bims-mistre 2025-07-06 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–07–06
eighteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Energy imbalance in oPOI ovarian granulosa cells is linked to reduced glucose bioavailability and metabolism.
Dorothy Hodgkin lecture 2024: Insulin regulation of mitochondrial biogenesis and function-Impact of dysregulation of mitochondrial function in diabetes and its complications.
The role of mitochondrial dysfunction in ovarian granulosa cells in polycystic ovary syndrome.
Microplastics induce insulin resistance by causing mitochondrial dysfunction associated with mROS in skeletal muscle in vitro.
Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
SIRT3 as a potential biomarker and therapeutic target for cardiovascular diseases: a meta-analysis of clinical studies.
From hormones to neurodegeneration: how FSH drives Alzheimer's disease.
[NAD+ metabolism as a target for anti-aging].
Differential DNA methylation in blood in nuclear genes that encode mitochondrial proteins in mild cognitive impairment and Alzheimer's disease.
The pro-aging and rejuvenating effects of young and aged perivascular adipose tissues on endothelial function and inflammation.
Phytoconstituents-Mediated Targeting of Ferroptosis for the Treatment of Cardiovascular Disease.
Honokiol Targeting SIRT3: From Molecular Mechanisms to Therapeutic Opportunities.
The mitochondrial disease biomarker GDF15 is dynamic, quantifiable in saliva, and correlates with disease severity.
Naringin alleviates fluoride-induced neurodevelopmental disorders by modulation of SIRT1, autophagy, mitochondrial fission, and ROS generation.
Energetic cost of biosynthesis modulates the growth-longevity tradeoff in mice: Quantitative insights into four lifespan-altering manipulations.
The effect of cinnamon supplementation on cardiovascular risk factors in adults: a GRADE assessed systematic review, dose-response and meta-analysis of randomized controlled trials.
The role of NAD+ metabolism and its modulation of mitochondria in aging and disease.
Mitochondrial DNA affects tau phosphorylation in aging and Alzheimer's disease.

Reprod Biol Endocrinol. 2025 Jul 03. 23(1): 96

Energy imbalance in oPOI ovarian granulosa cells is linked to reduced glucose bioavailability and metabolism.

Weronika Marynowicz, Paulina Głód, Dawid Maduzia, Justyna Gogola-Mruk, Anna Ptak.

   BACKGROUND: Premature ovarian insufficiency (POI), affecting approximately 1% of women under 40, is associated with impaired fertility. Occult POI (oPOI), an initiating form, is more challenging to detect but still allows potential success with IVF. Recent studies suggest a possible link between granulosa cell (GC) mitochondrial dysfunction and POI, as mitochondria are critical for energy production and reproductive function.
METHODS: We recruited 81 women undergoing IVF which included: 25 women with oPOI defined as a low anti-Müllerian hormone (AMH) level (≤ 1.1 ng/mL) and under the age of 40 without raised follicle-stimulating hormone (FSH) levels and 56 healthy women (male or tubal factor infertility). Molecular analysis of GCs and CCs involved RT-qPCR and functional assays, including Seahorse metabolic profiling, fluorometric/luminescent enzyme activity tests, and mitochondrial fluorescent staining.
RESULTS: We found that cumulus cells (CCs) from oPOI women showed reduced energy capacity. Similarly, GCs shifted toward glycolysis in oPOI, leading to lower ATP production. Despite similar glucose levels in FF between groups, oPOI CCs exhibited impaired glucose uptake and metabolism, with decreased GLUT1 and reduced hexokinase 2 (HK2) activity. In GCs, reduced GLUT1 but increased HK2 gene expression suggests compensatory metabolic reprogramming to maintain energy balance through enhanced glycolysis. Additionally, oPOI women had a lower level of estradiol, despite having a normal FSH level and a decreased estradiol/oocyte count.
CONCLUSIONS: This study indicated that in the case of oPOI, disruption may extend beyond the ovaries to impact the entire HPO axis. Furthermore, reduction of ATP production is connected with lower glucose uptake and may have implications for fertility in oPOI patients. It also highlights the potential for therapeutic strategies focused on improving glucose metabolism and mitochondrial biogenesis.

