bims-polgdi Biomed News
on POLG disease
Issue of 2026–03–15
forty-five papers selected by
Luca Bolliger, lxBio
  1. Revisiting the promise and pitfalls of mitochondrial replacement therapies.
  2. EV-Encapsulated Mitochondrial miRNAs: Enhancing Cardiomyocyte Bioenergetics.
  3. The Mitochondrial Blueprint of Skin Aging: From Damage Signals to Dermatologic Interventions.
  4. Clinical Heterogeneity and Candidate Biomarkers in POLG-Related Mitochondrial Disease.
  5. Mitochondrial Dysfunction in Monogenic Developmental and Epileptic Encephalopathies.
  6. Mitochondrial quality in aging and neurodegeneration: The emerging role of mitochondria-derived vesicles.
  7. First case of schizophrenia and OCD in TK2-related mitochondrial DNA depletion myopathy: a case report.
  8. Butyrate extends health and lifespan in mice with mitochondrial deficiency.
  9. The impact of dendritic mitochondrial heterogeneity on synapse function.
  10. The Dual Role of Extracellular Vesicles in Aging and Age-Related Diseases: Pathophysiology and Therapeutic Potential.
  11. Amyloid-β and Mitochondrial Membranes: A Missing Link in Alzheimer's Pathogenesis.
  12. Mitochondrial Quantity-Quality Imbalance in Cellular Senescence: Practical Readouts and Minimal Assay Bundles.
  13. COG5 deficiency disrupts cellular copper homeostasis and underlies the impaired mitochondrial OXPHOS function.
  14. DNA Polymerase Gamma Acetylation Governs Mitochondrial Homeostasis and Vascular Cell Senescence.
  15. Targeting mitochondrial metabolism with combined metabolic activators.
  16. APP Deficiency Ameliorates FAD Presenilin 1 F105C and A246E Mutations-induced Mitochondrial Dysfunction in Human Cortical Neurons.
  17. LA-MARRVEL: A Knowledge-Grounded, Language-Aware LLM Framework for Clinically Robust Rare Disease Gene Prioritization.
  18. NAD⁺ as a central metabolic hub Regulating the hallmarks of aging: Mechanisms and therapeutic implications.
  19. Morphological and Molecular Characteristics of Choroid Plexus Epithelium in Aged Brains.
  20. The goal attainment scale in primary mitochondrial disease: Construct validity and lessons learned from a randomized controlled trial.
  21. Potential Links Between Aging, Mitochondrial Dysfunction, and Drug Transporter Function-Molecular Mechanisms and Pharmacokinetic Implications.
  22. Energy Compensation Strategy: The Frontier of Neurodegenerative Disease Treatment.
  23. From Prohibition to Prudent Opening : Exploring the Legalization of Human Germline Gene Editing for Correcting Genetic Diseases.
  24. MitoMetrics: Incorporation of mtDNA profile discrepancies in likelihood ratio calculations.
  25. Sex-specific mitochondrial alterations in cognitively unimpaired older depressed individuals.
  26. From Microscopy to Nanoscopy: Contemporary Physical Methods in Mitochondrial Structural Biology.
  27. Mitochondrial Iron Handling and Lipid Peroxidation as Drivers of Ferroptosis.
  28. From bench to bedside: the promise and roadblocks of extracellular vesicle therapeutics.
  29. Network Rewiring in the Aging Immune System: From Chronic Inflammation to Age-Related Pathologies.
  30. Astrocytic Mitochondria Transplantation Rescues Neuron Loss and Dendritic Injuries in Acute Cerebral Ischemic Stroke Mouse Model by Flexibly Regulating Mitochondria Dynamics.
  31. Leber Hereditary Optic Neuropathy Caused by the Rare MT-ND1 m.3394T>C Mutation: A Case With Favorable Visual Prognosis and a Literature Review.
  32. Sex Differences in Metabolite-Immune Circuits of Neuroinflammation.
  33. Global Research Trends and Hotspots in Gene Editing and Stem Cell Therapies for Neurodegenerative Diseases: Bibliometric and Visualization Analysis.
  34. Two decades of induced pluripotent stem cell research: From discovery to diverse applications.
  35. Mitochondrial Electron Transport Chain Modulation Orchestrates Divergent TLR3 and TLR7 Responses.
  36. Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy.
  37. Structural and Functional Diversity of Mitochondria Isolated from Different Cell Types.
  38. Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification.
  39. Building a gene editing lexicon: a model for rare and inherited disorders.
  40. hUCMSC mitochondrial EVs confer neuroprotection after ischemia by Tom1l2-mediated mitochondrial fusion and Crls1-cardiolipin axis reprogramming.
  41. Modulation of mitochondrial quality by exercise mimetics: A potential strategy for the prevention and treatment of Alzheimer's disease.
