bims-polgdi Biomed News
on POLG disease
Issue of 2025–06–15
seventeen papers selected by
Luca Bolliger, lxBio
  1. Advances in Management of Mitochondrial Myopathies.
  2. Diagnostic Moments in the Rare Disease Life Narratives of Mitochondrial Disease Patients in Germany.
  3. Extracellular vesicle-mediated mitochondria delivery: Premise and promise.
  4. Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
  5. Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
  6. Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances.
  7. Mitochondrial Transplantation: A Novel Therapeutic Approach for Treating Diseases.
  8. Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.
  9. Polyphenols and Exercise in Mitochondrial Biogenesis: Focus on Age-Related CNS Disorders.
  10. mitoLEAF: mitochondrial DNA Lineage, Evolution, Annotation Framework.
  11. Open-label pilot study using hydroxytyrosol as dietary supplements in patients with mitochondrial diseases.
  12. Comparative analysis of mitochondrial and mesenchymal stem cell transplantation for angiogenesis and muscle regeneration.
  13. N-acetyl-L-cysteine improves mitochondrial and oxidative defects in the acadian variant of fanconi syndrome.
  14. Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.
  15. An Ounce of Prevention: The Growing Need for Preventive Neurologists.
  16. From Nutrient to Nanocarrier: The Multifaceted Role of Vitamin B12 in Drug Delivery.
  17. Aging on Chip: Harnessing the Potential of Microfluidic Technologies in Aging and Rejuvenation Research.
  1. Int J Mol Sci. 2025 Jun 05. pii: 5411. [Epub ahead of print]26(11):
    Advances in Management of Mitochondrial Myopathies.
    Athanasios Bangeas, Vasiliki Poulidou, Ioannis Liampas, Chrysa Marogianni, Athina-Maria Aloizou, Zisis Tsouris, Markos Sgantzos, Marianthi Arnaoutoglou, Dimitrios P Bogdanos, Efthimios Dardiotis, Vasileios Siokas.
      Mitochondria, the energy factories of human organisms, can be the cause of a variety of genetic disorders called mitochondrial myopathies. Mitochondrial diseases arise from genetic alterations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) and can manifest with great heterogeneity, leading to multiorgan dysfunction. The purpose of this article is to concisely review the pathophysiology, genetics and main clinical features of mitochondrial myopathies, focusing mainly on the treatment and management of these disorders. Currently, a particular treatment for mitochondrial myopathies does not exist, while the available guidelines concerning management are based on experts' opinions. The therapeutic options currently applied largely aim at symptom relief and amelioration of patients' quality of life. The most commonly used regimens involve the administration of vitamins and cofactors, although hard evidence regarding their true benefit for patients is still lacking. Recent studies have demonstrated promising results for elamipretide; however, phase III clinical trials are still ongoing. Regarding patient management, a multidisciplinary approach with the collaboration of different specialties is required. Further clinical trials for the already applied treatment options, as well as on novel experimental therapies, are of utmost importance in order to improve patients' outcomes.
    Keywords:  management; mitochondrial myopathies; treatment
    DOI:  https://doi.org/10.3390/ijms26115411
  2. Med Anthropol. 2025 Jun 08. 1-13
    Diagnostic Moments in the Rare Disease Life Narratives of Mitochondrial Disease Patients in Germany.
    Jacquelyne Luce.
      I draw on interviews I conducted in Germany with four individuals who were eventually diagnosed with mitochondrial disease, a category of rare neurogenetic disorders. Rather than the diagnosis of mitochondrial disease serving as a threshold between a before and after, I show how multiple ″diagnostic moments″ generate and shape mitochondrial disease life narratives as affected individuals embody emergent medical knowledge and navigate scientific unknowns. Attending to the plurality of diagnostic moments in rare disease life narratives illuminates the fragmented temporalities and incoherencies of illness experiences, which are often erased by an emphasis on a singular diagnostic moment.
