bims-mistre 2025-02-23 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–02–23
twenty-one papers selected by
Ellen Siobhan Mitchell, MitoQ

Idebenone improves mitochondrial respiratory activity and attenuates oxidative damage via the SIRT3-SOD2 pathway in a prion disease cell model.
Curcumin protects against MPP+-induced neurotoxicity in SH-SY5Y cells by modulating the TRPV4 channel.
The integrated stress response in neurodegenerative diseases.
The impact of mitochondrial dysfunction on ovarian aging.
Regular exercise alleviates metabolic dysfunction-associated steatohepatitis through rescuing mitochondrial oxidative stress and dysfunction in liver.
Reactive Oxygen Species: Role in Pathophysiology, and Mechanism of Endogenous and Dietary Antioxidants during Oxidative Stress.
Energy metabolism in health and diseases.
Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
Insights into therapeutic approaches for the treatment of neurodegenerative diseases targeting metabolic syndrome.
NCBP2-AS2 is a mitochondrial microprotein, regulates energy metabolism and neurogenesis, and is downregulated in Alzheimer's disease.
MitoQ alleviates H2O2-induced mitochondrial dysfunction in keratinocytes through the Nrf2/PINK1 pathway.
Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.
Mitophagy at the oocyte-to-zygote transition promotes species immortality.
Ferroptosis and pathogenesis of neuritic plaques in Alzheimer disease.
Bridging gap in the treatment of Alzheimer's disease via postbiotics: Current practices and future prospects.
Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
The link between Mitochondria and Sarcopenia.
Protection of Green Tea Polyphenols against Neurodegenerative Diseases: Evidence and Possible Mechanisms.
Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Type 3 diabetes and metabolic reprogramming of brain neurons: causes and therapeutic strategies.
Microglial Modulation in Alzheimer's Disease: Central Players in Neuroinflammation and Pathogenesis.

Life Sci. 2025 Feb 19. pii: S0024-3205(25)00114-6. [Epub ahead of print] 123481

Idebenone improves mitochondrial respiratory activity and attenuates oxidative damage via the SIRT3-SOD2 pathway in a prion disease cell model.

Zhixin Sun, Pei Wen, Dongming Yang, Jie Li, Zhiping Li, Mengyang Zhao, Dongdong Wang, Fengting Gou, Jingjing Wang, Qing Fan, Yuexin Dai, Yilan Ji, Xueyuan Li, Yingxin Tu, Tianying Ma, Xiaoyu Wang, Deming Zhao, Lifeng Yang.

  Prion diseases are neurodegenerative diseases that are transmitted between humans and animals, which cause spongiform brain degeneration and neuronal death. Prion diseases are difficult to treat. Mitochondrial damage and oxidative stress occurring early in disease progression. Reducing oxidative stress is a therapeutic strategy for disease. Idebenone (IDE) is an antioxidant that enhances electron transfer in the mitochondrial respiratory chain. To investigate IDE protection mechanisms in prion neuron models, we examined IDE effects on apoptosis, mitochondrial dysfunction, cellular respiratory chain damage, and oxidative stress in N2a cells treated with the prion toxic peptide PrP106-126. IDE effectively alleviated apoptosis and mitochondrial dysfunction, reduced mitochondrial reactive oxygen species (ROS), attenuated lipid peroxidation, improved glutathione percentages, increased important antioxidant enzyme (superoxide dismutase (SOD) and catalase) activities, and elevated mitochondrial DNA levels. IDE also modulated SOD2 deacetylation and oxidative damage by regulating SIRT3. Overall, IDE exerted significant antioxidant effects in our prion disease cell model and may have therapeutic applications for prion disease.

Keywords:  Idebenone; Mitochondrial dysfunction; Oxidative stress; PrP(106–126); Prion disease; SIRT3

DOI:  https://doi.org/10.1016/j.lfs.2025.123481
Mol Biol Rep. 2025 Feb 20. 52(1): 255

Curcumin protects against MPP+-induced neurotoxicity in SH-SY5Y cells by modulating the TRPV4 channel.

Ramazan Çınar, Kenan Yıldızhan.

