bims-polgdi 2025-08-31 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–08–31
twenty-one papers selected by
Luca Bolliger, lxBio

Blood and neuronal extracellular vesicle mitochondrial disruptions in schizophrenia.
Selective muscle MRI changes in a patient with a rare mitochondrial DNA variant causing myoclonic epilepsy with ragged red fibres.
Mitochondrial Extracellular Vesicles: A Novel Approach to Mitochondrial Quality Control.
Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.
Mitochondrial DNA methylation: State-of-the-art in molecular mechanisms and disease implications.
Cellular Models of Aging and Senescence.
Clinical and Molecular Characterizations of Mitochondrial Disorders: A Tertiary-Care Center Experience.
Endothelial mitochondria in the blood-brain barrier.
Radiolabeling isolated mitochondria with Tc-99m: A first-in-field protocol and early feasibility findings.
Systemic Lonp1 Haploinsufficiency Mitigates Cardiac Mitochondrial Dysfunction Induced by Cardiomyocyte-Specific Lonp1 Haploinsufficiency via Potential Inter-Organ Crosstalk.
Extracellular vesicles in clinical chemistry: A focus on biomarkers.
Potential of small extracellular vesicles as Cas9 delivery tool: A promising approach for gene editing livestock gametes and embryos.
Mitochondrial homeostasis dysfunctions during the epithelial-mesenchymal transition process in lens epithelial cells.
The homoplasmic MT-TK m.8357T > C mtDNA variant as a cause of multiorgan mitochondrial disease.
Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential.
The Transgenerational Impact of High-Fat Diet and Diabetic Pregnancy on Embryonic Transcriptomics and Mitochondrial Health.
Mitochondrial Transfer Between Cancer and T Cells: Implications for Immune Evasion.
Systematic review of exosomes derived from various stem cell sources: function and therapeutic potential in disease modulation.
Mitochondrial proteins as biomarkers of cellular senescence and age-associated diseases.
Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome.
CRISPR in Neurodegenerative Diseases Treatment: An Alternative Approach to Current Therapies.

Neuropsychopharmacology. 2025 Aug 23.

Blood and neuronal extracellular vesicle mitochondrial disruptions in schizophrenia.

A Ankeeta, Ashutosh Tripathi, Bindu Pillai, Yizhou Ma, Joshua J Chiappelli, Jessica N Jernberg, Keiko Kunitoki, Xiaoming Du, Si Gao, Bhim M Adhikari, Consuelo Walss-Bass, Giselli Scaini, Peter Kochunov, Anilkumar Pillai, L Elliot Hong.

The high energy demand of the human brain obligates robust mitochondrial energy metabolism, while mitochondrial dysfunctions have been linked to neuropsychiatric disorders, including schizophrenia spectrum disorders (SSD). However, in vivo assessments that can directly inform brain mitochondrial functioning and its etiopathophysiological path to SSD remain difficult to obtain. We hypothesized that system and brain mitochondrial dysfunctions in SSD may be indexed by elevated cell-free mitochondrial DNA (cf-mtDNA) levels in the blood and in neuronal extracellular vesicles (nEVs). We also explored if these mtDNA marker elevations were associated with brain metabolites as measured by magnetic resonance spectroscopy (MRS). We examined blood cf-mtDNA in 58 SSD patients and 33 healthy controls, followed by assessing nEV mtDNA and metabolite levels using MRS in a subgroup of patients and controls. We found that people with SSD had significantly elevated cf-mtDNA levels in both the blood (p = 0.0002) and neuronal EVs (p = 0.003) compared to controls. These mtDNA abnormalities can be linked back to brain lactate+ levels such that higher blood and nEV mtDNA levels were significantly associated with higher lactate+ levels measured at the anterior cingulate cortex (r = 0.53, 0.53; p = 0.008, 0.03, respectively) in SSD patients. Furthermore, higher developmental stress and trauma were significantly associated with higher cf-mtDNA levels in both the blood and neuronal EVs in SSD patients (r = 0.29, 0.49; p = 0.01, 0.03, respectively). In conclusion, if replicated and fully developed, blood and neuronal EV-based cell-free mtDNA may provide a clinically accessible biomarker to more directly evaluate the mitochondrial hypothesis and the abnormal bioenergetics pathways in schizophrenia.

DOI: https://doi.org/10.1038/s41386-025-02204-1
Neuromuscul Disord. 2025 Aug 13. pii: S0960-8966(25)00931-9. [Epub ahead of print]54 106204

Selective muscle MRI changes in a patient with a rare mitochondrial DNA variant causing myoclonic epilepsy with ragged red fibres.

Taylor Watson-Fargie, David G Anderson, William Stewart, Cheryl Longman, Sila Hopton, Yi Shiau Ng, Emma L Blakely, Robert W Taylor, Maria E Farrugia.