    Keywords:  Germany; diagnosis; diagnostic moments; mitochondrial disease; narrative; rare disease
    DOI:  https://doi.org/10.1080/01459740.2025.2504366
  3. J Cereb Blood Flow Metab. 2025 Jun 11. 271678X251349304
    Extracellular vesicle-mediated mitochondria delivery: Premise and promise.
    Devika S Manickam, Paromita Paul Pinky, Purva Khare.
      Mitochondrial transfer is highly significant under physiological as well as pathological states given the emerging recognition of mitochondria as cellular "processors" akin to microchip processors that control the operation of a mobile device. Mitochondria play indispensable roles in healthy functioning of the brain, the organ with the highest energy demand in the human body and therefore, loss of mitochondrial function plays a causal role in multiple brain diseases. In this review, we will discuss various aspects of extracellular vesicle (EV)-mediated mitochondrial transfer and their effects in increasing recipient cell/tissue bioenergetics with a focus on these processes in brain cells. A subset of EVs with particle diameters >200 nm, referred to as medium-to-large EVs (m/lEVs), are known to entrap mitochondria during EV biogenesis. The entrapped mitochondria are likely a combination of either polarized, depolarized mitochondria or a mixture of both. We will also discuss engineering approaches to control the quality and quantity of mitochondria entrapped in the m/lEVs. Controlling mitochondrial quality can allow for optimizing/maximizing the therapeutic potential of m/lEV mitochondria-a novel drug with immense potential to treat a wide range of disorders associated with mitochondrial dysfunction.
    Keywords:  Extracellular vesicles (EVs); medium-to-large EVs; microvesicles; mitochondria; small EVs
    DOI:  https://doi.org/10.1177/0271678X251349304
  4. bioRxiv. 2025 May 28. pii: 2025.05.25.655566. [Epub ahead of print]
    Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
    Rahul Gupta, Timothy J Durham, Grant Chau, Md Mesbah Uddin, Wenhan Lu, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.
      One of the strongest signatures of aging is an accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy. Here we investigate the mechanism underlying this phenomenon by calling mtDNA sequence, abundance, and heteroplasmic variation in human blood using whole genome sequences from ∼750,000 individuals. Our analyses reveal a simple, two-step mechanism: first, individual cells randomly accumulate low levels of "cryptic" mtDNA mutations; then, when a cell clone proliferates, the cryptic mtDNA variants are carried as passenger mutations and become detectable in whole blood. Four lines of evidence support this model: (1) the mutational spectrum of age-accumulating mtDNA variants is consistent with a well-established model of mtDNA replication errors, (2) these mutations are found primarily at low levels of heteroplasmy and do not show evidence of positive selection, (3) high mtDNA mutation burden tends to co-occur in samples harboring somatic driver mutations for clonal hematopoiesis (CH), and (4) nuclear GWAS reveals that germline variants predisposing to CH (such as those near TERT , TCL1A , and SMC4 ) also increase mtDNA mutation burden. We propose that the high copy number and high mutation rate of mtDNA make it a particularly sensitive blood-based marker of CH. Importantly, our work helps to mechanistically unify three prominent signatures of aging: common germline variants in TERT , clonal hematopoiesis, and observed mtDNA mutation accrual.
    DOI:  https://doi.org/10.1101/2025.05.25.655566
  5. Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]
    Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
    Daniel A Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu.
      Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.
    Keywords:  cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.cell.2025.05.020
  6. Signal Transduct Target Ther. 2025 Jun 11. 10(1): 190
    Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances.
    Xieyang Xu, Yan Pang, Xianqun Fan.