   BACKGROUND: It is well acknowledged that neuroinflammation, mitochondrial dysfunction, and oxidative stress (OS) play a role in the etiology of Parkinson's disease (PD). Curcumin (CUR) protect neuronal cells by interfering with the production of reactive oxygen species (ROS) in neuronal cells and suppressing OS. In this study, we investigated the role of the TRPV4 channel under CUR stimulation in the PD model induced by MPP+ in SH-SY5Y cells.
METHODS: The cells were divided into four groups: control, CUR, MPP+ and MPP++CUR. In addition, incubations were performed with TRPV4 channel agonist GSK1016790A (GSK) and its antagonist Ruthenium red (Rr) to follow the Ca2+ current induced through the TRPV4 channel.
RESULTS: MPP+ exposure increased mitochondrial and intracellular ROS production and mitochondrial membrane potential in the cell, while decreasing GSH levels. During CUR and Rr incubation, MPP+ exposure and TRPV4 agonist GSK-induced TRPV4 overstimulation were down-regulated. The effects of MPP+ on intracellular damage were changed by CUR treatment, as seen in changes in GSH levels, mROS, iROS, JC/1, apoptosis, and TRPV4 expression value compared to the MPP+ group.
CONCLUSIONS: The CUR treatment in the in vitro PD model created with MPP+ reduced cellular damage by regulating mitochondrial dysfunction, OS and TRPV4 channel activation in MPP+-induced neurotoxicity with the antioxidant properties of CUR.

Keywords:  Curcumin; MPP+ ; Parkinson’s disease; SH-SY5Y cells; TRPV4 channel

DOI:  https://doi.org/10.1007/s11033-025-10345-1
Mol Neurodegener. 2025 Feb 19. 20(1): 20

The integrated stress response in neurodegenerative diseases.

Maria Astrid Bravo-Jimenez, Shivangi Sharma, Soheila Karimi-Abdolrezaee.

The integrated stress response (ISR) is a conserved network in eukaryotic cells that mediates adaptive responses to diverse stressors. The ISR pathway ensures cell survival and homeostasis by regulating protein synthesis in response to internal or external stresses. In recent years, the ISR has emerged as an important regulator of the central nervous system (CNS) development, homeostasis and pathology. Dysregulation of ISR signaling has been linked to several neurodegenerative diseases. Intriguingly, while acute ISR provide neuroprotection through the activation of cell survival mechanisms, prolonged ISR can promote neurodegeneration through protein misfolding, oxidative stress, and mitochondrial dysfunction. Understanding the molecular mechanisms and dynamics of the ISR in neurodegenerative diseases aids in the development of effective therapies. Here, we will provide a timely review on the cellular and molecular mechanisms of the ISR in neurodegenerative diseases. We will highlight the current knowledge on the dual role that ISR plays as a protective or disease worsening pathway and will discuss recent advances on the therapeutic approaches that have been developed to target ISR activity in neurodegenerative diseases.

DOI: https://doi.org/10.1186/s13024-025-00811-6
J Transl Med. 2025 Feb 20. 23(1): 211

The impact of mitochondrial dysfunction on ovarian aging.

Xiaoyue Zhang, Ling Zhang, Wenpei Xiang.

   IMPORTANCE: Ovarian aging has become a focal point in current research on female aging and refers to the gradual decline in ovarian function as women age. Numerous factors influence ovarian aging, among which mitochondrial function is one because it plays a crucial role by affecting oocytes and granulosa cells. Mitochondrial deterioration not only leads to a decrease in oocyte quality but also hinders follicle development, further impacting women's reproductive health and fertility.
OBJECTIVE: This review summarizes and integrates research on the impact of mitochondrial function on ovarian aging, outlining the mechanisms by which mitochondria regulate the functions of oocytes and granulosa cells. This study aims to provide potential therapeutic directions to mitigate mitochondrial decline and support female reproductive health.
EVIDENCE REVIEW: According to a 2023 study published in Cell, factors such as oxidative stress, mitochondrial dysfunction, chronic inflammation, and telomere shortening collectively drive ovarian aging, directly affecting female fertility. Among these factors, mitochondrial dysfunction plays a key role. This study reviewed literature from databases such as PubMed, Google Scholar, and CNKI, using keywords such as "mitochondrial dysfunction", "decline in oocyte quality and quantity", and "ovarian aging", aiming to summarize current research on the mechanisms of the impact of mitochondrial dysfunction on ovarian aging and provide theoretical support for future exploration of related therapeutic strategies.
FINDINGS: The main characteristics of ovarian aging include a decline in oocyte quantity and quality, fluctuations in hormone levels, and a reduction in granulosa cell function. Studies have shown that mitochondria affect fertility by regulating cellular energy metabolism, exacerbating oxidative stress, causing mitochondrial DNA (mtDNA) damage, and impacting the physiological function of granulosa cells within the ovary, gradually diminishing the ovarian reserve.
CONCLUSION: This review focuses on analyzing the effects of mitochondrial decline on energy production in oocytes and granulosa cells, the accumulation of reactive oxygen species (ROS), and the calcium ion (Ca2+) concentration, which all contribute to the ovarian aging process, and understanding them will provide new insights into the mechanisms of ovarian aging.
RELEVANCE: Therapeutic interventions targeting mitochondrial dysfunction may help delay ovarian aging and improve female reproductive health.