Keywords:  Energy metabolism; Glucose transporters; Granulosa cells; Mitochondrial dysfunction; Occult premature ovarian insufficiency (oPOI)

DOI:  https://doi.org/10.1186/s12958-025-01426-8
Diabet Med. 2025 Jul 01. e70086

Dorothy Hodgkin lecture 2024: Insulin regulation of mitochondrial biogenesis and function-Impact of dysregulation of mitochondrial function in diabetes and its complications.

K Sreekumaran Nair.

  Skeletal muscle atrophy was a characteristic of type 1 diabetes (T1DM) prior to insulin discovery and replacement. Indirect calorimetry during the post-absorptive state demonstrated that increased fuel oxidation during transient insulin deprivation in T1DM caused depletion of energy stores. Further, insulin has a critical role in preserving muscle mitochondrial content and function by enhancing mitochondrial biogenesis and proteostasis. Insulin deficiency not only inhibits mitochondrial biogenesis but also accelerates the degradation of mitochondrial proteins, causing a decline in mitochondrial content and efficiency. Inefficient mitochondrial respiration, reflected by the uncoupling of oxidative phosphorylation and consequent decline in ATP production, adversely affects many cellular functions and causes high oxidative stress. Oxidative stress adversely affects cardiovascular functions and damages many skeletal muscle proteins, accelerating their degradation and explaining muscle atrophy. Increased degradation of muscle proteins increases amino acid efflux that stimulates the liver to synthesize many non-insulin-dependent proteins, potentially contributing to macrovascular complications. This phenomenon explains a paradoxical increase in whole-body protein synthesis during insulin deficiency. Further, the mitochondrial biology of brain regions rich in insulin receptors concurrent with accelerated transport of ketones and lactate across the blood-brain barrier during insulin deficiency seems to protect the brain from oxidative stress. In contrast, insulin resistance associated with less ketone and lactate production renders the brain susceptible to protein oxidative damage. Oxidative damage and reduced ATP production potentially explain the higher prevalence of dementia in insulin-resistant people. Enhancement of insulin sensitivity by aerobic exercise and metformin in pre-clinical studies prevents mitochondrial dysfunction and oxidative damage to the brain.

Keywords:  ATP; dementia; diabetes; insulin; mitochondria; muscle atrophy; oxidative stress

DOI:  https://doi.org/10.1111/dme.70086
Endocr Connect. 2025 Jun 01. pii: EC-25-0186. [Epub ahead of print]

The role of mitochondrial dysfunction in ovarian granulosa cells in polycystic ovary syndrome.

Xuejun Yan, Dan Ma, Rongnian Li, Jing Xu, Ying Zou, Minmin He.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder that significantly impacts women's reproductive capabilities and metabolic health, leading to a range of complications that can affect their quality of life. Recent studies have highlighted mitochondrial dysfunction as a crucial factor in the complex pathogenesis of PCOS, suggesting that the health of these cellular powerhouses plays a pivotal role in the condition. This review meticulously examines the effects of mitochondrial dysfunction specifically in ovarian granulosa cells, delving into the intricate mechanisms of action that contribute to the development and progression of PCOS, as well as identifying potential therapeutic targets that could be explored for effective treatment. By thoroughly analyzing relevant literature and synthesizing findings from various studies, this paper aims to provide new insights into the multifaceted nature of PCOS research and promote advancements in clinical treatment strategies that could ultimately improve the health and well-being of women affected by this disorder.

DOI: https://doi.org/10.1530/EC-25-0186
Ecotoxicol Environ Saf. 2025 Jun 30. pii: S0147-6513(25)00930-3. [Epub ahead of print]302 118585

Microplastics induce insulin resistance by causing mitochondrial dysfunction associated with mROS in skeletal muscle in vitro.

Yuzhen Tang, Yaxin Suo, Zewen Sun, Xiafang Wu, Qingyang Xing, Yinglong Bai.