  Primary mitochondrial disease refers to a group of genetic disorders caused by pathogenic variants in either the nuclear or mitochondrial genomes, leading to an impairment of oxidative phosphorylation. We present a young female with a prominent myopathic phenotype associated with an episode of cardiac decompensation. MRI of lower limb musculature revealed a selective pattern of fatty infiltration and muscle oedema. Skeletal muscle biopsy confirmed significant evidence of mitochondrial histopathological abnormalities characterised by multiple respiratory chain deficiencies whilst complete sequencing of the entire mitochondrial genome identified a rare, likely pathogenic m.8362T>G MT-TK gene (NC_012920.1) variant at high levels of heteroplasmy, which we confirmed to be maternally-inherited.

Keywords:  MERRF; Multi-system disorder; Muscle MRI; Primary mitochondrial disorder

DOI:  https://doi.org/10.1016/j.nmd.2025.106204
Biomolecules. 2025 Aug 08. pii: 1145. [Epub ahead of print]15(8):

Mitochondrial Extracellular Vesicles: A Novel Approach to Mitochondrial Quality Control.

Jie Kong, Rui Sun, Chengying Du, Yiyang Tang, Chengzhi Xie, Qian Li, Li Lin, Hongyan Wang.

  Mitochondria are central to cellular energy metabolism and play a key role in regulating important physiological processes, including apoptosis and oxidative stress. Mitochondrial quality control has recently garnered significant attention, with the underlying mechanisms traditionally considered to be mitophagy and its dynamics. Various studies have demonstrated that extracellular vesicles are crucial for the transmission of mitochondria and their components. These vesicles effectively transport mitochondria to target cells, facilitating intercellular material exchange and signal transmission, thereby enhancing cellular function and viability. This review explores the mechanisms of mitochondrial transfer through mitochondrial extracellular vesicles (MitoEVs), analyzes the novel roles of MitoEVs in mitochondrial quality control, and discusses their applications in disease treatment. We aim to provide new perspectives for future research and support the development of relevant therapeutic strategies.

Keywords:  MitoEVs; extracellular vesicle; intercellular material exchange; mitochondria; mitochondrial quality control; signal transmission

DOI:  https://doi.org/10.3390/biom15081145
Biochem Soc Trans. 2025 Aug 26. pii: BST20253044. [Epub ahead of print]

Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.

Megan J Baker, Kai Qi Yek, Diana Stojanovski.

  Intrinsic protein quality control (QC) mechanisms are essential in maintaining mitochondrial health and function. These sophisticated molecular machineries govern protein trafficking and import, processing, folding, maturation and degradation, ensuring the organelle's health. Disruption in mitochondrial protein QC can lead to severe, multisystem disorders with variable age of onset and progression. In this review, we provide a snapshot of the intrinsic molecular protein QC machineries in mitochondria detailing their function, localisation and substrate specificity. We also highlight how dysfunction of these molecular machines contributes to mitochondrial disease. Ultimately, elucidating the consequences of proteostatic failure offers critical insights into the pathogenesis of complex mitochondrial disorders.

Keywords:  AAA+; chaperone; disaggregase; extractase; mitochondria; mitochondrial disease; protease; protein quality control

DOI:  https://doi.org/10.1042/BST20253044
J Adv Res. 2025 Aug 21. pii: S2090-1232(25)00644-7. [Epub ahead of print]

Mitochondrial DNA methylation: State-of-the-art in molecular mechanisms and disease implications.

Meng-Ting Yin, Liang Guo.

   BACKGROUND: Mitochondrial DNA (mtDNA), a circular genome essential for cellular energy production, is increasingly recognized to exhibit aberrant methylation under pathological conditions. Dysregulated methylation in regulatory regions can impair mtDNA replication, transcription, and metabolic homeostasis, thereby promoting disease progression, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, as well as aging. Despite challenges posed by nuclear pseudogene interference, advanced detection technologies have significantly improved the resolution of mtDNA methylation analysis.
AIM OF REVIEW: This review focuses on three key mtDNA methylation patterns, 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and N6-methyladenine (6mA), summarizing the evidence for their existence as well as their molecular mechanisms in diseases and offering insights into recent advances in mtDNA detection techniques. Key Scientific Concepts of Review: Under pathological conditions, the dysregulation of mtDNA methylation highlights its emerging promise as both a biomarker and therapeutic target. Therefore, this epigenetic aberration provides a foundational framework for elucidating the molecular mechanisms underlying mitochondrial dysfunction across diverse diseases and advancing precision medicine strategies.

Keywords:  5-hydroxymethylcytosine; 5-methylcytosine; MtDNA methylation; N6-methyladenine

DOI:  https://doi.org/10.1016/j.jare.2025.08.029
Cells. 2025 Aug 18. pii: 1278. [Epub ahead of print]14(16):

Cellular Models of Aging and Senescence.