      Mitochondria are the energy production centers in cells and have unique genetic information. Due to the irreplaceable function of mitochondria, mitochondrial dysfunction often leads to pathological changes. Mitochondrial dysfunction induces an imbalance between oxidation and antioxidation, mitochondrial DNA (mtDNA) damage, mitochondrial dynamics dysregulation, and changes in mitophagy. It results in oxidative stress due to excessive reactive oxygen species (ROS) generation, which contributes to cell damage and death. Mitochondrial dysfunction can also trigger inflammation through the activation of damage-associated molecular patterns (DAMPs), inflammasomes and inflammatory cells. Besides, mitochondrial alterations in the functional regulation, energy metabolism and genetic stability accompany the aging process, and there has been a lot of evidence suggesting that oxidative stress and inflammation, both of which are associated with mitochondrial dysfunction, are predisposing factors of aging. Therefore, this review hypothesizes that mitochondria serve as central hubs regulating oxidative stress, inflammation, and aging, and their dysfunction contributes to various diseases, including cancers, cardiovascular diseases, neurodegenerative disorders, metabolic diseases, sepsis, ocular pathologies, liver diseases, and autoimmune conditions. Moreover, we outline therapies aimed at various mitochondrial dysfunctions, highlighting their performance in animal models and human trials. Additionally, we focus on the limitations of mitochondrial therapy in clinical applications, and discuss potential future research directions for mitochondrial therapy.
    DOI:  https://doi.org/10.1038/s41392-025-02253-4
  7. MedComm (2020). 2025 Jun;6(6): e70253
    Mitochondrial Transplantation: A Novel Therapeutic Approach for Treating Diseases.
    Xinglu Miao, Pei Jiang, Zhaoping Wang, Weihua Kong, Lei Feng.
      Advances in mitochondrial biology have led to the development of mitochondrial transplantation as a novel and promising therapeutic strategy. This review provides a comprehensive analysis of the multifaceted roles of mitochondria in health and disease, highlighting their central functions in energy production, antioxidant defense, calcium signaling, apoptosis regulation, and mitochondrial homeostasis maintenance. We explore the mechanisms by which transplanted mitochondria exert their therapeutic effects, including restoring ATP production, attenuating oxidative stress, modulating inflammatory responses, reducing cellular apoptosis, promoting cell repair and regeneration, facilitating neural circuit reconstruction, and exhibiting antitumor properties. Key preclinical studies demonstrating the efficacy of mitochondrial transplantation across in vitro and in vivo disease models are discussed, along with the status of clinical trials. The review also critically compares mitochondrial transplantation with other mitochondria-targeted therapies, evaluating their relative advantages and limitations. Finally, we discuss the current challenges of translating this innovative therapy into clinical practice, such as mitochondrial isolation and purification, storage, targeted delivery, potential immune responses, and long-term safety and efficacy concerns. This review aims to stimulate further research and development in this promising field, paving the way for novel therapeutic interventions for various diseases.
    Keywords:  disease therapy; mitochondria; mitochondrial transplantation; therapeutic strategy
    DOI:  https://doi.org/10.1002/mco2.70253
  8. Life Metab. 2025 Jun;4(3): loaf012
    Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.
    Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard.
      Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have consistently high, while others show consistently low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mitochondrial DNA (mtDNA) density was correlated between tissues (median r = -0.01 to 0.16), indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues. Similarly, RNA sequencing (RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men (genotype-tissue expression [GTEx]) showed only small to moderate coherence between some tissues, such as between brain regions (r = 0.26), but not between brain-body tissue pairs (r = 0.01). The mtDNA copy number (mtDNAcn) also lacked coherence across human tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were partially attributable to (i) tissue-specific activation of energy sensing pathways, including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the integrated stress response (ISR), and other molecular regulators of mitochondrial biology, and (ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes. These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.
    Keywords:  disease risk; energy sensing; gene regulation; inter-organ crosstalk; mitochondrial biogenesis; mitochondrion
    DOI:  https://doi.org/10.1093/lifemeta/loaf012
  9. Mol Neurobiol. 2025 Jun 13.
    Polyphenols and Exercise in Mitochondrial Biogenesis: Focus on Age-Related CNS Disorders.
    Junbiao Tu.