  Microplastics pose an emerging threat to both ecological and human health. It is worth noting that muscle has proved to be the target organ of microplastic particles. Skeletal muscle is the major site of insulin-stimulated glucose disposal and subsequent glucose homeostasis and plays a key role in the regulation of glucose metabolism in the body. However, studies on the effects of microplastics on glucose metabolism and insulin sensitivity in human skeletal muscle are limited. Herein, human rhabdomyosarcoma (RD) cells were exposed to two sizes (3 μm and 100 nm) of polystyrene microplastics/nanoplastics (PS-MPs/NPs) at three concentrations (75, 150, and 300 μg/mL) to investigate the possible molecular mechanisms. Our results showed that PS-MPs/NPs could be internalized into RD cells and lead to a reduction in cellular uptake of glucose. These results suggest that PS-MPs/NPs may cause skeletal muscle insulin resistance (IR) at the cellular level. Additionally, we observed that PS-MPs/NPs not only resulted in mitochondrial damage but also induced intracellular oxidative stress. However, treatment with the mitochondria-targeted antioxidant MitoQ improved mitochondrial dysfunction and IR at the cellular level. These findings indicate that PS-MPs/NPs induce IR by causing mitochondrial dysfunction associated with mROS in skeletal muscle in vitro. The identification of these molecular mechanisms is helpful for deeply understanding of the health hazards posed by microplastics.

Keywords:  Insulin resistance; Microplastics; Mitochondrial dysfunction; Oxidative stress; Skeletal muscle

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118585
Nat Commun. 2025 Jul 01. 16(1): 5465

Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.

Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.

The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.

DOI: https://doi.org/10.1038/s41467-025-60670-z
Future Cardiol. 2025 Jul 04. 1-10

SIRT3 as a potential biomarker and therapeutic target for cardiovascular diseases: a meta-analysis of clinical studies.

Nikhil Gupta, Vikas Kumar, Abhinav Kanwal.

   BACKGROUND: Cardiovascular diseases (CVDs) remain the leading cause of mortality globally, with mitochondrial dysfunction playing a key role in their pathogenesis. SIRT3 (Sirtuin 3), a mitochondrial deacetylase, has emerged as a critical regulator of mitochondrial function and oxidative stress, with evidence linking its reduction to the progression of CVDs. This meta-analysis aimed to evaluate the association between SIRT3 levels and CVDs in order to elucidate its role in CVD pathogenesis and its potential as a biomarker.
METHODS: A systematic search of MEDLINE and Embase databases was conducted up to August 2024, adhering to PRISMA guidelines. Observational studies evaluating SIRT3 levels in human patients with CVDs as compared to healthy controls were included.
RESULTS: 8 studies comprising 397 participants were included in this meta-analysis. Overall, SIRT3 levels were found to be significantly lower in individuals with CVDs compared to healthy controls (SMD: 1.08, 95% CI: 0.495-1.662, p = 0.0032). The reduction in SIRT3 levels was most pronounced in hypertension (SMD: 1.82) and dilated cardiomyopathy (SMD: 1.08).
CONCLUSION: This meta-analysis provides compelling evidence of gsignificantly reduced SIRT3 levels in CVD patients, highlighting its critical role in cardiovascular diseases. These findings underscore the potential of SIRT3 as a biomarker and therapeutic target in CVDs.

Keywords:  Cardiovascular diseases; SIRT3; biomarker; meta-analysis; mitochondria

DOI:  https://doi.org/10.1080/14796678.2025.2527535
Front Aging Neurosci. 2025 ;17 1578439

From hormones to neurodegeneration: how FSH drives Alzheimer's disease.

Yafei Xue, Shuqi Zuo, Fei Wang, Xiaoyi Qi.

  The role and function of follicle-stimulating hormone in the gonads have been extremely studied. However, recent research has begun to explore the relationship between elevated follicle-stimulating hormone levels and the prevalence of extragonadal disorders, particularly in perimenopausal and postmenopausal women. These disorders include endometrial cancer, osteoporosis, obesity, and atherosclerosis. This review provides new insights into the relationship between follicle-stimulating hormone and the development of age-related diseases, with a focus on Alzheimer's disease. Follicle-stimulating hormone does not act alone in promoting Alzheimer's disease but often works in conjunction with inflammation, lipid accumulation, and vascular alterations. Furthermore, follicle-stimulating hormone synergizes with obesity, gut microbiota, autophagy, and aging, creating conditions that facilitate the onset and progression of Alzheimer's disease. This review also summarizes the therapeutic potential of FSH-blocking antibodies in treating these diseases.

Keywords:  Alzheimer’s disease; FSH-blocking antibodies; aging; follicle-stimulating hormone; lipid accumulation; neuroinflammation

DOI:  https://doi.org/10.3389/fnagi.2025.1578439
Nihon Yakurigaku Zasshi. 2025 ;160(4): 268-273

[NAD+ metabolism as a target for anti-aging].

Hitoshi Uchida, Takashi Nakagawa.

