchial epithelium), as well as T98G (glioblastoma cell line) cells are used in this study.

Keywords:  Metabolism; Mitochondrial function; Taurine; Taxol

DOI:  https://doi.org/10.1117/12.3091945
Trends Endocrinol Metab. 2026 Mar 25. pii: S1043-2760(25)00267-X. [Epub ahead of print]

Mitochondrial NADP(H) integrates redox and metabolism.

Ren Zhang, Kezhong Zhang.

  The compartmentalization of NAD(H) and NADP(H) is fundamental to cellular metabolism, enabling precise coordination of redox balance, biosynthetic reactions, and energy homeostasis. Within mitochondria, NADP(H) has long been viewed as a redox buffer supporting antioxidant defense and reductive biosynthesis. Emerging evidence, however, reveals that mitochondrial NADP(H) also drives oxidative metabolism and metabolic flexibility. Loss of the mitochondrial NAD kinase, which phosphorylates NAD(H) to generate mitochondrial NADP(H), disrupts NADP(H)-dependent pathways that sustain oxidative metabolism and systemic energy balance. These advances reposition mitochondrial NADP(H) as an integrative regulator that links redox homeostasis with energy metabolism across cellular and systemic levels, with broad implications for metabolic disease.

Keywords:  NAD(H); NADK2; NADP(H); fatty acid oxidation; mitochondria; redox

DOI:  https://doi.org/10.1016/j.tem.2025.12.003
Clin Nutr. 2026 Mar 14. pii: S0261-5614(26)00052-X. [Epub ahead of print]60 106625

Effect of caloric restriction on organ-specific biological aging in a randomized clinical trial.

Yucan Li, Xinming Xu, Raghav Sehgal, Xinyi He, Yi Zheng, Xingdong Chen, Kelin Xu.

   BACKGROUND AND AIMS: Caloric restriction (CR) has demonstrated benefits in improving individual biomarkers and longevity, but its organ-specific systemic effects remain unclear. We aimed to quantify the effects of long-term CR on longitudinal changes in organ-specific biological age across multiple physiological systems.
METHODS: In the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 randomized controlled trial, a subset of 185 participants (120 CR, 65 ad libitum) with available organ-specific biomarkers at baseline and at least one follow-up assessment at 12 or 24 months was analyzed. Participants were assigned to 2 years of sustained CR or an ad libitum diet. Five organ-specific biological ages (cardiovascular, immune, kidney, liver, metabolic) and the whole body age were assessed at both time points. Intention-to-treat, dose-response, and treatment-on-the-treated analyses were performed to evaluate changes in these biological age measures over time.
RESULTS: CR mitigated organ-specific increases in biological age relative to the ad libitum diet, with the most robust effects in metabolic system (-0.54 years at 12 months, P = 1.26 × 10-5; -0.63 years at 24 months, P = 3.02 × 10-7) and cardiovascular system (-0.82, P = 9.55 × 10-5; -1.00, P = 1.96 × 10-6), followed by whole body (-1.00, P = 2.53 × 10-3; -1.27, P = 1.20 × 10-4) and immune system (-0.65, P = 1.83 × 10-3; -0.62, P = 2.92 × 10-3); liver age increase was modestly slowed only at 24 months (-0.54, P = 8.30 × 10-3), while kidney age remained unaffected. Participants with a higher dose of CR (≥12.4%) showed a more pronounced attenuation of increases in metabolic and whole body age. Adherence analysis further showed that achieving the 20% CR target led to significant declines in multiple biological ages.
CONCLUSION: CR exerts heterogeneous effects on biological aging across organ systems, with the most pronounced responses in metabolic, cardiovascular, immune, and whole body systems. These findings support organ-specific biological ages as sensitive surrogate endpoints for detecting early responses to anti-aging interventions and as practical tools for monitoring or targeting organ-specific aging in future efforts.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00427193 (registered January 25, 2007; URL: https://clinicaltrials.gov/study/NCT00427193).

Keywords:  Aging; Biological age; CALERIE™ phase 2; Caloric restriction; Organ-specific biological age

DOI:  https://doi.org/10.1016/j.clnu.2026.106625
Biomolecules. 2026 Mar 09. pii: 403. [Epub ahead of print]16(3):

Rosmarinic Acid Targets AKR1B1 to Ameliorate Atherosclerosis via Vascular Endothelial Cell Energy Metabolism Regulation.

Taoli Sun, Quanye Luo, Tingting Liu, Xuzhen Lv, Limei Lin, Duanfang Liao, Qinhui Tuo, Wen Chen.