  42. Mechanistic Modulation of Autophagy by Bioactive Natural Products: Implications for Human Aging and Longevity.
  43. The segregation of organelles and organellar genomes across eukaryotic biology.
  44. Innovative mitochondria-based holistic 3PM approach to female health status: Facts and outlook.
  45. ATG9B Regulates Mitochondrial Integrity and Apoptotic Tumor Cell Death.
  1. Hum Reprod. 2026 Mar 08. pii: deag020. [Epub ahead of print]
    Revisiting the promise and pitfalls of mitochondrial replacement therapies.
    Nuno Costa-Borges, Dagan Wells.
      Mitochondrial replacement therapies (MRTs) have been proposed as a means of avoiding the transmission of pathogenic mitochondrial DNA (mtDNA) mutations from mother to child. While clinical cases using this groundbreaking strategy have now been reported for the two principal MRT methods-pronuclear transfer and maternal spindle transfer-recent data continues to raise questions about the reliability of these approaches for disease prevention.
    Keywords:  female infertility; maternal spindle transfer; mitochondrial diseases; mitochondrial replacement therapies; mitochondrial reversal; oocyte quality; pronuclear transfer
    DOI:  https://doi.org/10.1093/humrep/deag020
  2. Int J Mol Sci. 2026 Feb 26. pii: 2224. [Epub ahead of print]27(5):
    EV-Encapsulated Mitochondrial miRNAs: Enhancing Cardiomyocyte Bioenergetics.
    Dhienda C Shahannaz, Tadahisa Sugiura.
      Mitochondrial dysfunction lies at the core of numerous cardiac pathologies, yet restoring mitochondrial health remains a therapeutic frontier. In recent years, extracellular vesicles (EVs) have emerged as nature's delivery nanocarriers, capable of transporting a wide array of biomolecules, including mitochondrial-associated microRNAs (mito-miRs). These miRNAs regulate bioenergetics, redox homeostasis, and apoptotic signaling-making them prime candidates for non-cellular mitochondrial therapy. This review explores the evolving landscape of mitochondrial miRNA encapsulation within EVs, focusing on their potential to restore mitochondrial transcriptional and metabolic programs governing ATP synthesis and redox balance, enhance cellular energy output, and mitigate oxidative stress. We integrate insights from stem cell biology, RNA epigenetics, systems cardiology, and bioengineering, offering a unifying framework for therapeutic applications across ischemic heart disease, heart failure, and chemotherapy-induced cardiomyopathy. An integrative narrative synthesis of recent peer-reviewed literature was performed across major biomedical databases, prioritizing mechanistic studies linking EV-mediated mito-miR delivery to cardiomyocyte mitochondrial function. By harmonizing multi-omic signaling, vesicle engineering, and mitochondrial medicine, this review seeks to guide future research toward targeted, customizable, and scalable bioenergetic interventions-unlocking a next-generation path for cardiovascular regeneration.
    Keywords:  RNA therapeutics; cardiomyocyte bioenergetics; extracellular vesicles (EVs); heart failure; miRNA engineering; mitochondrial microRNAs; non-cellular mitochondrial therapy; regenerative cardiology; systems biology; translational nanomedicine
    DOI:  https://doi.org/10.3390/ijms27052224
  3. Aging Dis. 2026 Mar 04.
    The Mitochondrial Blueprint of Skin Aging: From Damage Signals to Dermatologic Interventions.
    Sarah M Antonevich, Kate M Miller, Shasa Hu, Monica Rodriguez-Silva, Carlos T Moraes, Ivan Jozic.
      Mitochondria are increasingly recognized as central regulators of skin health and aging, providing ATP and coordinating redox signaling, mitophagy, and cell fate decisions. In cutaneous tissues, mitochondrial integrity sustains fibroblast-driven collagen synthesis, keratinocyte proliferation, melanocyte homeostasis, and efficient wound repair. With advancing age and cumulative ultraviolet exposure, mitochondria accumulate hallmark defects. Mitochondrial DNA mutations and deletions, impaired oxidative phosphorylation, excessive reactive oxygen species production, diminished mitophagy and biogenesis, disrupted fission-fusion dynamics, NAD⁺ decline, and sirtuin dysregulation all converge to undermine energy metabolism, amplify inflammatory signaling, and accelerate fibroblast senescence, extracellular matrix degradation, pigmentary changes, and delayed wound healing. Recent research also highlights weakened antioxidant defenses and extracellular vesicle-mediated propagation of mitochondrial stress across the cutaneous microenvironment, underscoring the organelle's central role in skin aging. Against this mechanistic backdrop, mitochondria-targeted interventions are emerging as promising therapeutic strategies. Extracellular vesicles loaded with NAD⁺ precursors, antioxidant enzymes, or mitophagy stimulators show preclinical efficacy in restoring bioenergetics and accelerating wound closure. Mitochondria-directed antioxidants such as melatonin and coenzyme Q10, NAD⁺ boosters and sirtuin activators, red and near-infrared photobiomodulation, and NRF2-based redox reprogramming each enhance mitochondrial homeostasis while improving collagen synthesis, pigmentation balance, and re-epithelialization. Early translational and clinical studies indicate that these approaches protect against UV-induced mitochondrial DNA damage, reduce oxidative stress, and improve cutaneous structure and function. Collectively, these findings position mitochondria as a modifiable hub for cutaneous aging and wound repair, and highlight the potential of integrated metabolic, antioxidant, and vesicle-based approaches to transform dermatologic anti-aging and wound-care interventions.