Byunggik Kim, Dong I Lee, Nathan Basisty, Dao-Fu Dai.

  Aging, a state of progressive decline in physiological function, is an important risk factor for chronic diseases, ranging from cancer and musculoskeletal frailty to cardiovascular and neurodegenerative diseases. Understanding its cellular basis is critical for developing interventions to extend human health span. This review highlights the crucial role of in vitro models, discussing foundational discoveries like the Hayflick limit and the senescence-associated secretory phenotype (SASP), the utility of immortalized cell lines, and transformative human induced pluripotent stem cells (iPSCs) for aging and disease modeling and rejuvenation studies. We also examine methods to induce senescence and discuss the distinction between chronological time and biological clock, with examples of applying cells from progeroid syndromes and mitochondrial diseases to recapitulate some signaling mechanisms in aging. Although no in vitro model can perfectly recapitulate organismal aging, well-chosen models are invaluable for addressing specific mechanistic questions. We focus on experimental strategies to manipulate cellular aging: from "steering" cells toward resilience to "reversing" age-related phenotypes via senolytics, partial epigenetic reprogramming, and targeted modulation of proteostasis and mitochondrial health. This review ultimately underscores the value of in vitro systems for discovery and therapeutic testing while acknowledging the challenge of translating insights from cell studies into effective, organism-wide strategies to promote healthy aging.

Keywords:  cardiovascular aging; cellular aging; epigenetic reprogramming; in vitro models; induced pluripotent stem cells (iPSCs); mitochondrial dysfunction; neurodegeneration; progeroid syndromes; senescence; senolytics

DOI:  https://doi.org/10.3390/cells14161278
Children (Basel). 2025 Aug 21. pii: 1102. [Epub ahead of print]12(8):

Clinical and Molecular Characterizations of Mitochondrial Disorders: A Tertiary-Care Center Experience.

Mohammed Almuqbil, Najla Binsabbar, Shahad Alsaif, Sulaiman Almasoud, Talah Albasry, Duaa Baarmah, Waleed Altwaijri, Ahmed Alrumayyan.

   BACKGROUND: Given the limited research on mitochondrial diseases in our area, specifically regarding their genetic variability and diverse clinical manifestations, and considering the significant number of consanguineous marriages in our region, we aimed to investigate the clinical and molecular characteristics of patients with mitochondrial disorders in Saudi Arabia.
METHODS: This retrospective cross-sectional cohort study involved a chart review of patients diagnosed with mitochondrial disorders at the Ministry of National Guard Health Affairs tertiary health care centers in Saudi Arabia between 2013 and 2022.
RESULTS: The study population comprised 116 patients with a mean age of 10 years (±7 SD). Among the study cohort, 34.5% (n = 40) had died. The primary cause of death was cardiopulmonary arrest (55.0%, n = 22). The most prevalent condition was developmental delay (67.9%). Around 56.9% were diagnosed using Whole Exome Sequencing (WES), 10.3% by Whole Genome Sequencing due to negative WES, 23.3% through a single-gene approach, 7.8% were analyzed through a mitochondrial panel, and 1.7% via a gene panel. The distributions of current age and age at diagnosis were significantly different between the nuclear and mitochondrial gene types. Notably, the diagnostic delay time (time taken from symptom onset to genetic diagnosis) averaged 1.5 years for nDNA variants compared to an average of 10 years for mDNA variants.
CONCLUSIONS: This study shows that gene type affects clinical characteristics, highlighting the importance of genetic studies in disease manifestation.

Keywords:  Saudi Arabia; disorders; genetic disorders; mitochondria; mitochondrial diseases; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/children12081102
Fluids Barriers CNS. 2025 Aug 25. 22(1): 88

Endothelial mitochondria in the blood-brain barrier.

Yunwei Shao, Lingling Mai, Ruogu Qiao, Yi Liang, Yuying Jiao, Judith Homburg, Zhenfu Jiang, Laiyu Song.

  The blood-brain barrier (BBB) is a highly selective interface between the peripheral circulation and the central nervous system (CNS), crucial for maintaining brain homeostasis. Disruptions to the BBB, such as increased permeability or structural damage, can lead to neurological damage. Mitochondria, the primary energy producers within endothelial cells, play a key role in the function of the BBB by maintaining its integrity and low permeability. This review first outlines the structural components of the BBB, then examines the role of mitochondria in endothelial cells under physiological conditions. We further focus on alterations in mitochondrial function during pathological states, discussing their impact on BBB stability. Briefly, this review explores the involvement of mitochondria in BBB endothelial cells in both physiological processes and the pathological progression of neurological diseases, while proposing potential therapeutic directions for treating CNS disorders.

Keywords:  Blood-brain barrier; Endothelial cells; Mitochondria; Nervous system

DOI:  https://doi.org/10.1186/s12987-025-00699-w
Biol Methods Protoc. 2025 ;10(1): bpaf063

Radiolabeling isolated mitochondria with Tc-99m: A first-in-field protocol and early feasibility findings.