Aging is a physiological process caused by various genetic and environmental factors. Recently, it has been proposed that the disturbance of the nutritional-metabolic sensing pathway is one of the aging characteristics. In particular, nicotinamide adenine dinucleotide (NAD+) plays an important role in this pathway and is considered the regulator of aging. NAD+ regulates an energy metabolism as a co-factor and is also involved in various biological processes including transcription, stress responses, DNA repair, inflammatory responses as well as post-transcriptional modifications, as a substrate for sirtuins, poly ADP-ribose polymerase (PARP), and CD38. With age, DNA damage and chronic inflammation increase in organs, resulting in overconsumption of NAD+ via PARP and CD38. The reduced NAD+ levels decrease the activity of sirtuins and PARPs and impair energy metabolism, ultimately leading to aging and aging-related diseases. However, the precise metabolism of NAD+ in vivo and the mechanism of how NAD+ regulates aging remain elusive. Moreover, the clinical application of NAD+ supplementation therapy is still under development. In this review, we overview the NAD+ metabolism and its relation to aging. In addition, we describe the current issue and perspective of NAD+ supplementation therapy to promote a healthy lifespan.

DOI: https://doi.org/10.1254/fpj.24072
bioRxiv. 2025 Jun 20. pii: 2025.06.16.659556. [Epub ahead of print]

Differential DNA methylation in blood in nuclear genes that encode mitochondrial proteins in mild cognitive impairment and Alzheimer's disease.

Alexander E Boruch, Andy Madrid, Ligia A Papale, Phillip E Bergmann, Isabelle Renteria, Samuel Faasen, Dane B Cook, Reid S Alisch, Kirk J Hogan.

Background: Altered mitochondrial function contributes to the pathogenesis of mild cognitive impairment (MCI) and late-onset dementia due to Alzheimer's disease (AD).
Objective: To test for differential methylation in nuclear genes that encode proteins that participate in mitochondrial function between cognitively unimpaired participants (CU) and those with MCI and AD.
Methods: Recently published whole genome methylation sequencing (WGMS) in blood from CU participants ( N =174), and those with MCI ( N =99) and AD ( N =109) was used to test for differential methylation in 1,121 nuclear genes that encode proteins that participate in mitochondrial function in the Human Protein Atlas .
Results: Seventy-four nuclear genes that encode proteins that participate in mitochondrial function were differentially methylated between persons with MCI and CU. Seventy-one genes were differentially methylated between persons with AD and CU, and 132 genes were differentially methylated between persons with MCI and AD. Thirteen differentially methylated genes shared between the 3 comparisons support contributions from disrupted metabolism and oxidative stress pathways in AD pathogenesis.
Conclusions: Nuclear genes that encode proteins that participate in mitochondrial glucose metabolism, fatty acid metabolism and oxidative stress pathways are differentially methylated between persons who are CU and those with MCI and AD.

DOI: https://doi.org/10.1101/2025.06.16.659556
Biogerontology. 2025 Jun 28. 26(4): 134

The pro-aging and rejuvenating effects of young and aged perivascular adipose tissues on endothelial function and inflammation.

Chak Kwong Cheng, Xingtao Huang, Shuhui Meng, Yu Huang.

  Aging is considered as an independent risk factor for cardiovascular diseases. Common hallmarks of vascular aging include endothelial dysfunction, vascular inflammation, elevated oxidative stress, and telomere dysfunction. Perivascular adipose tissue (PVAT) is the local aggregate of adipose tissue surrounding the vascular bed, serving as a critical regulator of vascular function via either paracrine or endocrine manners. Aging-dependent malfunction of adipose tissues increases the risk of cardiometabolic diseases. Aging was previously shown to attenuate the anticontractile effect of PVAT in rodent arteries. Therefore, this study sought to understand whether aged and young PVAT promote and retard vascular aging in young and aged mice. PVAT-free aortas from aged and young mice were co-cultured with aortic PVAT from young and aged donor mice for 48 h, respectively. Endothelium-dependent relaxations (EDRs) in mouse aortas were determined by wire myography. Aged PVAT co-culture impaired endothelial function in the aortas of young mice, while young PVAT co-culture slightly alleviated endothelial dysfunction in aged mice. Aged PVAT co-culture induced vascular oxidative stress and inflammation, impaired telomere function, and suppressed AMPK/SIRT1 signaling in young mouse aortas. Conversely, these detrimental effects were partially reversed by young PVAT co-culture in aged mouse aortas. We further showed that these pro-aging and rejuvenating effects of PVAT were partially mediated by growth differentiation factor 15 (GDF15) and inflammatory cytokines. These findings highlight a substantial role of PVAT in modulating endothelial function and vascular aging, implying adipose-vascular axis as potential intervention target against cardiovascular aging and diseases.