  Atherosclerosis (AS), a chronic cardiovascular disease, originates from endothelial dysfunction, a process closely linked to cellular energy metabolism. While rosmarinic acid (RA) exhibits protective cardiovascular effects, its precise mechanism against AS remains undefined. This study demonstrates that RA alleviates AS in ApoE-/- mice, as evidenced by reduced aortic plaques, enhanced CD31 expression, and improved serum NO and ET-levels. Integrating network pharmacology and experimental validation, we identified Aldo-keto reductase family 1 member B1 (AKR1B1) as a direct functional target of RA. Mechanistically, RA downregulated AKR1B1, thereby activating the SIRT3/PFKFB3 axis. In Ox-LDL-induced HUVECs, RA enhanced viability, reduced ROS, and boosted energy metabolism, indicated by elevated ECAR, OCR, and levels of G-6-P, F-6-P, and ATP. Crucially, RA rescued endothelial injury induced by AKR1B1 overexpression via this pathway. Our findings establish that RA protects against AS by directly targeting AKR1B1 to restore endothelial energy homeostasis through the AKR1B1/SIRT3/PFKFB3 signaling axis, offering a novel therapeutic strategy.

Keywords:  AKR1B1; atherosclerosis; endothelial cells; energy metabolism; rosmarinic acid

DOI:  https://doi.org/10.3390/biom16030403
World J Exp Med. 2026 Mar 20. 16(1): 113259

Renin-angiotensin system blockade attenuates brain mitochondrial dysfunction, oxidative stress, and neuroinflammation associated with hypertension, metabolic disorders, and aging.

Sebastián García Menéndez, Felipe Inserra, Elena Mv de Cavanagh, Leon Ferder, Walter Manucha.

  Although aging is an inherent part of life, it represents a process of progressive dysfunction rather than a fixed biological outcome. Consequently, highly prevalent conditions such as cardiorenal-metabolic syndrome-which encompasses obesity, hypertension (HTN), and metabolic disorders-can accelerate age-related changes. The renin-angiotensin system (RAS) plays a critical role in pathophysiology and affects multiple organs, including the brain. The central nervous system contains both RAS branches: The ACE/Ang II/AT1 and AT2 receptor axis, as well as the ACE2/Ang-(1-7)/Mas receptor axis. Neuroinflammation is a chronic process characterized by glial cell activation triggered by increased production of reactive oxygen and nitrogen species, resulting in oxidative stress. Mitochondria are the primary cellular sites where these processes occur. Under conditions such as metabolic disorders, obesity, HTN, and aging, these reactions are markedly accelerated. Associated mechanisms include insulin resistance, elevated levels of advanced glycation end-products, and disruption of the blood-brain barrier. The consequences of these alterations may include brain dysfunction, cognitive decline, Parkinson's disease, and neurodegenerative conditions such as Alzheimer's disease. This review focuses on the primary effects of therapeutic interventions on mitochondrial function, with particular attention to the modulation of oxidative stress, chronic neuroinflammation, and glial dysregulation. We highlight the strategic use of angiotensin receptor blockers and ACE2 activators as promising tools that may redefine the prevention and treatment of vascular dementia and other neurodegenerative diseases of inflammatory origin.

Keywords:  Aging; Central nervous system inflammation; Hypertension; Metabolic disorders; Mitochondria; Neurodegeneration; Oxidative stress; Renin-angiotensin system blockade

DOI:  https://doi.org/10.5493/wjem.v16.i1.113259
Biomolecules. 2026 03 20. pii: 470. [Epub ahead of print]16(3):

Oxidative Stress in Diabetic Cardiomyopathy: Molecular Mechanisms and Emerging Therapeutic Targets.

Umberto Capece, Davide Nilo, Cassandra Morciano, Roberto Nilo, Serenella Spiezia, Marta Chiara Sircana, Vincenzo Russo, Marco Alfonso Perrone, Leonilde Bonfrate, Carlo Acierno, Ferdinando Carlo Sasso, Alfredo Caturano.