      Age-related central nervous system (CNS) disorders, including neurodegenerative diseases, represent a growing global health burden. Mitochondrial dysfunction is a recognized hallmark in the pathogenesis of these conditions, emphasizing the critical importance of maintaining neuronal energy homeostasis and cellular integrity. Mitochondrial biogenesis, the dynamic process of generating new, functional mitochondria, is paramount for neuronal health and resilience against age-related decline. This review investigates the therapeutic potential of physical activity and polyphenols in modulating mitochondrial biogenesis and offering neuroprotection within the context of age-related CNS disorders. We explore how regular exercise profoundly impacts the brain by enhancing synaptic plasticity, promoting neurogenesis via neurotrophic factors like BDNF, and stimulating mitochondrial biogenesis through pathways such as PGC-1alpha activation. These adaptations collectively improve cognitive function and bolster neuronal resistance to damage. Concurrently, polyphenols, known for their antioxidant and anti-inflammatory properties, demonstrate significant neuroprotective effects. They are capable of crossing the blood-brain barrier and influencing key neuronal signaling pathways, directly stimulating mitochondrial biogenesis, and mitigating oxidative stress, thereby supporting neuronal survival. By synthesizing current evidence, this review highlights the complementary and potentially synergistic roles of exercise and polyphenols in preserving mitochondrial health and function in the CNS. The combined impact of these interventions offers a promising non-pharmacological strategy to combat age-related neurodegeneration. Future research should focus on optimizing exercise protocols and polyphenol interventions in human trials to maximize their neurotherapeutic benefits for CNS disorders.
    Keywords:  Age-related central nervous system disorders; Exercise; Mitochondrial biogenesis; Polyphenol
    DOI:  https://doi.org/10.1007/s12035-025-05121-y
  10. NAR Genom Bioinform. 2025 Jun;7(2): lqaf079
    mitoLEAF: mitochondrial DNA Lineage, Evolution, Annotation Framework.
    Nicole Huber, Noah Hurmer, Arne Dür, Walther Parson.
      The study of mitochondrial DNA (mtDNA) provides invaluable insights into genetic variation, human evolution, and disease mechanisms. However, maintaining a consistent and reliable classification system requires continuous updates. Since Phylotree updates ended in 2016, the accumulation of new haplogroup findings in individual studies has highlighted the critical need for a centralized resource to ensure consistent classifications. To address this gap, we present mitoLEAF, a collaborative, freely accessible, and academically driven repository for mitochondrial phylogenetic analyses. Unlike commercial alternatives that restrict access to their customers through subscription or purchase, mitoLEAF is openly accessible and replicable, ensuring transparency and scientific reproducibility. Hosted as a GitHub repository and supported by an interactive website, mitoLEAF provides an evolving, quality-controlled phylogenetic resource derived from GenBank, EMPOP, and peer-reviewed literature. In this first release, it expands the haplogroup landscape from 5435 to 6409 haplogroups, integrating recent findings and improving phylogenetic accuracy. By excluding known pathogenic variants, mitoLEAF aims to mitigate ethical concerns associated with reporting medically relevant variants. By prioritizing open science over commercial interests, mitoLEAF serves as a vital, community-driven platform for mitochondrial research, fostering collaboration and continuous development.
    DOI:  https://doi.org/10.1093/nargab/lqaf079
  11. Orphanet J Rare Dis. 2025 Jun 06. 20(1): 283
    Open-label pilot study using hydroxytyrosol as dietary supplements in patients with mitochondrial diseases.
    Tsz Sum Wong, Emily Man, Ian Chi Kei Wong, Shirley Xue Li, Hui Zhi, Ka Man Carmen Yeung, Ka Yee Yip, Anna Ka Yee Kwong, Kiran Moti Belaramani, Suet Na Wong, Anne Mei Kwun Kwok, Miu Mak, Toby Chun Hei Chan, Pui Yee Lau, Yee Ling Elaine Kan, Kwok Chun Wong, Freddie Poon, Vansie Kwok, Chun Yin Dick Li, Paul Lau, Sze Man Lam, Vanessa Chu, Chi Fung Godfrey Chan, Cheuk Wing Fung.