Keywords:  Mitochondrial DNA; Mitochondrial dysfunction; Oocyte function; Ovarian aging

DOI:  https://doi.org/10.1186/s12967-025-06223-w
Free Radic Biol Med. 2025 Feb 13. pii: S0891-5849(25)00092-9. [Epub ahead of print]230 163-176

Regular exercise alleviates metabolic dysfunction-associated steatohepatitis through rescuing mitochondrial oxidative stress and dysfunction in liver.

Baoxuan Lin, Tong Wu, Mohammad Nasb, Zeyun Li, Ning Chen.

  Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe mitochondrial dysfunction, associated with the production of mitochondrial reactive oxygen species (mROS). The substantial generation of mROS in the MASH liver, resulting from lipid surplus and electron transport chain (ETC) overload, impairs mitochondrial structure and functionality, thereby contributing to the development of severe hepatic steatosis and inflammation. Regular exercise represents an effective strategy for the treatment of MASH. Understanding the effects of exercise on oxidative stress and mitochondrial function is essential for effective treatment of MASH. This article reviews the pathological alterations in mitochondrial β-oxidation, ETC efficiency and mROS production within MASH liver. Additionally, it discusses how exercise influences the redox state and mitochondrial quality control mechanisms-such as biogenesis, mitophagy, fusion, and fission-within the MASH liver. The article emphasizes the importance of in-depth studies on exercise-induced MASH mitigation through the enhancement of mitochondrial redox balance, quality control, and function. Exploring the relationship between exercise and hepatic mitochondria could provide valuable insights into identifying potential therapeutic targets for MASH.

Keywords:  MASH; Mitochondrial quality control; Oxidative stress; Reactive oxygen species; Regular exercise

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.017
Chonnam Med J. 2025 Jan;61(1): 32-45

Reactive Oxygen Species: Role in Pathophysiology, and Mechanism of Endogenous and Dietary Antioxidants during Oxidative Stress.

Mohammad Mamun Sikder, Xiaodong Li, Steeve Akumwami, Sanzida Akter Labony.

  Redox imbalances, which result from excessive production of reactive oxygen species (ROS) or malfunctioning of the antioxidant system, are the source of oxidative stress. ROS affects all structural and functional components of cells, either directly or indirectly. In addition to causing genetic abnormalities, excessive ROS also oxidatively modifies proteins by protein oxidation and peroxidation and alters lipid structure via advanced lipoxidation, decreasing function and promoting damage or cell death. On the other hand, low levels of ROS constitute important redox-signaling molecules in various pathways that maintain cellular homeostasis and regulate key transcription factors. As a result, ROS can affect various cellular processes, such as apoptosis, migration, differentiation, and proliferation. ROS can act as signaling molecules, controlling various normal physiological activities at the cellular level. Furthermore, there is an increasing body of evidence indicating the role of ROS in various clinical conditions. In this review, we will summarize the role of ROS in physiological and pathological processes and antioxidant action during oxidative stress.

Keywords:  Antioxidant; Homeostasis; Oxidative Stress; Reactive Oxygen Species

DOI:  https://doi.org/10.4068/cmj.2025.61.1.32
Signal Transduct Target Ther. 2025 Feb 18. 10(1): 69

Energy metabolism in health and diseases.

Hui Liu, Shuo Wang, Jianhua Wang, Xin Guo, Yujing Song, Kun Fu, Zhenjie Gao, Danfeng Liu, Wei He, Lei-Lei Yang.

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

DOI: https://doi.org/10.1038/s41392-025-02141-x
Nat Metab. 2025 Feb 19.

Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.

Alva M Casey, Dylan G Ryan, Hiran A Prag, Suvagata Roy Chowdhury, Eloïse Marques, Keira Turner, Anja V Gruszczyk, Ming Yang, Dane M Wolf, Jan Lj Miljkovic, Joyce Valadares, Patrick F Chinnery, Richard C Hartley, Christian Frezza, Julien Prudent, Michael P Murphy.

Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψm) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher ∆p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.

DOI: https://doi.org/10.1038/s42255-025-01224-x
Mol Biol Rep. 2025 Feb 21. 52(1): 260

Insights into therapeutic approaches for the treatment of neurodegenerative diseases targeting metabolic syndrome.

Komal Thapa, Heena Khan, Samrat Chahuan, Sanchit Dhankhar, Amarjot Kaur, Nitika Garg, Monika Saini, Thakur Gurjeet Singh.

  Due to the significant energy requirements of nerve cells, glucose is rapidly oxidized to generate ATP and works in conjunction with mitochondria in metabolic pathways, resulting in a combinatorial impact. The purpose of this review is to show how glucose metabolism disorder invariably disrupts the normal functioning of neurons, a phenomenon commonly observed in neurodegenerative diseases. Interventions in these systems may alleviate the degenerative load on neurons. Research on the concepts of metabolic adaptability during disease progression has become a key focus. The majority of the existing treatments are effective in mitigating some clinical symptoms, but they are unsuccessful in preventing neurodegeneration. Hence, there is an urgent need for breakthrough and highly effective therapies for neurodegenerative diseases. Here, we summarise the interactions that various neurodegenerative diseases have with abnormalities in insulin signalling, lipid metabolism, glucose control, and mitochondrial bioenergetics. These factors have a crucial role in brain activity and cognition, and also significantly contribute to neuronal degeneration in pathological conditions. In this article, we have discussed the latest and most promising treatment methods, ranging from molecular advancements to clinical trials, that aim at improving the stability of neurons.

Keywords:  Autophagy; Lipid metabolism; Metabolic syndrome; Mitophagy; Neurodegenerative diseases

DOI:  https://doi.org/10.1007/s11033-025-10346-0
bioRxiv. 2025 Jan 27. pii: 2025.01.25.634884. [Epub ahead of print]

NCBP2-AS2 is a mitochondrial microprotein, regulates energy metabolism and neurogenesis, and is downregulated in Alzheimer's disease.

Stanislava Popova, Prabesh Bhattarai, Elanur Yilmaz, Daniela Lascu, Juo-Han Kuo, Gizem Erdem, Basak Coban, Jitka Michling, Mehmet Ilyas Cosacak, Huseyin Tayran, Thomas Kurth, Alexandra Schambony, Frank Buchholz, Marc Gentzel, Caghan Kizil.

Microproteins, short functional peptides encoded by small genes, are emerging as critical regulators of cellular processes, yet their roles in mitochondrial function and neurodegeneration remain underexplored. In this study, we identify NCBP2-AS2 as an evolutionarily conserved mitochondrial microprotein with significant roles in energy metabolism and neurogenesis. Using a combination of cellular and molecular approaches, including CRISPR/Cas9 knockout models, stoichiometric co- immunoprecipitation, and advanced imaging techniques, we demonstrate that NCBP2-AS2 localizes to the inner mitochondrial space and interacts with translocase of the inner membrane (TIM) chaperones. These interactions suggest a role in ATPase subunit transport, supported by the observed reductions in ATPase subunit levels and impaired glucose metabolism in NCBP2-AS2-deficient cells. In zebrafish, NCBP2-AS2 knockout led to increased astroglial proliferation, microglial abundance, and enhanced neurogenesis, particularly under amyloid pathology. Notably, we show that NCBP2-AS2 expression is consistently downregulated in human Alzheimer's disease brains and zebrafish amyloidosis models, suggesting a conserved role in neurodegenerative pathology. These findings reveal a novel link between mitochondrial protein transport, energy metabolism, and neural regeneration, positioning NCBP2-AS2 as a potential therapeutic target for mitigating mitochondrial dysfunction and promoting neurogenesis in neurodegenerative diseases such as Alzheimer's disease.

DOI: https://doi.org/10.1101/2025.01.25.634884
Biochem Pharmacol. 2025 Feb 18. pii: S0006-2952(25)00073-5. [Epub ahead of print]234 116811

MitoQ alleviates H2O2-induced mitochondrial dysfunction in keratinocytes through the Nrf2/PINK1 pathway.

Yan Zhao, Renxue Xiong, Shiyu Jin, Yujie Li, Tingru Dong, Wei Wang, Xiuzu Song, Cuiping Guan.