  Diabetic cardiomyopathy (DCM) is a distinct myocardial disorder that develops independently of coronary artery disease and hypertension and represents a major contributor to heart failure in patients with diabetes. Beyond hemodynamic alterations, DCM is driven by complex molecular mechanisms involving metabolic dysregulation, mitochondrial dysfunction, inflammation, and fibrotic remodeling. Increasing evidence identifies oxidative stress as a central integrative process linking these pathogenic pathways in the diabetic heart. Chronic hyperglycemia, insulin resistance, and altered substrate utilization promote excessive generation of reactive oxygen species, overwhelming endogenous antioxidant defenses and disrupting myocardial redox homeostasis. Oxidative stress induces direct damage to lipids, proteins, and DNA while simultaneously activating redox-sensitive signaling pathways that amplify inflammation, endothelial dysfunction, cardiomyocyte apoptosis, and fibrosis. In addition, epicardial and visceral adipose tissue have emerged as active contributors to myocardial oxidative stress through paracrine and systemic mechanisms, reinforcing inflammatory and fibrotic crosstalk. This review provides a comprehensive overview of the molecular sources and targets of oxidative damage in DCM, examines the impairment of antioxidant defense systems, and discusses emerging therapeutic strategies aimed at restoring redox balance.

Keywords:  antioxidant defense; diabetes mellitus; diabetic cardiomyopathy; epicardial adipose tissue; heart failure; mitochondrial dysfunction; myocardial fibrosis; oxidative stress; reactive oxygen species; redox signaling

DOI:  https://doi.org/10.3390/biom16030470
medRxiv. 2026 Mar 19. pii: 2026.03.12.26347263. [Epub ahead of print]

Multi-omics liquid biopsy identifies mitochondrial dysfunction in geographic atrophy and supports the longevity-associated metabolite α-ketoglutarate as a therapeutic strategy.

Tsai-Chu Yeh, Gabriel Velez, Architesh Prasad, Soo Hyeon Lee, Ditte K Rasmussen, Aarushi Kumar, Madhumeeta Chadha, Mohamed Ziad Dabaja, Aneal M Singh, Steven Sanislo, Stephen Smith, Prithvi Mryuthyunjaya, Artis Montague, Alexander G Bassuk, David Almeida, Antoine Dufour, Vinit B Mahajan.

Background: Mitochondrial dysfunction is an emerging metabolic hallmark of age-related diseases, yet tools to directly profile mitochondrial pathways and test metabolic interventions in the living human eye remain limited. Multi-omics ocular liquid biopsy enables real-time proteomic and metabolomic profiling of the intraocular microenvironment, complementing systemic biomarkers and imaging surrogates. Here, we used this approach to define mitochondrial and tricarboxylic acid (TCA) cycle dysregulation in geographic atrophy (GA) and to assess whether oral α-ketoglutarate (α-KG) supplementation can modulate mitochondrial metabolites within the eye.
Methods: Mitochondrial and TCA cycle-related proteins were profiled in aqueous humor (AH) samples from patients with GA using DNA-aptamer-based proteomics. In a phase 0 study, a second cohort undergoing sequential cataract surgery provided paired AH samples collected at first-eye surgery and at second-eye surgery after interim α-KG supplementation. These samples underwent targeted metabolomic profiling using hydrophilic interaction liquid chromatography coupled with mass spectrometry.
Results: In GA, 64 mitochondrial proteins were differentially expressed, including coordinated TCA-cycle deficiencies marked by reduced expression of enzymes regulating TCA entry and flux, including PDHB and DLST. In the phase 0 cohort, oral α-KG supplementation significantly increased intraocular α-KG levels and the α-KG-to-succinate ratio (P < 0.05), with coordinated shifts across TCA intermediates consistent with enhanced TCA cycle flux.
Conclusions: AH proteomics demonstrated mitochondrial pathway depletion in GA, consistent with reduced oxidative bioenergetic capacity. AH metabolomics provided first-in-human in vivo evidence that systemic α-KG supplementation can modify intraocular metabolites and may enhance intraocular energy metabolism. These findings support ocular liquid biopsy as a precision-health framework for per-patient biomarker-guided metabolic trials in GA.
Plain Language Summary: Geographic atrophy (GA) is an advanced form of age-related macular degeneration and a major cause of irreversible vision loss. To better understand the biology of GA, we studied proteins and small molecules in aqueous humor, the fluid inside the eye. We found that eyes with GA showed clear signs of mitochondrial dysfunction, including disruptions in the tricarboxylic acid (TCA) cycle, a key pathway for energy production. This suggests that impaired cellular metabolism is an important feature of the disease. We then tested whether oral α-ketoglutarate (α-KG), a metabolite involved in mitochondrial function and previously shown to have life-extending effects in preclinical studies, could alter these metabolic pathways in the human eye. We found that α-KG supplementation not only increased intraocular α-KG levels but changed metabolic markers linked to mitochondrial activity, providing the first direct evidence that oral supplementation can reach the eye and measurably modify metabolism inside the living human eye. Together, these findings show that liquid biopsy can provide a direct molecular snapshot of the living human eye and may help accelerate the development of biomarker-guided therapies for ocular diseases.
Key Points: Questions: What specific mitochondrial and TCA-cycle dysfunctions occur in the aqueous humor (AH) of patients with geographic atrophy (GA), and can oral α-ketoglutarate (α-KG) supplementation measurably remodel these metabolic pathways in the living human eye?Findings: AH proteomics in GA patients revealed significant mitochondrial disruption and a coordinated depletion of TCA-cycle enzymes. In a paired-eye interventional metabolomics study, oral α-KG significantly increased intraocular α-KG levels and the α-KG-to-succinate ratio, proving that systemic therapy can drive measurable metabolic modulation within the human eye.Meaning: Multi-omics liquid biopsy provides a direct, eye-specific readout of mitochondrial metabolism in GA and offers early human proof-of-concept that a systemic metabolic therapy can successfully reach and modify intraocular pathways, paving the way for biomarker-guided clinical trials in AMD.