Melanie Walker, Francisco Javier Miralles, Keiko Prijoles, Jacob S Kazmi, Jennifer Hough, David Lewis, Michael R Levitt, Yasemin Sancak.

  Mitochondrial transplantation is a promising but still experimental strategy for treating ischemic and metabolic disorders. A key barrier to its advancement is the lack of scalable, non-invasive methods for tracking transplanted extracellular mitochondria in vivo. Technetium-99m (Tc-99m) radiopharmaceuticals, widely used in SPECT imaging, may offer a clinically compatible solution. Cryopreserved mitochondria derived from HEK-293 cells were incubated with Tc-99m sestamibi, tetrofosmin, pertechnetate, or control solutions. After brief incubation and washing, mitochondrial pellets were analyzed for retained radioactivity. ATP content was measured to assess metabolic function, and electron microscopy was used to evaluate ultrastructural integrity. Tc-99m sestamibi and tetrofosmin showed labeling efficiencies of 2.74% and 2.68%, respectively. Pertechnetate demonstrated minimal uptake (0.34%). Radiolabeled mitochondria retained ATP production comparable to controls. Electron microscopy showed preserved double membranes and cristae. Controls confirmed assay specificity and viability. To our knowledge, this is the first report of radiolabeling isolated mitochondria with clinically approved Tc-99m agents. This platform supports the development of SPECT-compatible protocols for visualizing viable transplanted mitochondria in recipient tissues.

Keywords:  SPECT; Technetium-99m; electron microscopy; mitochondria; mitochondrial transplantation; radiopharmaceuticals

DOI:  https://doi.org/10.1093/biomethods/bpaf063
Biomolecules. 2025 Aug 13. pii: 1159. [Epub ahead of print]15(8):

Systemic Lonp1 Haploinsufficiency Mitigates Cardiac Mitochondrial Dysfunction Induced by Cardiomyocyte-Specific Lonp1 Haploinsufficiency via Potential Inter-Organ Crosstalk.

Sakthijothi Muthu, Zinnia Tran, Ramasamy Saminathan, Pratikshya Shrestha, Sundararajan Venkatesh.

  Efficient mitochondrial matrix protein quality control (mPQC), regulated by the mitochondrial matrix protease LONP1, is essential for preserving cardiac bioenergetics, particularly in post-mitotic cardiomyocytes, which are highly susceptible to mitochondrial dysfunction. While cardiac mPQC defects could impair heart function, it remains unclear whether such defects can be mitigated through inter-organ crosstalk by modulating mPQC in extra-cardiac tissues, a potentially valuable strategy given the challenges of directly targeting the heart. To investigate this, we examined two mouse models of Lonp1 haploinsufficiency at young adulthood: a cardiomyocyte-specific heterozygous knockout (Lonp1CKO-HET) and a whole-body heterozygous knockout (Lonp1GKO-HET). Despite similar reductions in Lonp1 mRNA expression in the hearts, Lonp1GKO-HET mice exhibited no cardiac dysfunction, whereas Lonp1CKO-HET mice showed mild cardiac dysfunction accompanied by activation of the mitochondrial stress response, including induction of genes such as Clpx, Spg7, Hspa9, and Hspd1, increased mitochondrial dynamics (Pink1, Dnm1l), reduced mitochondrial biogenesis, and compensatory upregulation of the mtDNA transcriptional regulator Tfam, all occurring without overt structural remodeling. These alterations were absent in Lonp1GKO-HET hearts. Our findings reveal a novel adaptive mechanism in which systemic mPQC deficiency can buffer mitochondrial dysfunction in the heart through inter-organ communication that is lost with cardiomyocyte-specific mPQC disruption. This study identifies systemic modulation of Lonp1-mediated mitochondrial stress pathways as a promising strategy to promote cardiac resilience through protective inter-organ signaling.

Keywords:  LONP1; cardiac dysfunction; heart; mitochondria; mitochondrial dysfunction; mitochondrial matrix; protein quality control

DOI:  https://doi.org/10.3390/biom15081159
Adv Clin Chem. 2025 ;pii: S0065-2423(25)00046-0. [Epub ahead of print]128 1-81

Extracellular vesicles in clinical chemistry: A focus on biomarkers.

Cristina Mas-Bargues, Javier Huete-Acevedo, Marta Arnal-Forné, Sandra Atencia-Rabadán, Consuelo Borrás.