    DOI:  https://doi.org/10.14336/AD.2025.1585
  4. Neurol Genet. 2026 Apr;12(2): e200365
    Clinical Heterogeneity and Candidate Biomarkers in POLG-Related Mitochondrial Disease.
    Laura Bermejo-Guerrero, Juan Luis Restrepo-Vera, Paloma Martin-Jimenez, Maria Navarro-Riquelme, Rocío Garrido-Moraga, Luz Edith Ochoa, Adrián González-Quintana, Aurelio Hernandez-Lain, Jessica Castillo-Villalba, Germán Morís, Nuria Muelas, Elena García-Arumí, Victoria González, Elena Martínez-Sáez, Ana Vesperinas, Laura Llansó, Raul Juntas-Morales, Carmen Paradas, Solange Kapetanovic, Alberto Blázquez, Ramon Martí, Joaquín Arenas, Miguel A Martín, Cristina Domínguez-González.
       Background and Objectives: POLG-related disorders exhibit marked phenotypic heterogeneity and frequent clinical overlap, often leading to delayed diagnosis. A precise delineation of their clinical spectrum, natural history, and the identification of reliable biomarkers is essential to improve diagnostic accuracy and guide therapeutic development.
    Methods: We analyzed a cohort of 34 patients with confirmed pathogenic POLG variants, assessing clinical phenotypes, molecular findings, and biomarkers (plasma growth differentiation factor-15 [GDF15] in 16, plasma neurofilament light chain [NF-L] in 14, and mitochondrial DNA [mtDNA] copy number in muscle in 16).
    Results: Thirty four patients (0.6-71 years) from 33 families were included. Juvenile/adult onset (12-40 years) was the most common presentation (62%). The predominant phenotypic categories were ataxia-neuropathy spectrum ([ANS], 44%), autosomal recessive PEO-plus (arPEO-plus, 26%), and autosomal dominant PEO-plus ([adPEO-plus], 15%), with frequent phenotypic overlap. Recessive inheritance accounted for 74% of cases, with the most common variants being p.([Thr251Ile; Pro587Leu]) paired on 1 allele, p.(Ala467Thr), and p.(Trp748Ser). Dominant variants were associated with milder, primarily myopathic phenotypes. The most common dominant variant was p.(Tyr955Cys). No clear genotype-phenotype correlations were identified among recessive variants. Compared with previously reported cohorts, our patients exhibited a lower prevalence of seizures, hepatopathy, and stroke-like episodes. GDF15 was elevated in 87.5% of patients, with a mean level of 3,315 pg/mL (±1,559.79), showing no significant differences between myopathic and ANS phenotypes, supporting its role as a general biomarker of mitochondrial dysfunction. NF-L was elevated in 78.6% of tested individuals but did not correlate with phenotype or clinical severity (as per Newcastle Mitochondrial Disease Adult Scale score).On average, muscle mtDNA copy number in patients was 76% of that observed in controls, with no differences by phenotype or inheritance pattern. All but 1 patient exhibited multiple mtDNA deletions, likely representing the primary mechanism of oxidative phosphorylation dysfunction rather than mtDNA depletion.
    Discussion: POLG-related disorders demonstrate extensive clinical variability with no consistent genotype-phenotype correlation. GDF15 and NF-L may serve as useful, though nonspecific, biomarkers of mitochondrial and neuroaxonal dysfunction, respectively. Prospective studies incorporating advanced molecular profiling are essential to establish reliable outcome measures and inform future therapeutic strategies.
    DOI:  https://doi.org/10.1212/NXG.0000000000200365
  5. Pediatr Neurol. 2026 Feb 13. pii: S0887-8994(26)00048-2. [Epub ahead of print]178 138-146
    Mitochondrial Dysfunction in Monogenic Developmental and Epileptic Encephalopathies.
    Crista A Minderhoud, Eva H Brilstra, Floor E Jansen, Kees P J Braun, Peter M van Hasselt.