DOI: https://doi.org/10.64898/2026.03.12.26347263
Cells. 2026 Mar 16. pii: 529. [Epub ahead of print]15(6):

Estrogen, Epigenetics, and Cardiometabolic Health: Mechanisms and Therapeutic Strategies in Postmenopausal Women.

Ailene Edwards, Pranjal Singh, Vyan Shah, Vivek Chander, Sumita Mishra.

  The loss of estrogen following menopause is associated with a marked increase in cardiometabolic risk, accompanied by adverse changes in lipid metabolism, insulin sensitivity, vascular function, and systemic inflammatory tone. Emerging evidence suggests that estrogen signaling interacts with chromatin regulatory mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, across multiple metabolic tissues. In this review, we examine current evidence linking estrogen receptor signaling to epigenetic modulation in cardiovascular, hepatic, adipose, vascular, and immune systems. We propose that epigenetic remodeling represents a plausible and testable mechanistic framework connecting estrogen depletion to cardiometabolic disease progression, while acknowledging that much of the mechanistic evidence derives from preclinical and in vitro systems and that direct longitudinal validation in human cardiovascular tissues remains limited. We further explore how this framework may contribute to understanding the "estrogen paradox" and the heterogeneous outcomes of hormone replacement therapy (HRT), particularly within the context of the timing hypothesis. Finally, we evaluate pharmacologic and lifestyle interventions, including structured exercise, dietary modulation, and cardiometabolic therapeutics, through the lens of potential epigenetic influence. Clarifying tissue-specific and immune-integrated chromatin responses to estrogen loss will be essential for advancing precision strategies aimed at improving cardiometabolic health in postmenopausal women.

Keywords:  cardiometabolic health; epigenetic regulation; estrogen signaling; hormone replacement therapy; postmenopausal women

DOI:  https://doi.org/10.3390/cells15060529
Front Genet. 2026 ;17 1733593

Age at natural menopause, reproductive lifespan and Alzheimer's disease in females: is APOE ε4 the missing link?

Francesco Bruno, Patrizia Spadafora, Paolo Abondio, Antonio Qualtieri, Ersilia Paparazzo, Mirella Aurora Aceto, Ida Veltri, Selene De Benedittis, Beatrice Maria Greco, Annamaria Cerantonio, Luigi Citrigno, Gemma Di Palma, Olivier Gallo, Giuseppe Passarino, Alberto Montesanto, Francesca Cavalcanti.

   Background: The apolipoprotein E (APOE) gene represents the strongest genetic determinant of sporadic Alzheimer's disease (AD), yet its interaction with sex-specific endocrine factors remains poorly understood. Lifetime estrogen exposure, estimated through reproductive lifespan, may modulate neurodegenerative risk, but findings are inconsistent. Previous studies have examined reproductive factors and APOE interactions in relation to cognitive outcomes, but dose-dependent effects across all APOE alleles (ε2, ε3, ε4) in clinically diagnosed AD patients remain underexplored. This study investigates the joint effects of reproductive lifespan, age at natural menopause (ANM), and APOE genotype on AD risk in females.
Methods: A total of 396 female participants (103 with AD, 293 cognitively healthy controls) were retrospectively analyzed. Demographic, clinical, and reproductive data were extracted from medical records. APOE genotyping was performed by sequencing rs429358 and rs7412 polymorphisms. Logistic regression models tested associations between ANM, reproductive lifespan, and AD diagnosis, adjusting for education, body mass index (BMI), smoking, diabetes, hypertension, and number of children. Moderation analyses assessed the interaction between reproductive variables and APOE ε2, ε3, and ε4 alleles, and were followed by simple slope analyses to clarify the direction of significant effects.
Results: AD females exhibited later ANM (50.3 ± 4.4 vs. 48.3 ± 6.2 years; p = 0.004) and longer reproductive lifespan (37.4 ± 4.4 vs. 35.4 ± 6.0 years; p = 0.005) than controls. Both ANM and reproductive lifespan independently predicted higher AD risk (adjusted OR = 1.07, 95% CI = 1.02-1.12, p < 0.01). These effects were amplified by APOE ε4 and attenuated by ε3, while ε2 showed no influence. Simple slope analyses confirmed an allele-specific gradient, with the association between later menopause and AD risk steepest in ε4 carriers and absent in high ε3 carriers.
Conclusion: This work provides novel evidence that extended ovarian function is associated with increased AD vulnerability in females, particularly among APOE ε4 carriers. These findings highlight a dose-dependent, genotype-specific interaction between reproductive aging and neurodegeneration, suggesting APOE as a molecular bridge linking estrogenic exposure and AD risk.