       BACKGROUND: Mitochondrial Diseases (MDs) refers to a heterogeneous group of inherited metabolic disorders resulting in defective cellular energy production due to abnormal oxidative phosphorylation (OXPHOS) caused by pathogenic mitochondrial DNA or nuclear DNA variants. As mitochondria are pivotal for cell bioenergetics, MDs could potentially affect multisystem, leaving a devastating and life-threatening impact. The treatment of MDs present significant challenges due to the complexity of the disease and the wide heterogeneity of its molecular defects. Thus, the need for innovative and more comprehensive therapeutic approaches is evident.
    METHODS: This longitudinal, open-label study was a pilot trial involving 9 paediatric MD patients, aiming to gain a better understanding on the impact of hydroxytyrosol (HT) on the clinical outcomes of MD patients and to assess the feasibility and logistics of using HT as a dietary supplement for MD patients. Subjects received HT daily as dietary supplements for 12 months. Following this period, patients were then randomly assigned to either discontinue HT or continue receiving HT as their dietary supplements for an additional 6 months. Outcome measures that were assessed included the International Paediatric Mitochondrial Disease Scores, biochemical parameters, and quality of life assessments.
    RESULTS: Among the outcome measures assessed, HT supplementation demonstrated the most considerable impact on improving the health-related quality of life according to the PedsQL scoring system and potential effects on a subgroup of MD patients with Mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS).
    DISCUSSION: This study demonstrated that HT supplementation resulted in improvement in health-related quality of life in MD patients, while the subgroup of MELAS patients showed additional potential beneficial effect from HT use. As a pilot trial, this study importantly highlighted HT's tolerability in MD patients, which would facilitate trials of larger scale to be performed in the future.
    CONCLUSION: This study highlights the use of HT as a health supplement and its potential therapeutic effects in paediatric patients diagnosed with MDs, especially in MELAS patients. The results lay the foundation for future large-scale clinical trials. Consequently, further clinical intervention studies and investigations into HT's potential therapeutic mechanisms at the molecular and intercellular levels are strongly encouraged.
    Keywords:  Hydroxytyrosol; MELAS; Mitochondrial diseases; Pilot study
    DOI:  https://doi.org/10.1186/s13023-025-03795-0
  12. Cell Transplant. 2025 Jan-Dec;34:34 9636897251347391
    Comparative analysis of mitochondrial and mesenchymal stem cell transplantation for angiogenesis and muscle regeneration.
    Mi Jin Kim, Jung Wook Hwang, Chang-Koo Yun, Ikhyun Lim, Kyunghoon Min, Yong-Soo Choi.
      Mitochondrial transplantation has emerged as a promising strategy for treating ischemic diseases by restoring mitochondrial function in damaged tissues. This study investigated the therapeutic potential of mitochondria isolated from placenta-derived mesenchymal stem cells (PD-MSCs) in a murine critical limb ischemia (CLI) model. The isolated mitochondria were characterized to confirm their structural integrity, purity, and ATP production capacity before transplantation into an ischemic hindlimb. Results showed that mitochondrial transplantation significantly improved blood flow and muscle regeneration compared with MSC transplantation, as evidenced by laser Doppler perfusion imaging and histological analysis. Enhanced ATP production and increased oxidative phosphorylation complex protein levels were observed, supporting energy metabolism in ischemic conditions. Mitochondrial transplantation also reduced mitochondrial reactive oxygen species (mROS) levels and increased antioxidant enzyme expression, including SOD-2, leading to reduced oxidative stress and apoptosis, as indicated by decreased Bax, cytosolic cytochrome c, and cleaved caspase-3 levels. Furthermore, mitochondrial transplantation promoted angiogenesis and increased vascular density in ischemic muscles by enhancing endothelial cell function. Overall, PD-MSC-derived mitochondrial transplantation demonstrated proved more effective over MSC transplantation in reducing inflammation, restoring mitochondrial function, and supporting tissue recovery, highlighting its promise as an effective therapeutic approach for CLI and other ischemic conditions by directly addressing mitochondrial dysfunction and overcoming the limitations of conventional cell therapies.