Keywords:  Aging; Endothelial cell; Endothelial function; Inflammation; Oxidative stress; Perivascular adipose tissue

DOI:  https://doi.org/10.1007/s10522-025-10283-2
Curr Cardiol Rev. 2025 Jun 24.

Phytoconstituents-Mediated Targeting of Ferroptosis for the Treatment of Cardiovascular Disease.

Parul Gupta, Anjali Sharma, Sachin, Shubham Sharma, Devkant Sharma.

  Ferroptosis, an instance of iron-dependent programmable cell death that results from oxidative stress & lipid peroxidation, has garnered interest due to its associations with cardiovascular diseases, such as atherosclerosis, myocardial infarction, as well as heart failure. Unlike necrosis or apoptosis, ferroptosis involves unique metabolic pathways that disrupt cellular redox balance and lipid homeostasis, leading to substantial cell damage in cardiovascular tissues. It is becoming recognized that phytoconstituents-bioactive compounds derived from plants-can modify ferroptosis pathways and provide cardioprotective advantages. Compounds including curcumin, resveratrol, quercetin, tanshinone IIA, and epigallocatechin gallate (EGCG) have shown potential in preclinical studies by concentrating on significant ferroptotic processes. Finally, by controlling iron homeostasis, boosting antioxidant responses (such as Nrf2 pathway activation), and reducing lipid peroxidation, these phytochemicals may mitigate ferroptosisinduced cardiac cell death. In animal studies, these natural compounds have shown promise in reducing oxidative damage and improving heart function after injury. This article summarises the mechanisms via which a variety of phytoconstituents influence ferroptosis and discusses their potential as an adjuvant treatment for CVD. While these findings are encouraging, further research is needed to use them in clinical settings, with a focus on long-term safety in human populations, optimal dose, and absorption. The cardioprotective properties of phytoconstituents, which focus on ferroptosis, may provide a unique, plant-based therapeutic strategy for the treatment of CVDs.

Keywords:  CVD; Ferroptosis; atherosclerosis; phytoconstituents; quercetin.; redox balance; resveratrol

DOI:  https://doi.org/10.2174/011573403X370981250618074406
FASEB J. 2025 Jul 15. 39(13): e70798

Honokiol Targeting SIRT3: From Molecular Mechanisms to Therapeutic Opportunities.

Feng Xiang, Zhimin Zhang, Yamei Li, Bohou Xia, Yingyan Liao, Chen Yang, Zhiqiang He, Limei Lin, Jingchen Xie.

  Honokiol (HKL), one of the major bioactive components of the traditional Chinese medicine Magnolia officinalis, has garnered significant attention because of its extensive pharmacological activities. Numerous studies have demonstrated that SIRT3 plays a crucial regulatory role in the disease intervention mechanisms mediated by HKL. HKL can bind to the SIRT3 protein, not only directly increasing its deacetylase activity but also forming a positive feedback loop by activating its transcription factors, thereby further promoting SIRT3 expression. This dual regulatory mechanism effectively restores the function of downstream proteins, activates intracellular protective mechanisms, and combats a variety of pathological processes, including aging, oxidative stress, inflammation, cell death, mitochondrial dysfunction, and metabolic disorders. It has shown broad prospects in the prevention and treatment of chronic diseases such as neurodegenerative diseases, cardiovascular diseases, degenerative bone and joint diseases, lung diseases, and metabolic disorders. Although HKL is a highly recognized SIRT3 activator, there is currently no comprehensive review systematically summarizing the research on HKL as a SIRT3 activator. This review comprehensively summarizes the research progress over the past decade since the discovery of HKL as a SIRT3 activator. Through in-depth analysis of the literature, we focused on elucidating the biological functions of HKL through SIRT3 activation in various disease models and the signaling pathways involved. These findings emphasize the therapeutic development value and significant application potential of HKL as a SIRT3 activator, providing a theoretical basis for the development of natural products that target SIRT3.