Keywords:  APOE genotype; Alzheimer’s disease; age at natural menopause; dementia risk; estrogen exposure; females; reproductive lifespan; sex differences

DOI:  https://doi.org/10.3389/fgene.2026.1733593
Cells. 2026 Mar 12. pii: 507. [Epub ahead of print]15(6):

Antiaging Properties of the Klotho Protein.

Gérald J Prud'homme, Qinghua Wang.

  Mice genetically deficient in α-Klotho (henceforth Klotho) display accelerated aging. The mechanisms are only partially understood. Here, we examine how these relate to the 12 hallmarks of aging consisting of chronic inflammation (inflammaging), as well as damaging changes to the genome (DNA damage), telomeres, epigenetic regulation, proteostasis, nutrient sensing, mitochondria, stem cells, intercellular communication, macroautophagy, microbiome and cell replication (senescence). Inflammation aggravates the other hallmarks. We report that Klotho counters the majority of these hallmarks. It ameliorates mitochondrial function and reduces reactive oxygen species (ROS), telomere attrition and cellular senescence. It protects against inflammation by inhibiting NF-κB and the NLRP3 inflammasome. This applies to inflammaging, several chronic inflammatory diseases, atherosclerosis, diabetes, and Alzheimer's disease. Klotho also counters some aging factors outside of these hallmarks. Low Klotho (often due to kidney disease) produces hyperphosphatemia, which injures cells (especially endothelial cells) and promotes aging. Another key action of Klotho is the mitigation of fibrosis in major organs (kidneys, heart, lungs and other), mainly through the inhibition of TGF-β and Wnt. Klotho also protects against muscle atrophy (sarcopenia)-a common feature of aging-and exhibits anti-cancer activity. We describe several factors that increase Klotho, and are potentially amenable to clinical therapy.

Keywords:  Alzheimer; FGF23; Klotho; NF-κB; TGF-β; aging; cancer; fibrosis; hallmarks; inflammaging

DOI:  https://doi.org/10.3390/cells15060507
BMC Complement Med Ther. 2026 Mar 24.

Curcuminoid supplementation for vasomotor symptoms in postmenopausal women: a pilot, randomized, double-blind, placebo-controlled proof-of-concept trial.

Jinjutha Buntoonprayuk, Kitti Chattrakulchai, Orawin Vallibhakara, Pimpun Prasanchit, Sakda Arj-Ong Vallibhakara.



Keywords:  Curcuminoids; Hot flashes; Menopause; Pilot study; Quality of life; Randomized controlled trial; Vasomotor symptoms

DOI:  https://doi.org/10.1186/s12906-026-05358-7
Int J Gynaecol Obstet. 2026 Mar 27.

Cognition in menopausal women.

Suvarna Khadilkar, Jharna Mahajan Bhanushali, Anuradha P Mahto, Satish Khadilkar.

  Cognitive health in postmenopausal women is significantly affected by hormonal shifts, especially the drop in estrogen levels. This review explores the intricate relationship between menopause and cognitive functions across six domains: perception, attention, memory, language, executive functioning, and motor skills. The hormonal changes associated with menopause are linked to impairments in memory, attention, executive functioning, and social cognition, with verbal and working memory showing the most significant decline. Neuropsychiatric issues such as anxiety, mood fluctuations, and "brain fog" might arise, often overlapping with symptoms related to cognitive decline. Screening tools like the Mini-Mental Status Examination and the Montreal Cognitive Assessment assist in the early identification of cognitive decline. This review outlines interventions to preserve cognitive function and emphasizes the timing and advantages of initiating menopausal hormonal therapy during the early menopausal stage. Lifestyle modifications such as adopting a balanced diet, engaging in strength-building activities, and incorporating regular aerobic exercise play a vital role in enhancing cognitive resilience. Addressing modifiable risk factors such as hypertension, obesity, and sedentary behavior is crucial to prevent cognitive decline. Neuroimaging studies can now demonstrate gender-specific brain changes during the preclinical phase of Alzheimer's disease (AD), reinforcing the necessity for early intervention. This review recommends a comprehensive strategy that combines hormonal, dietary, physical, and mental stimulation methods to help postmenopausal women sustain their cognitive health and overall wellness. By raising awareness and advocating for preventive actions, women can face the challenges of menopause with assurance, safeguarding their quality of life and cognitive function.