  Extracellular vesicles (EVs) are nanoscale particles released by cells into body fluids and serve as crucial mediators of intercellular communication. This chapter explores their biogenesis, cargo composition, and biological functions on target cells. It discusses the diverse molecular cargo of EVs that includes lipids, proteins, and nucleic acid and focuses on their sorting, analysis, and functional significance. It highlights their importance as biomarkers as diagnostic and prognostic tools, particularly their potential application in clinical chemistry. The chapter also provides an overview of the current techniques for isolating and characterizing EVs from various body fluids and recent technological advancements. It compares EV and liquid biopsy biomarkers, outlines their advantages and limitations, and examines their translational impact on personalized medicine. Furthermore, this chapter emphasizes the clinical relevance of EV biomarkers, especially in monitoring aging, evaluating anti-aging therapy, and diagnosing age-related diseases such as neurodegenerative, cardiovascular, and musculoskeletal disorders. The chapter concludes with a critical discussion about the potential of EV research to revolutionize clinical diagnostics, which unfortunately remains constrained by regulatory hurdles and a lack of standardization.

Keywords:  Aging; Biomarker; Cargo content; Extracellular vesicles; Liquid biopsy

DOI:  https://doi.org/10.1016/bs.acc.2025.06.001
Biol Reprod. 2025 Aug 21. pii: ioaf195. [Epub ahead of print]

Potential of small extracellular vesicles as Cas9 delivery tool: A promising approach for gene editing livestock gametes and embryos.

Giuliana A Ferronato, Juliano C Silveira, Marcia de Almeida Monteiro Melo Ferraz.

  Genome editing is a rapidly advancing technology with transformative potential in livestock, offering opportunities that range from enhanced production traits to the generation of biomedical models for human disease and xenotransplantation. The CRISPR/Cas9 system, originally identified as a bacterial defense mechanism, has become the most widely used tool for precise genome editing. In this review, we first summarize the potential applications of CRISPR/Cas9 in livestock and highlight notable successes to date. We then address the ongoing challenges associated with delivering CRISPR/Cas9 into gametes and embryos, as current methods such as microinjection and electroporation often result in high mosaicism and cellular damage. We subsequently introduce extracellular vesicles (EVs) as a promising alternative delivery system. Secreted by virtually all cell types, EVs can efficiently transport bioactive molecules and are readily internalized by gametes and embryos. Although EV-mediated delivery of CRISPR/Cas9 has shown success in somatic cells, its use in reproductive cells remains largely unexplored. We review emerging strategies for loading EVs with CRISPR/Cas components and discuss the potential advantages of combining this approach with recently developed smaller Cas variants to overcome delivery barriers. Collectively, these innovations support the promise of EVs as a biologically compatible, efficient, and minimally invasive system for targeted genome editing in livestock reproduction.

Keywords:  ev-mediated cas9 delivery; exosome engineering; reproductive medicine; transgenic animals

DOI:  https://doi.org/10.1093/biolre/ioaf195
Exp Eye Res. 2025 Aug 19. pii: S0014-4835(25)00354-9. [Epub ahead of print]260 110583

Mitochondrial homeostasis dysfunctions during the epithelial-mesenchymal transition process in lens epithelial cells.

Hang Xie, Rong Huang, Ke Xu, Lei Du, Xingyu Yang, Weichen Xu, Xiaoyu Guo, Guojing Lu, Tingting Fan, Changzheng Chen.

  Lens epithelial cells (LECs), the main mitochondria-containing cells in the lens, play a vital role in maintaining lens transparency. Mitochondrial homeostasis is essential for cellular function, yet its changes during epithelial-mesenchymal transition (EMT) in LECs remain unclear. In this study, EMT was induced in LECs using transforming growth factor-β2 (TGF-β2), and mitochondrial function was evaluated through ROS, ATP levels, membrane potential, Mitotracker staining, and electron microscopy. TGF-β2 treatment resulted in mitochondrial dysfunction, evidenced by increased ROS, decreased ATP production, and reduced membrane potential. Mitochondria changed from elongated tubular shapes to fragmented spherical forms. Mitochondrial dynamics were disrupted, with downregulation of fusion proteins (Mfn1, Mfn2, Opa1) and upregulation of fission protein Drp1. Mitophagy was impaired despite activation of the PINK1/Parkin pathway, and mitochondrial biogenesis was suppressed, as shown by decreased expression of PGC-1α and TFAM and reduced mtDNA copy number. These findings highlight a significant imbalance in mitochondrial homeostasis during TGF-β2-induced EMT in LECs, which may contribute to lens opacity and fibrotic cataract formation, offering potential targets for therapeutic intervention.

Keywords:  EMT; Mitochondrial biogenesis; Mitochondrial fusion and fission; Mitochondrial homeostasis; Mitophagy

DOI:  https://doi.org/10.1016/j.exer.2025.110583
Mitochondrion. 2025 Aug 18. pii: S1567-7249(25)00077-7. [Epub ahead of print]85 102080

The homoplasmic MT-TK m.8357T > C mtDNA variant as a cause of multiorgan mitochondrial disease.