Keywords:  SIRT3; deacetylation; degenerative disease; honokiol; mitochondrial dysfunction

DOI:  https://doi.org/10.1096/fj.202501428R
Mol Genet Metab. 2025 Jun 16. pii: S1096-7192(25)00170-2. [Epub ahead of print]145(4): 109179

The mitochondrial disease biomarker GDF15 is dynamic, quantifiable in saliva, and correlates with disease severity.

Qiuhan Huang, Caroline Trumpff, Anna S Monzel, Shannon Rausser, Jack Devine, Cynthia C Liu, Catherine Kelly, Mangesh Kurade, Shufang Li, Kris Engelstad, Kurenai Tanji, Vincenzo Lauriola, Tian Wang, Shuang Wang, Richard Sloan, Robert-Paul Juster, Michio Hirano, Martin Picard.

Circulating growth differentiation factor 15 (GDF15) is a biomarker of mitochondrial diseases and aging, but its natural dynamics and response to acute stress in blood and other biofluids have not been well defined. Using extensive samples from MiSBIE participants with rare mitochondrial diseases (MitoD), we examined GDF15 biology in 290 plasma and 860 saliva aliquots from 40 subjects with the m.3243 A > G mutation (n = 25) or with single, large-scale mtDNA deletions (n = 15). Compared to healthy controls, both MitoD groups exhibited significantly elevated blood and saliva GDF15 (p < 0.0001). To examine the origin of GDF15 protein in saliva, we profiled GDF15 expression in 48 tissues from the GTEx dataset and identified high GDF15 expression in salivary gland secretory cells. Despite being chronically elevated in MitoD, saliva GDF15 further increased in response to experimental laboratory mental stress alone (without physical exertion), whereas the stress-induced plasma GDF15 reactivity was blunted in MitoD compared to controls. Using a home-based saliva collection protocol, we show that similar to other stress-related metabolic hormones, saliva GDF15 is highest upon awakening and declines rapidly by 61.2 % within 45 min. Elevated saliva GDF15 levels persisted throughout the day in MitoD. Clinically, saliva GDF15 correlated with neurological symptoms, fatigue, and functional capacity. Importantly, stress-evoked changes in GDF15 did not amplify noisy disease severity associations, but rather consistently increased the effects sizes for GDF15-symptoms connections, pointing to converging psychobiology underlying the responses to mitochondrial OxPhos defects and acute mental stress. These results open the door to exploring saliva GDF15 as a non-invasive monitoring approach for mitochondrial diseases and call for further studies examining the psychobiological processes linking mitochondria, mental stress, and GDF15 dynamics.

DOI: https://doi.org/10.1016/j.ymgme.2025.109179
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 30.

Naringin alleviates fluoride-induced neurodevelopmental disorders by modulation of SIRT1, autophagy, mitochondrial fission, and ROS generation.

Vishal Chhabra, Ravindra Shantakumar Swamy, Annem Ravi Teja Reddy, Rashmi Bhushan, Smita Shenoy, Shreya Maiti, Abubakar, Sarasa Meenakshi, Krishna Murti, Nitesh Kumar.

  The present study explored the mechanism behind the fluorosis-mediated neurodevelopmental disorder and its intervention by naringin in prenatal and perinatal models in Wistar rats. Both in vitro and in vivo studies were conducted to assess autophagy, oxidative stress, neurogenesis, and impaired molecular dynamics markers. The experiment was conducted over a period of 120 days. Twelve Wistar rats were divided into four groups: control, sodium fluoride (NaF)-treated (10 ppm in drinking water), NaF + naringin-treated (50 mg/kg via oral gavage), and NaF with naringin administered to pups via breastfeeding. Treatments lasted 60 days for adults, with NaF exposure beginning 30 days pre-mating. Pups were evaluated at days 90 (prenatal) and 120 (perinatal) to assess developmental effects. Fluoride was administered by mixing NaF in drinking water at a dose of 10 ppm, and naringin was given via oral gavage at a dose of 50 mg/kg body weight. Fluoride toxicity showed altered behavior in the open field test (OFT), novel object recognition test (NORT), forced swim test (FST), and Morris Water Maze tests and impaired motor coordination in neonatal tests using nest seeking, locomotion, righting reflex, forelimb grasp reflex, cliff avoidance, and negative geotactic reflex. At the end of the experiment, prenatal and natal pups were sacrificed postweaning. Biochemical assays, fluoride concentration estimation, Western blotting, and immunohistochemistry were performed for the brain tissues. Naringin showed improvement in these behavioral studies, probably due to neuroprotection by modulation of SIRT-1, Dnm1L, and Lc3B levels, which were assessed by western blot. These findings highlight naringin as a promising therapeutic agent for mitigating fluoride-induced neurodevelopmental toxicity through pathways involving oxidative stress regulation, autophagy, and mitochondrial dynamics.