Keywords:  cognitive decline; menopausal hormonal therapy; menopause; mental health

DOI:  https://doi.org/10.1002/ijgo.70944
FASEB J. 2026 Mar 31. 40(6): e71692

Integrative Insights Into Mitochondrial Dysfunction and Organelle Crosstalk in Diabetic Kidney Disease.

Wanyu Cao, Guoding Cao, Qingtai Meng, Dingfei Li, Jie Zhang, Tianhui Wu, Fengmin Zhang.

  Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease and is driven in large part by early, sustained mitochondrial dysfunction, which promotes metabolic reprogramming, oxidative stress and inflammation that accelerate glomerular and tubular injury. We review recent mechanistic and translational advances linking mitochondrial dysfunction and organelle crosstalk to DKD progression. We synthesize evidence across four interrelated mitochondrial axes-metabolic reprogramming, altered fission-fusion dynamics, defective mitophagy, and mtDNA release-and highlight mitochondria-ER contacts (MAMs) as a nexus integrating redox signaling and calcium homeostasis. Preclinical studies indicate that interventions restoring mitochondrial biogenesis, rebalancing dynamics, enhancing selective mitophagy and preserving mtDNA attenuate glomerular and tubular injury. Clinically, several approved agents (metformin, SGLT2 inhibitors, finerenone, GLP-1RAs) exert renoprotective effects involving mitochondrial pathways; deconvolution of multi-component formulations, targeted antioxidants, metabolic activators and fission inhibitors expand therapeutic options, while organelle-level approaches such as mitochondrial transplantation are emergent. We propose a translational framework that links redox-centered mitochondrial mechanisms to actionable therapeutic strategies for DKD.

Keywords:  diabetic kidney disease; metabolism reprogramming; mitochondrial dynamics; mitochondria‐associated membranes; mitophagy; mtDNA

DOI:  https://doi.org/10.1096/fj.202504735R
Med Sci (Basel). 2026 Mar 06. pii: 124. [Epub ahead of print]14(1):

Modulation of Microbiome-Mitochondria Axis as a Novel Approach for Treatment of Obesity: A Scoping Review.

Andreea Roxana Lista, Ciskey Vanessa Ayala Mosqueda, Rafael Palacios, María José García Mansilla, María Jesús Rodríguez Sojo, Ailec Ho Plágaro, Jorge Garcia Garcia, Julio Gálvez, Alba Rodríguez Nogales, Antonio Jesús Ruiz Malagón, María José Rodríguez Sánchez.

  Background: Obesity is a multifactorial, chronic disease characterised by excessive fat accumulation, low-grade inflammation, and metabolic dysfunction. Emerging evidence suggests that the gut microbiome-mitochondria axis may play a significant role in the pathophysiology of obesity, particularly in regulating energy metabolism, inflammatory responses, and mitochondrial function. However, most mechanistic insights into this axis derive from preclinical animal studies, while human evidence remains limited and largely associative. Mitochondrial dysfunction disrupts cellular energy balance, increases reactive oxygen species production, and may exacerbate gut dysbiosis, further contributing to metabolic disturbances. In addition, factors such as micronutrient deficiencies also play a relevant role in obesity development and progression. Objectives: This review aims to examine the bidirectional interactions between the gut microbiome and mitochondrial systems in obesity, with a focus on the underlying molecular mechanisms and their potential as therapeutic targets. Methods: Evidence from experimental models and clinical studies was analysed to evaluate how modulation of the microbiome-mitochondria axis through probiotics, prebiotics, dietary strategies, and faecal microbiota transplantation influences mitochondrial function, inflammation, and metabolic regulation. Results: Preclinical studies indicate that the gut microbiome modulates mitochondrial activity through the production of bioactive metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan-derived compounds, which influence mitochondrial efficiency, lipid metabolism, and glucose regulation. Dysbiosis reduces these beneficial metabolites, impairing mitochondrial signalling and promoting adiposity and insulin resistance. Interventions targeting this axis have shown potential in restoring metabolic balance, improving mitochondrial function, and mitigating obesity-related complications such as hyperlipidaemia and glucose intolerance. Conclusions: Targeting the microbiome-mitochondria axis represents a promising therapeutic strategy for obesity, with the evidence based largely on preclinical findings. However, further well-designed human studies are required to clarify causality, optimise interventions, assess long-term safety and efficacy, and establish standardised clinical protocols for implementation.