  Oxidative stress plays a critical role in the pathogenesis of vitiligo by damaging keratinocytes, which disrupts their biological functions and influences the progression of the disease. MitoQ, a mitochondria-specific antioxidant, has the potential to prevent disorders associated with oxidative stress and to exert protective effects specifically on mitochondria. This study investigated the protective effects of MitoQ against oxidative stress in keratinocytes. We observed downregulated expression levels of Nrf2, PINK1, Parkin, and LC3 in vitiligo patients. HaCaT cells were treated with 900 μM H2O2 and/or 50 nM MitoQ, revealing that MitoQ mitigated the downregulation of Nrf2, PINK1, and Parkin; reduced the nuclear translocation of Nrf2; and decreased the level of mitophagy induced by H2O2. Following the knockdown of NFE2L2 or PINK1 in HaCaT cells, we noted an increase in intracellular reactive oxygen species, changes in mitochondrial morphology, a dramatic decrease in the mitochondrial membrane potential, and a significant rise in cell death levels. In comparison to the group without NFE2L2 or PINK1 knockdown, MitoQ treatment failed to alleviate these conditions. These results suggest that MitoQ may regulate the PINK1/Parkin signaling pathway via Nrf2 to counteract mitochondrial oxidative stress induced by H2O2 and protect cells from damage. Therefore, our study offers experimental evidence and insights that may inform the development of therapeutic interventions for vitiligo.

Keywords:  Keratinocyte; MitoQ; Mitophagy; Oxidative stress; PINK1/Parkin pathway; Vitiligo

DOI:  https://doi.org/10.1016/j.bcp.2025.116811
J Biomed Sci. 2025 Feb 18. 32(1): 29

Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.

Fasih A Rahman, Mackenzie Q Graham, Amanda M Adam, Emma S Juracic, A Russell Tupling, Joe Quadrilatero.

   BACKGROUND: Skeletal muscle atrophy involves significant remodeling of fibers and is characterized by deficits in mitochondrial content and function. These changes are intimately connected to shifts in mitochondrial turnover, encompassing processes such as mitophagy and mitochondrial biogenesis. However, the role of these mitochondrial turnover processes in muscle atrophy remains poorly understood.
METHODS: We used a novel mitophagy reporter model, mt-Keima mice, to perform hindlimb immobilization and accurately measure mitophagy. A comprehensive set of analyses were conducted to investigate biochemical and molecular changes at the muscle and mitochondrial levels. We also performed image analyses to determine mitophagic flux. To further explore the role of mitophagy in immobilization-induced atrophy, we treated animals with N-acetylcysteine (NAC; 150 mg/kg/day) to modify reactive oxygen species (ROS) signaling and colchicine (0.4 mg/kg/day) to inhibit autophagy.
RESULTS: Our study revealed that hindlimb immobilization leads to muscle weakness and atrophy of fast-twitch muscle fibers (types IIA, IIX, and IIB), with recovery observed in IIA fibers following remobilization. This atrophy was accompanied by a significant increase in mitophagic flux. Additionally, immobilization induced notable mitochondrial dysfunction, as shown by diminished respiration, increased mitochondrial ROS, and greater whole muscle lipid peroxidation. Treatment of immobilized mice with NAC enhanced mitochondrial respiration and reduced ROS generation but suppressed mitophagic flux and intensified atrophy of type IIX and IIB fibers. Additionally, administration of colchicine to immobilized mice suppressed mitophagic flux, which also exacerbated atrophy of IIX and IIB fibers. Colchicine treatment led to significant reductions in mitochondrial function, accompanied by CASP9 and CASP3 activation.
CONCLUSION: These findings emphasize the role of mitophagy in limiting excessive muscle atrophy during immobilization. Targeting mitophagy may offer new strategies to preserve muscle function during prolonged periods of immobilization.

Keywords:  Apoptosis; BNIP3; Disuse atrophy; Mitochondria; Mitophagy; Skeletal muscle

DOI:  https://doi.org/10.1186/s12929-025-01118-w
bioRxiv. 2025 Feb 03. pii: 2025.02.01.636045. [Epub ahead of print]

Mitophagy at the oocyte-to-zygote transition promotes species immortality.

Siddharthan Balachandar Thendral, Sasha Bacot, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.