Luisa Zupin, Valeria Capaci, Maria Teresa Bonati, Eleonora Lamantea, Muhammad Suleman, Andrea Marsala, Fulvio Celsi, Beatrice Spedicati, Sergio Crovella, Giulia Gortani, Giorgia Girotto, Irene Bruno, Massimo Zeviani.

  The diagnosis of disorders associated with mitochondrial DNA (mtDNA) variants presents substantial complexity due to their genetic and clinical heterogeneity, which is largely influenced by mtDNA heteroplasmy. However, the level of heteroplasmy alone is often not sufficient to predict the clinical phenotype including its severity and progression. This study concerns the characterization of the m.8357T > C variant in the MT-TK gene, encoding for mt-tRNA-Lys found in two pediatric siblings. Both had symptoms suggestive of a mitochondrial disease, including severe hearing loss, easy fatigability, decreased activity of mitochondrial complex I in muscle samples, epilepsy, metabolic acidosis with hyperkalemia, and mild kidney impairment. The m.8357T > C mtDNA variant was homoplasmic in muscle, blood, urine and fibroblasts. Immortalized fibroblasts from the patients showed reduced activity of mitochondrial complexes I, III and IV, decreased mitochondrial respiration, and abnormal depolarization of the mitochondrial membrane potential. The mt-tRNA-Lys levels were reduced as compared to the mt-tRNA-Leu (UUR) or the snRNA encoded by RNU6B nuclear gene; the level of three mitochondrial DNA encoded proteins was decreased, altogether suggesting a defective translation machinery in cells carrying the variant. Consistently, fibroblasts from the mother, who had only mild hearing loss, despite high level of heteroplasmy, showed some biochemical abnormalities, however milder than in her daughter and son. Contrariwise, their maternal aunt, who showed intellectual disability, mild hearing loss, easy fatigability and weakness was also virtually homoplasmic for the m.8357T > C in blood and urinary sediment cells. These findings suggest the pathogenicity of the m.8357T > C variant but only in condition of homoplasmy.

Keywords:  Heteroplasmy; Mitochondrial disease; mt-tRNA-Lys

DOI:  https://doi.org/10.1016/j.mito.2025.102080
Metabolites. 2025 Jul 31. pii: 508. [Epub ahead of print]15(8):

Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential.

Marta Pawłowska, Joanna Kruszka, Marta Porzych, Jakub Garbarek, Jarosław Nuszkiewicz.

  Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and share key pathological features such as oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Recent research has highlighted the potential of ketogenic metabolism, particularly the use of ketone bodies like β-hydroxybutyrate, as a therapeutic approach targeting these shared mechanisms. This review provides a comprehensive synthesis of current knowledge on the neuroprotective effects of ketogenic interventions, including both dietary strategies and exogenous ketone supplementation. We discuss how ketone bodies improve mitochondrial function, reduce reactive oxygen species, modulate inflammatory pathways, and influence neurotransmission and synaptic plasticity. Additionally, we examine experimental and clinical evidence supporting the application of ketogenic therapies in neurodegenerative diseases, highlighting disease-specific findings, benefits, and limitations. While preclinical data are robust and suggest meaningful therapeutic potential, clinical studies remain limited and heterogeneous, with challenges related to adherence, safety, and patient selection. The review also addresses the translational relevance of ketogenic strategies, considering their feasibility, combination with other therapies, and the need for personalized approaches based on genetic and metabolic profiles. By critically evaluating existing data, this article aims to clarify the mechanisms through which ketogenic metabolism may exert neuroprotective effects and to outline future directions for research and clinical application in the context of neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; beta-hydroxybutyrate; cognitive decline; ketogenic diet; ketone bodies; mitochondrial dysfunction; neuroinflammation

DOI:  https://doi.org/10.3390/metabo15080508
Biomedicines. 2025 Aug 19. pii: 2019. [Epub ahead of print]13(8):

The Transgenerational Impact of High-Fat Diet and Diabetic Pregnancy on Embryonic Transcriptomics and Mitochondrial Health.

Abigail K Klein, Benjamin P Derenge, Malini Mukherjee, Srikrishna P Reddy, Tricia D Larsen, Prathapan Ayyappan, Tyler C T Gandy, Kyle M Siemers, Michael S Kareta, Michelle L Baack.