    Keywords:  angiogenesis; ischemia; mitochondria; mitochondrial transplantation; tissue regeneration
    DOI:  https://doi.org/10.1177/09636897251347391
  13. Exp Biol Med (Maywood). 2025 ;250 10448
    N-acetyl-L-cysteine improves mitochondrial and oxidative defects in the acadian variant of fanconi syndrome.
    Inas Al-Younis, Rebeca Martín-Jiménez, Mehtab Khan, Yann Baussan, Caroline Jose, Yves Thibeault, Etienne Hebert-Chatelain.
      The Acadian variant of Fanconi Syndrome (AVFS) is a rare genetic disorder characterized by renal deficiencies. AVFS is caused by a mutation to NDUFAF6 encoding a complex I assembly factor, and leading to metabolic alterations. We confirmed that fibroblasts derived from AVFS patients have lower complex I activity, mitochondrial membrane potential and cellular respiration. These mitochondrial defects were accompanied by higher levels of 8-hydroxy-2'deoxyguanosine, malondialdehyde and carbonyl, which are markers of oxidative damage to DNA, lipids and proteins, respectively. Thus, we hypothesized that the antioxidant N-Acetyl-L-cysteine (NAC) would reduce oxidative stress and mitochondrial defects in AVFS fibroblasts. Treatment with NAC during 5 days partially restored complex I activity, mitochondrial membrane potential and cellular respiration in AVFS fibroblasts. NAC also prevented oxidative damage in AVFS fibroblasts. This work shows for the first time that the physiopathology of AVFS includes high oxidative stress. It also reveals that NAC and other antioxidant-based strategies might represent an effective pharmacological treatment for AVFS.
    Keywords:  antioxidant; kidney disease; mitochondrial disease; oxidative stress; rare disease
    DOI:  https://doi.org/10.3389/ebm.2025.10448
  14. Cells. 2025 Jun 04. pii: 845. [Epub ahead of print]14(11):
    Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.
    Jessica Tittelmeier, Carmen Nussbaum-Krammer.
      Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital role in maintaining cellular homeostasis by mediating the degradation and recycling of proteins, lipids, and other macromolecules. As such, it serves as a central hub for both proteostasis and lipostasis. This review outlines genetic and mechanistic parallels between rare lysosomal lipid storage diseases, such as Gaucher disease and Niemann-Pick disease, and more prevalent neurodegenerative diseases. We discuss how impaired lysosomal sphingolipid metabolism compromises lysosomal integrity, disrupts proteostasis, and contributes to neurodegeneration. Furthermore, we describe how age-related decline in lysosomal function may similarly drive neurodegeneration in the absence of overt genetic mutations. Taken together, this review highlights the lysosome as a central integrator of protein and lipid homeostasis and emphasizes the bidirectional relationship between lipostasis and proteostasis, whereby disruption of one adversely affects the other in the pathogenesis of multiple neurodegenerative diseases.
    Keywords:  lipostasis; lysosomal lipid storage diseases; lysosome; neurodegenerative diseases; prion-like propagation; proteostasis; sphingolipidoses
    DOI:  https://doi.org/10.3390/cells14110845
  15. Neurology. 2025 Jul 08. 105(1): e213785
    An Ounce of Prevention: The Growing Need for Preventive Neurologists.
    Behnam Sabayan, Bernadette Boden-Albala, Natalia S Rost.