The quality of inherited mitochondria determines embryonic viability 1 , metabolic health during adulthood and future generation endurance. The oocyte is the source of all zygotic mitochondria 2 , and mitochondrial health is under strict developmental regulation during early oogenesis 3-5 . Yet, fully developed oocytes exhibit the presence of deleterious mitochondrial DNA (mtDNA) 6,7 and mitochondrial dysfunction from high levels of endogenous reactive oxygen species 8 and exogenous toxicants 9 . How fully developed oocytes prevent transmission of damaged mitochondria to the zygotes is unknown. Here we discover that the onset of oocyte-to-zygote transition (OZT) developmentally triggers a robust and rapid mitophagy event that we term mitophagy at OZT (MOZT). We show that MOZT requires mitochondrial fragmentation, activation of the macroautophagy system and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Oocytes upregulate expression of FUNDC1 in response to diverse mitochondrial insults, including mtDNA mutations and damage, uncoupling stress, and mitochondrial dysfunction, thereby promoting selection against damaged mitochondria. Loss of MOZT leads to increased inheritance of deleterious mtDNA and impaired bioenergetic health in the progeny, resulting in diminished embryonic viability and the extinction of descendent populations. Our findings reveal FUNDC1-mediated MOZT as a mechanism that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity. These results may explain how mature oocytes from many species harboring mutant mtDNA give rise to healthy embryos with reduced deleterious mtDNA.

DOI: https://doi.org/10.1101/2025.02.01.636045
Pharmacol Rev. 2025 01;pii: S0031-6997(24)11605-5. [Epub ahead of print]77(1): 100005

Ferroptosis and pathogenesis of neuritic plaques in Alzheimer disease.

Wolfgang J Streit, Leah Phan, Ingo Bechmann.

  Neuritic plaques are pathognomonic and terminal lesions of Alzheimer disease (AD). They embody AD pathogenesis because they harbor in one space critical pathologic features of the disease: amyloid deposits, neurofibrillary degeneration, neuroinflammation, and iron accumulation. Neuritic plaques are thought to arise from the conversion of diffuse extracellular deposits of amyloid-β protein (Aβ), and it is believed that during conversion, amyloid toxicity creates the dystrophic neurites of neuritic plaques, as well as neurofibrillary tangles However, recent evidence from human postmortem studies suggests a much different mechanism of neuritic plaque formation, where the first step in their creation is neuronal degeneration driven by iron overload and ferroptosis. Similarly, neurofibrillary tangles represent the corpses of iron-laden neurons that develop independently of Aβ deposits. In this review, we will focus on the role of free redox-active iron in the development of typical AD pathology, as determined largely by evidence obtained in the human temporal lobe during early, preclinical stages of AD. The findings have allowed the construction of a scheme of AD pathogenesis where brain iron is center stage and is involved in every step of the sequence of events that produce characteristic AD pathology. We will discuss how the study of preclinical AD has produced a fresh and revised assessment of AD pathogenesis that may be important for reconsidering current therapeutic efforts and guiding future ones. SIGNIFICANCE STATEMENT: This review offers a novel perspective on Alzheimer disease pathogenesis where elevated brain iron plays a central role and is involved throughout the development of lesions. Herein, we review arguments against the amyloid cascade theory and explain how recent findings in humans during early preclinical disease support iron-mediated cell death and endogenous iron containment mechanisms as critical components of neuritic plaque formation and ensuing dementia.

Keywords:  Alzheimer's Disease; Neuroinflammation; beta-amyloid; blood-brain barrier; microglia; neuro-glial interactions; neurodegeneration

DOI:  https://doi.org/10.1124/pharmrev.123.000823
Ageing Res Rev. 2025 Feb 12. pii: S1568-1637(25)00035-2. [Epub ahead of print]105 102689

Bridging gap in the treatment of Alzheimer's disease via postbiotics: Current practices and future prospects.

Bushra Bashir, Monica Gulati, Sukriti Vishwas, Gaurav Gupta, Muralikrishnan Dhanasekaran, Keshav Raj Paudel, Dinesh Kumar Chellappan, Krishnan Anand, Poonam Negi, Pankaj Kumar Singh, Amarjitsing Rajput, Kamal Dua, Sachin Kumar Singh.