  Background/Objectives: Overnutrition increases comorbidities such as gestational diabetes during pregnancy that can have detrimental consequences for both parent and progeny. We previously reported that high-fat (HF) diet and late-gestation diabetes (DM) incite mitochondrial dysfunction, oxidative stress, and cardiometabolic disease in first generation (F1) rat offspring, partially through epigenomic and transcriptomic programming. Primordial germ cells, which become the second generation (F2), are also exposed, which could incite generational risk. This study aimed to determine whether the F2 transcriptome already has genomic variation at the preimplantation embryo stage, and whether variations normalize, persist or compound in the third generation (F3). Methods: F0 female rats were fed a control or HF diet, then DM was induced in HF-fed dams on gestational day (GD)14, exposing F1 offspring and F2 primordial germ cells to hyperlipidemia, hyperglycemia and fetal hyperinsulinemia during the last third of pregnancy. F1 pups were reared by healthy dams and bred to produce F2 embryos (F2e) and F2 pups. F2 offspring were bred to produce F3 embryos (F3e). Embryos were assessed by a novel grading method, live cell imaging, and single-cell RNA sequencing. Results: Embryo grades were not different, but HF+DM F2e had more cells while F3e had fewer cells and overall fewer embryos. HF+DM F2e had similar mitochondria quantity but a downregulation of genes involved in lipid metabolism and more oxidative stress, consistent with mitochondrial dysfunction. They also had an upregulation of chromatin-remodeling genes. The predicted developmental effect is accelerated embryo aging and epigenetic drift. In contrast, HF+DM F3e had an adaptive stress response leading to increased mitochondria quantity and an upregulation of genes involved in mitochondrial respiration, metabolism, and genomic repair that led to a predicted developmental effect of delayed embryo maturation. Conclusions: Although pathways vary, both generations have metabolically linked differentially expressed genes that influence cell fate and developmental pathways. In conclusion, HF+DM pregnancy can program the early embryonic transcriptome for three generations, despite an intergenerational healthy diet.

Keywords:  diabetes; embryo; high fat; mitochondria; overnutrition; oxidative stress; transcriptome; transgenerational

DOI:  https://doi.org/10.3390/biomedicines13082019
Antioxidants (Basel). 2025 Aug 18. pii: 1008. [Epub ahead of print]14(8):

Mitochondrial Transfer Between Cancer and T Cells: Implications for Immune Evasion.

Soohyun Chun, Jin An, Man S Kim.

  Intercellular mitochondrial transfer in the tumor microenvironment (TME) is a paradigm-shifting process that redefines cancer-T cell crosstalk. This review explores its dual nature as both a tumor immune evasion strategy and a promising therapeutic avenue. Crucially, oxidative stress acts as a key regulator, inducing tunneling nanotube (TNT) formation to facilitate this organelle exchange. Tumors exploit this by transferring dysfunctional, reactive oxygen species (ROS) generating mitochondria to T cells to induce senescence while simultaneously hijacking healthy mitochondria from T cells to empower their own metabolism. This directional exchange, quantified by computational tools like mitochondrial-enabled reconstruction of cellular interactions (MERCI), is linked to poor clinical outcomes. Transfer occurs via TNTs, extracellular vesicles, and direct contact. Conversely, the therapeutic transfer of healthy mitochondria from sources like mesenchymal stromal cells can revitalize exhausted T cells, improving chimeric antigen receptor T (CAR-T) cell efficacy. Clinical translation is guided by emerging biomarkers, including circulating mitochondrial DNA (mtDNA), mitochondrial haplogroups, and the tumor mitochondrial transfer (TMT) score. Harnessing this biological axis for next-generation immunotherapies requires overcoming challenges in transfer efficiency and standardization to effectively modulate the tumor redox landscape and immune response.

Keywords:  MERCI methodology; T cell exhaustion; cancer metabolism; immune evasion; immunotherapy; mitochondrial transfer; oxidative stress; single-cell analysis; tumor microenvironment; tunneling nanotubes

DOI:  https://doi.org/10.3390/antiox14081008
Mol Biol Rep. 2025 Aug 23. 52(1): 842

Systematic review of exosomes derived from various stem cell sources: function and therapeutic potential in disease modulation.

Ratna Puspita, Ahmad Aulia Jusuf.

  Exosomes, nanosized extracellular vesicles ranging from 30 to 150 nm, are secreted by all cell types through the endocytic pathway and have emerged as promising candidates for both biomarkers and therapeutic agents due to their capability to transport bioactive molecules such as proteins, lipids, and nucleic acids between cells. This intercellular communication facilitates numerous biological processes, including cellular signaling, immune modulation, and tissue regeneration. Despite their therapeutic potential, a comprehensive understanding of the diverse functions and clinical applications of exosomes remains limited, representing a significant gap in the current biomedical literature. To address this, we conducted a systematic analysis of 27 relevant studies examining exosome applications across various medical fields including neurodegenerative diseases, cardiovascular conditions, cancer therapy, regenerative medicine, autoimmune disorders, inflammatory diseases, and respiratory ailments. Our findings demonstrate that exosomes actively participate in immune regulation, angiogenesis, and tissue repair mechanisms. However, several challenges must be overcome to translate these findings into clinical practice, such as establishing standardized large-scale production methods, achieving precise cargo loading and targeted delivery, and ensuring safety regarding immunogenicity and biodistribution. In conclusion, our study highlights the critical role of exosomes as leading cell-free therapeutic tools and underscores the necessity for further research to validate their potential as substitutes for cell-based therapies, thereby advancing innovative, non-cellular treatment strategies in clinical medicine.