Keywords:  microbiome-mitochondria axis; microbiota; mitochondria; obesity; treatment

DOI:  https://doi.org/10.3390/medsci14010124
Nat Commun. 2026 Mar 25.

Therapeutic potential of dihydronicotinamide riboside (NRH) on obesity and glucose intolerance in mice.

Marie Rumpler, Guido van Mierlo, Kasper T Vinten, Maria Pilar Giner, Stefan Christen, Faisal Hayat, Mikhail V Makarov, Vincent Gardeux, Julie Russeil, Bauke V Schomakers, Laurine van Gijn, Horia Hashimi, Clémence Steiner, Judith Giroud-Gerbetant, Magali Joffraud, Jose Luis Sanchez Garcia, Sofia Moco, Marie E Migaud, Riekelt H Houtkooper, Bart Deplancke, Carles Canto.

NAD+ is a crucial metabolic cofactor whose intracellular levels can influence the progression of multiple metabolic and age-related complications. There is therefore a strong interest in using NAD+ precursors (vitamin B3s) as therapeutic tools, but most current precursors exhibit either poor bioavailability or adverse effects. This study examines the metabolic impact of chronic dietary supplementation with a newly described NAD+ precursor, dihydronicotinamide riboside (NRH), in mice using a comprehensive approach including phenotyping tests, RNA sequencing in different tissues and microbiome analyses. We show that chronic NRH administration at 100 mg/(kg*day) is well tolerated, yet has minimal metabolic effects in mice on a regular diet. However, NRH mitigates high-fat diet-induced metabolic complications when used as a preventive or as a treatment strategy, including improvements in glucose tolerance, increased hepatic expression of lipid catabolism genes and fat redistribution. These results highlight the potential of NRH as a therapeutic agent, although further studies are needed to optimize its use, as higher doses reveal signs of toxicity.

DOI: https://doi.org/10.1038/s41467-026-70965-4
Int J Mol Sci. 2026 Mar 20. pii: 2816. [Epub ahead of print]27(6):

Immunohistochemical Markers of Mitochondrial Electron Transport Chain Instability in Human Brain Regions: A Study of Aging and Alzheimer's Disease.

Tatiana I Baranich, Vladimir S Sukhorukov, Olga V Velts, Dmitry N Voronkov, Ekaterina V Shcherbak, Anna V Egorova, Alexander S Romanenko, Dmitry S Lazarev, Alexander P Raksha, Irina G Charyeva, Alexander N Yatskovskiy, Valeria V Glinkina, Sergey N Illarioshkin.

  Expanding research indicates that oxidative stress, particularly mitochondrial oxidative stress, is one of the key components in the pathogenesis of Alzheimer's disease (AD). Mitochondrial oxidative stress is largely driven by impaired function of electron transport chain (ETC) complexes and their regulators. This study conducted an immunohistochemical analysis of ETC proteins (α-subunit of complex V, subunits MTCO1 and MTCO2 of complex IV) and mitochondrial complex V inhibitor IF-1 in the neurons of the caudate nucleus head, hippocampus, anterior cingulate gyrus, middle frontal gyrus, and inferior parietal lobule using autopsy material from patients with sporadic AD. Comparisons were made with similar brain regions in autopsy material from age-matched elderly patients and young patients. The results revealed a pattern of ETC impairment in AD fundamentally distinct from that observed in physiological aging. Specifically, a hippocampus-specific failure of the adaptive response was identified: unlike other brain regions, compensatory upregulation of ATP synthase does not occur here despite critical reduction in the protective protein IF-1, directly explaining the heightened vulnerability of hippocampal neurons to damage. Our data deepen the understanding of AD pathogenesis by highlighting region-specific mitochondrial defects as promising targets for tailored therapeutic intervention.

Keywords:  Alzheimer’s disease; aging; hippocampus; mitochondria; neuron; oxidative stress

DOI:  https://doi.org/10.3390/ijms27062816
Folia Med (Plovdiv). 2026 Feb 24. 68(1):

Disorders in lipid metabolism, oxidative stress, and antioxidants in patients with amnestic mild cognitive impairment without major depression.