  Aging is an extremely significant risk associated with neurodegeneration. The most prevalent neurodegenerative disorders (NDs), such as Alzheimer's disease (AD) are distinguished by the prevalence of proteinopathy, aberrant glial cell activation, oxidative stress, neuroinflammation, defective autophagy, cellular senescence, mitochondrial dysfunction, epigenetic changes, neurogenesis suppression, increased blood-brain barrier permeability, and intestinal dysbiosis that is excessive for the patient's age. Substantial body studies have documented a close relationship between gut microbiota and AD, and restoring a healthy gut microbiota may reduce or even ameliorate AD symptoms and progression. Thus, control of the microbiota in the gut has become an innovative model for clinical management of AD, and rising emphasis is focused on finding new techniques for preventing and/or managing the disease. The etiopathogenesis of gut microbiota in driving AD progression and supplementing postbiotics as a preventive and therapeutic treatment for AD is discussed. The review additionally discusses the use of postbiotics in AD prophylaxis and therapy, portraying them as substances that address senescence-triggered dysfunctions and are worthy of translating from bench to biopharmaceutical market in response to "silver consumers" needs. The current review examines and evaluates the impact of postbiotics as whole and specific metabolites, such as short-chain fatty acids (SCFAs), lactate, polyamines, polyphenols, tryptophan metabolites, exopolysaccharides, and bacterial extracellular vesicles, on the aging-associated processes that reinforce AD. Moreover, it provides an overview of the most recent data from both clinical and preclinical research involving the use of postbiotics in AD.

Keywords:  Alzheimer's disease; Gut-brain relationship; Neurodegeneration; Neuroprotection; Postbiotics; Short chain fatty acids

DOI:  https://doi.org/10.1016/j.arr.2025.102689
Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00024-5. [Epub ahead of print]

Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.

Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Amanda L Smythers, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Joao A Paulo, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman.

  Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

Keywords:  MPST; ergothioneine; exercise; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.01.024
J Physiol Biochem. 2025 Feb 19.

The link between Mitochondria and Sarcopenia.

Nurul Tihani Kamarulzaman, Suzana Makpol.

  Sarcopenia, a widespread condition, is characterized by a variety of factors influencing its development. The causes of sarcopenia differ depending on the age of the individual. It is defined as the combination of decreased muscle mass and impaired muscle function, primarily observed in association with ageing. As people age from 20 to 80 years old, there is an approximate 30% reduction in muscle mass and a 20% decline in cross-sectional area. This decline is attributed to a decrease in the size and number of muscle fibres. The regression of muscle mass and strength increases the risk of fractures, frailty, reduced quality of life, and loss of independence. Muscle cells, fibres, and tissues shrink, resulting in diminished muscle power, volume, and strength in major muscle groups. One prominent theory of cellular ageing posits a strong positive relationship between age and oxidative damage. Heightened oxidative stress leads to early-onset sarcopenia, characterized by neuromuscular innervation breakdown, muscle atrophy, and dysfunctional mitochondrial muscles. Ageing muscles generate more reactive oxygen species (ROS), and experience decreased oxygen consumption and ATP synthesis compared to younger muscles. Additionally, changes in mitochondrial protein interactions, cristae structure, and networks may contribute to ADP insensitivity, which ultimately leads to sarcopenia. Within this framework, this review provides a comprehensive summary of our current understanding of the role of mitochondria in sarcopenia and other muscle degenerative diseases, highlighting the crucial need for further research in these areas.

Keywords:  Mitochondria; Mitochondrial protein interactions; Muscle ageing; Oxidative stress; Sarcopenia

DOI:  https://doi.org/10.1007/s13105-024-01062-7
J Nutr. 2025 Feb 14. pii: S0022-3166(25)00092-6. [Epub ahead of print]

Protection of Green Tea Polyphenols against Neurodegenerative Diseases: Evidence and Possible Mechanisms.

Yan Zhao, Baolu Zhao.

  Aging is a major risk factor for neurodegenerative diseases. With aging of the global population, the prevalence of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) has increased worldwide. Unfortunately, the available therapeutic options for these neurodegenerative diseases are limited, most of which only provide symptomatic relief and have potentially serious side effects. Epidemiological studies have shown that green tea consumption is associated with a lower prevalence of cognitive decline and decreased risk of AD and PD, providing an attractive preventive and therapeutic option. Polyphenols are major bioactive components in green tea which contribute to the beneficial effects of green tea. Accumulating data suggest that green tea polyphenols (GTPs) have neuroprotective properties that inhibit the pathological development of neurodegenerative diseases; however, the underlying mechanisms are not yet completely understood. The present paper reviews both in vitro and in vivo evidence that demonstrates the neuroprotective effects of GTPs against neurodegenerative diseases, with the main focus on AD and PD, and summarizes the possible molecular mechanisms by which GTPs impede the progression of neurodegeneration. In particular, this review highlights the modulation of GTPs on the common mechanisms involved in pathogenesis of neurodegenerative diseases, including oxidative stress-mediated neuronal toxicity, impaired proteostasis, and metal ion dyshomeostasis. The potential of using GTPs in the intervention of neurodegenerative diseases is also discussed, hopefully, providing useful insights into novel preventive and therapeutic strategies for these diseases.