Keywords:  Autophagy; Cognition; Drinking water; Mitochondrial dynamics; SIRT1; Sodium fluoride

DOI:  https://doi.org/10.1007/s00210-025-04398-z
Mech Ageing Dev. 2025 Jul 01. pii: S0047-6374(25)00064-8. [Epub ahead of print]226 112088

Energetic cost of biosynthesis modulates the growth-longevity tradeoff in mice: Quantitative insights into four lifespan-altering manipulations.

Chen Hou, Fahimeh Taheri.

  Life history theory proposes a tradeoff between growth rate and lifespan, typically explained by the allocation of limited energy resources between somatic growth and maintenance. However, this explanation does not give a complete picture of the energy tradeoff. This study investigates two energy allocation mechanisms that influence growth and longevity simultaneously: the redirection of metabolic energy from growth to maintenance under energy limitation, and increased energy investment in biosynthesis, enhancing bio-tissue quality and stress resistance but also slowing growth. By analyzing empirical data from laboratory mice subjected to diet restriction (DR), dwarfism through genetic manipulations (Dwarf), rapamycin treatment (Rap), and growth hormone transgenics (Super), we quantify changes in growth rate, metabolic rate, and biosynthesis energy costs (Em). Our quantitative analyses demonstrate that although both mechanisms slow growth and extend lifespan, they work differently depending on the type of manipulation. In DR, Dwarf, and Rap mice, these mechanisms act synergistically, significantly enhancing lifespan. These manipulations not only channel more energy from growth to somatic maintenance but also increase the energy investment to biosynthesis and therefore enhance the tissues' ability of resisting stress. Conversely, in Super mice, the mechanisms partially counteract each other. In this case, the treatment drains energy from somatic maintenance to growth, but slightly increases energy investment to biosynthesis, resulting in less pronounced effects on longevity. These findings suggest that the energetic cost of biosynthesis, a previously underappreciated factor, critically influences the balance between growth rate and lifespan, providing deeper insight into life history evolution and aging mechanisms.

Keywords:  Biosynthesis; Energy tradeoff; Lifespan extension; Lifespan shortening; Protein quality control

DOI:  https://doi.org/10.1016/j.mad.2025.112088
J Health Popul Nutr. 2025 Jul 03. 44(1): 233

The effect of cinnamon supplementation on cardiovascular risk factors in adults: a GRADE assessed systematic review, dose-response and meta-analysis of randomized controlled trials.

Ali Jafari, Helia Mardani, Amir Hossein Faghfouri, Minoo AhmadianMoghaddam, Vali Musazadeh, Alireza Alaghi.

   BACKGROUND: Numerous clinical studies have suggested that cinnamon supplementation may be effective for cardiovascular disease risk factors, but the findings are controversial. This comprehensive systematic review and meta-analysis aimed to assess the impact of cinnamon supplementation on cardiovascular disease risk factors.
METHODS: Relevant studies were identified through electronic searches of databases, including Web of Science, PubMed, Central, Scopus, and Embase, up to July 2024.
RESULTS: Forty-nine studies were included. Cinnamon supplementation significantly reduced WC (SMD = - 0.40; 95% (CI): - 0.73, - 0.06), DBP (SMD = - 1.04; 95% CI: - 1.54, - 0.55), SBP (SMD = - 0.85; 95% CI: - 1.54, - 0.16), fasting glucose (SMD = - 1.28; 95% CI: - 1.65, - 0.90), fasting insulin (SMD = - 0.26; 95% CI: - 0.50, - 0.02), HbA1c (SMD = - 0.71; 95% CI: - 1.02, - 0.40), HOMA-IR (SMD = - 0.54; 95% CI: - 0.82, - 0.26), postprandial blood glucose (SMD = - 2.28; 95% CI: - 3.48, - 1.08), CRP (SMD = - 0.78; 95% CI: - 1.28, - 0.27), LDL-C (SMD = - 0.71; 95% CI: - 1.02, - 0.40), total cholesterol (TC) (SMD = - 1.15; 95% CI: - 1.55, - 0.75), triglycerides (TG) (SMD = - 0.91; 95% CI: - 1.25, - 0.56), and MDA (SMD = - 0.76; 95% CI: - 1.07, - 0.45). Additionally, cinnamon supplementation significantly elevated HDL-C levels (SMD = 0.56; 95% CI: 0.23, 0.89).
CONCLUSION: Cinnamon supplementation demonstrated significant benefits in improving cardiovascular risk factors. These findings suggest its potential as an adjunct therapy for improving cardiovascular disease risk factors.