Gallayaporn Nantachai, Michael Maes, Vinh-Long Tran-Chi, Arisara Amrapala, Asara Vasupanrajit, Solaphat Hemrungrojn, Chavit Tunvirachaisakul.

   INTRODUCTION: Amnestic mild cognitive impairment (aMCI) is characterized by changes in lipids and oxidative stress (OS). It is crucial to exclude patients with major depression (MDD) to accurately evaluate these biomarkers in aMCI.

Keywords:  biomarkers depression oxidative and nitrosative stress pathophysiology physiological stress neurocognition

DOI:  https://doi.org/10.3897/folmed.68.e166867
Commun Med (Lond). 2026 Mar 23.

Association of leukocyte mitochondrial DNA copy number and inflammation with mortality among older adults.

I-Chien Wu, Chin-San Liu, Wen-Ling Cheng, Ta-Tsung Lin, Pei-Fen Chen.

BACKGROUND: As the population ages, a rising mortality burden is attributed to deaths in older adults, particularly deaths from inflammation-related chronic non-communicable diseases. The synergism between aging and inflammation remains unclear. Here, we conducted a study to examine whether a decrease in leukocyte mitochondrial DNA copy number (mtDNACN) with age modifies the association between inflammation and the mortality risk in older adults.
METHODS: A total of 3520 adults (mean [SD] age, 67.6 [7.4] years) underwent serial leukocyte mtDNACN and serum high-sensitivity C-reactive protein (hs-CRP) measurements and ascertainment of subsequent all-cause and cardiovascular diseases (CVD) deaths. Mortality risks were estimated using Cox proportional hazards models.
RESULTS: Compared to participants with both a sustainedly low serum hs-CRP and change in leukocyte mtDNACN at the highest tertile, the adjusted hazard ratios (95% CI) of all-cause and CVD death are 3.20 (2.20-4.66) and 5.77 (2.72-12.21) for those with both increased serum hs-CRP and change in leukocyte mtDNACN at the lowest tertile, 1.48 (0.93-2.38) and 1.24 (0.44-3.53) for those with increased serum hs-CRP alone, and 1.29 (0.93-1.81) and 1.44 (0.70-2.97) for those with a change in leukocyte mtDNACN at the lowest tertile alone. The relative excess risks due to interaction (95% CI) for all-cause and CVD death are 1.42 (0.19-2.65) and 4.08 (0.21-7.96). Similar results are observed for those with a change in leukocyte mtDNACN at the middle tertile and in sensitivity analyses.
CONCLUSIONS: We demonstrate super-additive interactions between decreases in leukocyte mtDNACN and inflammation on the mortality risk in older adults, indicating underlying synergism.

DOI: https://doi.org/10.1038/s43856-026-01531-8
Free Radic Biol Med. 2026 Mar 20. pii: S0891-5849(26)00224-8. [Epub ahead of print]250 49-63

Humanin as an evolutionarily tuned mitochondrial peptide: Insights from mammalian oxidative stress diversity.

Mohd Shahzaib, Domenico Aprile, Nicola Alessio, Gianluigi Laporta, Gianfranco Peluso, Giovanni Di Bernardo, Umberto Galderisi.

Humanin is a mitochondrial-derived peptide with cytoprotective properties, but how it has evolved in response to different oxidative stress levels in mammals is not fully understood. This study examines how Humanin sequences have adapted to species-specific metabolic and environmental pressures. We compared the peptide in several mammalian species categorized by their distinct oxidative stress profiles: small mammals such as shrews with high metabolic rates and elevated endogenous ROS production, cetaceans exposed to hypoxia-reoxygenation cycles during deep diving, and long-lived primates facing cumulative oxidative stress over extended lifespans. Using bioinformatic tools, we analyzed physicochemical traits such as structural stability, the aliphatic index, and oxidation susceptibility. We also used protein-protein docking to estimate binding affinities between Humanin variants and key ligands like BAX and FPRL1. Our results show that Humanin is not a static molecule. Species facing high oxidative stress, such as cetaceans and bats, possess variants that are more stable and chemically robust. In contrast, species with high ROS production but lower antioxidant capacity, like the shrew, have less robust versions of the peptide. Simulation data indicate that variants from mammals living in extreme conditions maintain or improve interactions with proteins involved in cell survival. These findings suggest that evolution has tuned Humanin to optimize mitochondrial protection across different physiological contexts. These natural isoforms provide a structural basis for designing new therapeutic analogs to treat oxidative stress-related diseases in humans.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.03.033