Keywords:  Alzheimer’s diseases; Parkinson’s diseases; green tea polyphenols; neurodegenerative diseases; neuroprotection; oxidative stress

DOI:  https://doi.org/10.1016/j.tjnut.2025.02.010
Physiology (Bethesda). 2025 Feb 17.

Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Abu Mohammad Syed, Alexander K Karius, Jin Ma, Ping-Yuan Wang, Paul M Hwang.

  ME/CFS is a debilitating multisystem disorder of unclear etiology that affects many individuals worldwide. One of its hallmark symptoms is prolonged fatigue following exertion, a feature also observed in long COVID, suggesting an underlying dysfunction in energy production in both conditions. Here, mitochondrial dysfunction and its potential pathogenetic role in these disorders are reviewed.

Keywords:  Wiskott-Aldrich syndrome protein family member 3 (WASF3); endoplasmic reticulum stress (ER stress); mitochondria; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

DOI:  https://doi.org/10.1152/physiol.00056.2024
Mol Med. 2025 Feb 18. 31(1): 61

Type 3 diabetes and metabolic reprogramming of brain neurons: causes and therapeutic strategies.

Xiangyuan Meng, Hui Zhang, Zhenhu Zhao, Siyao Li, Xin Zhang, Ruihan Guo, Huimin Liu, Yiling Yuan, Wanrui Li, Qi Song, Jinyu Liu.

  Abnormal glucose metabolism inevitably disrupts normal neuronal function, a phenomenon widely observed in Alzheimer's disease (AD). Investigating the mechanisms of metabolic adaptation during disease progression has become a central focus of research. Considering that impaired glucose metabolism is closely related to decreased insulin signaling and insulin resistance, a new concept "type 3 diabetes mellitus (T3DM)" has been coined. T3DM specifically refers to the brain's neurons becoming unresponsive to insulin, underscoring the strong link between diabetes and AD. Recent studies reveal that during brain insulin resistance, neurons exhibit mitochondrial dysfunction, reduced glucose metabolism, and elevated lactate levels. These findings suggest that impaired insulin signaling caused by T3DM may lead to a compensatory metabolic shift in neurons toward glycolysis. Consequently, this review aims to explore the underlying causes of T3DM and elucidate how insulin resistance drives metabolic reprogramming in neurons during AD progression. Additionally, it highlights therapeutic strategies targeting insulin sensitivity and mitochondrial function as promising avenues for the successful development of AD treatments.

Keywords:  Alzheimer’s disease; Insulin resistance; Metabolic reprogramming; Type 3 diabetes mellitus

DOI:  https://doi.org/10.1186/s10020-025-01101-z
Curr Alzheimer Res. 2025 Feb 19.

Microglial Modulation in Alzheimer's Disease: Central Players in Neuroinflammation and Pathogenesis.

Md Sadique Hussain, Yumna Khan, Rabab Fatima, Mudasir Maqbool, Prasanna Srinivasan Ramalingam, Mohammad Gayoor Khan, Ajay Singh Bisht.

  Alzheimer's disease (AD) is an age-related, progressive neurodegenerative disorder of cognition with clinical features and anatomical hallmarks of amyloid-β plaques and/or neurofibrillary tangles. New studies revealed that microglia, the native immune cells in the brain, are crucial in the development of AD. The present review aims at outlining various roles of microglia in AD especially targeting their role in neuroinflammation. These indicate that microglial dysfunction contributes to AD pathology by affecting both amyloid-β phagocytosis and tau hyperphosphorylation. Other investigative molecular perpetrators, including TREM2, also influence the microglial relevance to amyloid and tau, as well as the overall disease phase. The functional microglia can protect neurons, while the dysfunctional one has the capability of derailing neuronal potentials and aggravating neurodegeneration. We have also discussed therapeutic strategies that start with targeting microglia to reduce neuroinflammation and reinstate balance. However, certain problems, including the side effects of microglial modulation, cost constraint, and accessibility, are areas of concern. In this review, the author presents the current state of knowledge on the potential of microglia-targeted treatments, their risks, and benefits. Thus, this article emphasizes the importance of the expansion of research to decipher the exact manipulation of microglia in AD with the goal of applying these findings given therapeutic approaches.

Keywords:  Amyloid-β; Immunomodulation; Microglial dysfunction; TREM2.; Tau

DOI:  https://doi.org/10.2174/0115672050364292250113063513