      The global burden of neurologic disorders is rising, driven by aging populations and improved survival following acute neurologic events. As a result, more individuals are living with long-term disabilities from conditions such as stroke, dementia, and other neurodegenerative diseases. Despite significant advances in neurology, there remains an urgent need for a preventive approach to mitigate these trends. Growing evidence highlights the effectiveness of preventive strategies, including lifestyle modifications and risk factor management, in preserving brain health and reducing the risk of stroke, neurodegenerative conditions, and cognitive decline. Preventive neurology operates within a multilevel framework, ranging from direct patient-centered interventions to systemic policy actions requiring organizational and societal support. Neurologists are uniquely positioned as advocates for brain health, promoting preventive strategies in line with the American Academy of Neurology's Brain Health Initiative. This article explores how neurologists can drive change across individual, family, community, and policy levels by leveraging their clinical expertise, community engagement, and health policy influence. Sustainable progress in brain health will also require system-level changes that integrate preventive goals into the fabric of health care delivery, public health infrastructure, and policy frameworks. Special attention is given to underserved populations, who bear a disproportionate burden of neurologic diseases. Through targeted interventions, public health initiatives, and collaborative care models, preventive neurologists can shape brain health outcomes across the lifespan. Training neurologists with a preventive focus will integrate brain health promotion into standard neurology practice, complementing disease management. By addressing the root causes and risk factors of neurologic conditions, preventive neurology provides a pathway to improving quality of life while reducing the global health care burden.
    DOI:  https://doi.org/10.1212/WNL.0000000000213785
  16. Int J Mol Sci. 2025 May 26. pii: 5119. [Epub ahead of print]26(11):
    From Nutrient to Nanocarrier: The Multifaceted Role of Vitamin B12 in Drug Delivery.
    Nikita A Kuldyushev, Sergey Y Simonenko, Semen I Goreninskii, Tatiana N Pallaeva, Andrey A Zamyatnin, Alessandro Parodi.
      Vitamin B12 (B12), a crucial water-soluble vitamin, plays an essential role in various cellular functions, including DNA synthesis and cellular metabolism. This review explores recent advancements in B12 delivery systems and their potential applications in drug delivery. The unique absorption pathways of B12, which involve specific binding proteins and receptors, are highlighted, emphasizing the vitamin's protective mechanisms that enhance its bioavailability. The review discusses the intricate multi-protein network involved in B12 metabolism and the implications of B12 deficiency, which can lead to significant health issues, including neurological and hematological disorders. Additionally, the potential of B12 as a drug carrier to improve the pharmacokinetic properties of poorly bioavailable medications is examined. The findings suggest that optimizing B12 delivery could enhance therapeutic outcomes in nanomedicine and other clinical applications.
    Keywords:  cancer; drug delivery; nanomedicine; nanoparticles; neurological conditions; vitamin B12
    DOI:  https://doi.org/10.3390/ijms26115119
  17. Adv Healthc Mater. 2025 Jun 12. e2500217
    Aging on Chip: Harnessing the Potential of Microfluidic Technologies in Aging and Rejuvenation Research.
    Limor Zwi-Dantsis, Vignesh Jayarajan, George M Church, Roger D Kamm, João Pedro de Magalhães, Emad Moeendarbary.
      Aging is a complex process and the main risk factor for many common human diseases. Traditional aging research using short-lived animal models and two-dimensional cell cultures has led to key discoveries, but their relevance to human aging remains debatable. Microfluidics, a rapidly growing field that manipulates small volumes of fluids within microscale channels, offers new opportunities for aging research. By enabling the development of advanced three-dimensional cellular models that closely mimic human tissues, microfluidics allows more accurate investigation of aging processes while reducing costs, resource use, and culture time. This review explores how microfluidic systems, particularly organ-on-chip models, can improve our understanding of aging and age-related diseases, bridge the gap between animal models and human biology, and support the discovery of rejuvenation therapies. We highlight their role in monitoring aging biomarkers, analyzing functional cellular changes, and identifying longevity-promoting compounds. The ability of microfluidics to detect, analyze, and remove senescent cells is also discussed, along with emerging applications such as partial reprogramming for cellular rejuvenation. Furthermore, we summarize how these devices support single-cell analysis and recreate specific tissue microenvironments that influence aging. Insights from microfluidic approaches hold promise for developing therapeutic strategies to extend healthspan and promote longevity.
    Keywords:  aging research; microfluidics; organ‐on‐a‐chip; rejuvenation
    DOI:  https://doi.org/10.1002/adhm.202500217
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