Keywords:  Cellular signaling; Disease modulation; Extracellular vesicles; Molecular function; Regenerative medicine

DOI:  https://doi.org/10.1007/s11033-025-10943-z
Aging (Albany NY). 2025 Aug 25. 17

Mitochondrial proteins as biomarkers of cellular senescence and age-associated diseases.

Anna Panfilova, Tatiana Zubareva, Ekaterina Mironova, Gianluigi Mazzoccoli, Maria Greta Pia Marasco, Sofya Balazovskaia, Peter Yablonsky, Igor Kvetnoy.

  Research in the field of mitochondrial biomarkers plays an important role in understanding the processes of cellular aging. Mitochondria are not only the energy centers of the cell, but also key regulators of signaling within the cell. They significantly affect the life and function of the cell. The aging process of cells is associated with various factors, including DNA damage, disruption of the cell cycle, changes in mitochondria, and problems with signal transmission. Mitochondrial dysfunction is a major contributor to cellular and organismal aging. As we age, there is an accumulation of dysfunctional mitochondria, leading to decreased efficiency of oxidative phosphorylation and increased production of reactive oxygen species. This review focuses on the main mitochondrial markers involved in the mechanisms of cell aging: DRP1, Prohibitin, Parkin, PINK1, MFF, VDAC, TOM. These signaling molecules are involved in mitochondrial fission and the mechanisms of mitochondria-dependent apoptosis, in the regulation of mitochondrial respiratory activity, ensuring the stability of the organization and copying of mitochondrial DNA, protecting cells from oxidative stress, in the process of autophagy of damaged mitochondria, in protective mechanisms during stress-induced mitochondrial dysfunction. Analysis of mitochondrial markers can provide valuable information about the state of cells and their functional significance at various stages of aging, which could promote our understanding of cellular aging mechanisms and developing corrective methods. These insights highlight mitochondrial proteins as potential therapeutic targets to combat age-related diseases.

Keywords:  age-associated diseases; biomarkers; cellular senescence; mitochondria; mitochondrial proteins

DOI:  https://doi.org/10.18632/aging.206305
Sci Transl Med. 2025 08 20. 17(812): eads2116

Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome.

Alexis M Crockett, Maria C Vélez Colόn, Hania Kebir, Frances M Smith, Daniel M Iascone, Brianna Ciesielski, Sergei Koshkin, Andrew D Patterson, Adam J Rossano, Amita Sehgal, Stewart A Anderson, Jorge Ivan Alvarez.

Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared with peripheral endothelial cells, although the functional implications of this phenomenon are unclear. Here, we studied BBB mitochondrial function in the context of 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. Because the 22q11.2 deletion includes six mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and affect behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (iBMECs) from people with 22qDS and in BBB endothelial cells from a mouse model of 22qDS. We found that treatment with bezafibrate, an activator of mitochondrial biogenesis, attenuates mitochondrial deficits and enhances BBB function in both the iBMECs and a mouse model of 22qDS. This treatment also corrects social memory in the mouse model, a deficit previously associated with BBB dysfunction. Given that BBB integrity correlated with social memory performance, our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior.

DOI: https://doi.org/10.1126/scitranslmed.ads2116
Genes (Basel). 2025 Jul 22. pii: 850. [Epub ahead of print]16(8):

CRISPR in Neurodegenerative Diseases Treatment: An Alternative Approach to Current Therapies.

Amna Akbar, Rida Haider, Luisa Agnello, Bushra Noor, Nida Maqsood, Fatima Atif, Wajeeha Ali, Marcello Ciaccio, Hira Tariq.

  Neurodegenerative diseases (NDs) pose a major challenge to global healthcare systems owing to their devastating effects and limited treatment options. These disorders are characterized by progressive loss of neuronal structure and function, resulting in cognitive and motor impairments. Current therapies primarily focus on symptom management rather than on targeting the underlying causes. However, clustered regularly interspaced short palindromic repeat (CRISPR) technology offers a promising alternative by enabling precise genetic modifications that could halt or even reverse ND progression. CRISPR-Cas9, the most widely used CRISPR system, acts as a molecular scissor targeting specific DNA sequences for editing. By designing guide RNAs (gRNAs) to match sequences in genes associated with NDs, researchers can leverage CRISPR to knockout harmful genes, correct mutations, or insert protective genes. This review explores the potential of CRISPR-based therapies in comparison with traditional treatments for NDs. As research advances, CRISPR has the potential to revolutionize ND treatment by addressing its genetic underpinnings. Ongoing clinical trials and preclinical studies continue to expand our understanding and application of this powerful tool to fight debilitating conditions.

Keywords:  Alzheimer’s disease; CRISPR-Cas9; gene; neurodegenerative diseases; therapy; treatment

DOI:  https://doi.org/10.3390/genes16080850