Keywords:  Anthropometric indices; Blood pressure; Glycemic indices; Lipid profile; Nutritional supplement

DOI:  https://doi.org/10.1186/s41043-025-00967-3
npj metabolic health and disease... 2025 Jun 18. 3(1): 26

The role of NAD+ metabolism and its modulation of mitochondria in aging and disease.

Khalishah Yusri, Sandra Jose, Karen S Vermeulen, Trina Chia Min Tan, Vincenzo Sorrentino.

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme involved in a plethora of physiological reactions, with a key relevance in supporting mitochondrial function. Due to its critical role in these cellular processes, declining levels of NAD+ are associated with general aging and chronic disorders, including cognitive decline, sarcopenia, and metabolic diseases. These conditions are also typified by loss of mitochondrial health through dysfunction of homeostatic components such as mitophagy, unfolded protein response, and the antioxidant system. Therefore, raising cellular NAD+ through vitamin B3 family precursors or via drug-based interventions has become a broadly used strategy to restore mitochondrial and organismal homeostasis, with NAD+ precursors becoming a popular supplementation approach. As increasing components of the NAD+ biology are unraveled, this comprehensive review summarizes the advances in mechanisms of NAD+ metabolism and its modulation via compound-based strategies. Furthermore, it highlights the role of NAD+ in mitochondrial homeostasis in aging and disease conditions, the latest results of NAD+-boosting therapeutics in clinical trials, and areas of further translational development.

DOI: https://doi.org/10.1038/s44324-025-00067-0
Alzheimers Dement. 2025 Jul;21(7): e70390

Mitochondrial DNA affects tau phosphorylation in aging and Alzheimer's disease.

Riley E Kemna, Paul J Kueck, Robyn Honea, Zachary Clark, Michaella Rekowski, Ian Weidling, Hana Mayfield, Casey S John, Jeffrey Burns, Heather M Wilkins, Russell Swerdlow, Jill K Morris.

   INTRODUCTION: Impaired mitochondrial function is seen in Alzheimer's disease (AD), but its role is unclear. Mitochondrial DNA (mtDNA) supports bioenergetic metabolism, but it is uncertain how it might influence AD neuropathology.
METHODS: We used cytoplasmic hybrid (cybrid) cell lines made from SH-SY5Y cells expressing mtDNA from cognitively healthy (CH), mild cognitive impairment (MCI), or AD individuals to investigate the impact of mtDNA-determined mitochondrial function on amyloid, tau, and neurodegeneration (ATN) markers. Cybrid measurements were correlated with cognition and brain morphometry.
RESULTS: Relative to cybrids expressing mtDNA from CH individuals, MCI and AD cybrids contained more phosphorylated tau-217 (p-tau217), p-tau181, and total tau. Cybrid p-tau217 correlated with plasma p-tau217 from the mtDNA donor (β = 0.605, p < 0.001). We observed negative relationships between cybrid p-tau217 and cognition and brain morphometry. MCI and AD cybrid proteomes showed mitochondrial dysfunction.
DISCUSSION: mtDNA-determined mitochondrial function affects cell physiology in AD-relevant ways. Our study suggests that mtDNA affects ATN status and clinical state.
HIGHLIGHTS: Mitochondrial DNA (mtDNA)-determined mitochondrial function drives Alzheimer's disease (AD) hallmarks. Cytoplasmic hybrid outcomes associate with mtDNA-donor clinical measures. Proteomic analyses indicate mitochondrial dysfunction in AD.

Keywords:  Alzheimer's disease; aging; biomarkers; metabolism; mitochondrial DNA

DOI:  https://doi.org/10.1002/alz.70390