       BACKGROUND: Before diagnostic whole exome sequencing, monogenic/chromosomal developmental and epileptic encephalopathies (DEEs) were frequently misdiagnosed as mitochondrial disorders (MDs) with epilepsy, due to overlapping clinical and biochemical features. Assessing muscle functional assays in patients with a genetic diagnosis and epilepsy offers a unique opportunity to explore mitochondrial dysfunction in monogenic/chromosomal DEEs, in comparison to the mitochondrial dysfunction observed in genetically confirmed MDs.
    METHODS: In this retrospective cohort study, clinical and biochemical data were extracted from patients suspected of MD with epilepsy who underwent muscle/fibroblast biopsy (2005-2015). Patients were classified into four groups based on the final diagnosis. Mitochondrial Disease Criteria scores were assigned. Statistical analyses were conducted using Fisher's exact, analysis of variance, and Kruskal-Wallis tests.
    RESULTS: Of 27 included participants, eleven (40.7%) had DEEs, four (14.8%) had genetically confirmed MDs, eight (29.6%) were suspected MD cases without genetic confirmation, and four (14.8%) had nonmitochondrial metabolic diseases. Mitochondrial dysfunction was common across all groups; 85% of participants met probable/definite Mitochondrial Disease Criteria, over 70% had elevated plasma lactate (>2.5 mmol/L), and 92% exhibited impaired adenosine triphosphate production. Surprisingly, moderate to severe complex dysfunction was observed in all groups except genetically confirmed MDs.
    CONCLUSIONS: Our findings indicate that mitochondrial dysfunction is prevalent in nonmitochondrial DEEs. Patients previously diagnosed with an MD based only on muscle/fibroblast biopsy may benefit from whole exome sequencing to identify genetic variants, for which targeted therapy may be available. Future research should explore whether treatment or prognosis of nonmitochondrial DEEs should be tailored to improve mitochondrial function.
    Keywords:  DEE; Developmental and epileptic encephalopathies; Genetic epilepsy; Mitochondrial disease; Mitochondrial dysfunction; Muscle functional assay; Seizures
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2026.02.004
  6. Mech Ageing Dev. 2026 Mar 05. pii: S0047-6374(26)00019-9. [Epub ahead of print]231 112167
    Mitochondrial quality in aging and neurodegeneration: The emerging role of mitochondria-derived vesicles.
    Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Hélio José Coelho-Júnior, Ettore D'Argento, Vito Pesce, Francesco Landi, Cecilia Bucci, Flora Guerra, Anna Picca.
      Mitochondria are central to cellular energy metabolism, redox balance, and signaling, and their integrity is maintained by a multilayered mitochondrial quality control (MQC) system. This system includes proteostasis, dynamics, biogenesis, and mitophagy, which together repair or remove damaged organelles. Mitochondria-derived vesicles (MDVs) have emerged as an additional MQC component. MDVs are small vesicles that bud from mitochondria and selectively transport damaged mitochondrial proteins, lipids, and nucleic acids to endolysosomal compartments or other intracellular destinations, enabling rapid and localized responses to mitochondrial stress. Acting upstream of or in parallel with mitophagy, MDVs can avoid or delay irreversible mitochondrial damage and help preserve cellular homeostasis. Aging and age-associated disorders are characterized by progressive mitochondrial dysfunction and chronic inflammation. Age-related changes in intracellular trafficking, lysosomal function, and vesicle dynamics may impair MDV formation, cargo selection, and targeting. Under conditions of defective degradation, mitochondrial components may also appear in extracellular vesicles, potentially contributing to altered intercellular signaling and inflammation. In the nervous system, where energetic demands are high and mitochondrial turnover requires tight regulation, such alterations may be especially harmful. This review summarizes MQC mechanisms in neurons, with a focus on MDVs, their dysregulation during aging and neurodegeneration, and implications for biomarkers and therapeutic strategies.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; Tau protein, α-synuclein
    DOI:  https://doi.org/10.1016/j.mad.2026.112167
  7. BMC Psychiatry. 2026 Mar 10.
    First case of schizophrenia and OCD in TK2-related mitochondrial DNA depletion myopathy: a case report.
    Shu Hui Ngoh, Alakananda Gudi.
      
    Keywords:  Case report; Neuropsychiatry; Obsessive-compulsive; Psychopharmacology; Schizophrenia; TK2-related mitochondrial DNA depletion myopathy
    DOI:  https://doi.org/10.1186/s12888-026-07905-5
  8. Nat Commun. 2026 Mar 13.
    Butyrate extends health and lifespan in mice with mitochondrial deficiency.
    Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Cristina Vázquez-Muñoz, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.
      Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. Here, to investigate strategies that alleviate mitochondrial dysfunction, we first generate a ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfamfl/flUbcCre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-chain fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share insufficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity, extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-70547-4
  9. Trends Neurosci. 2026 Mar 11. pii: S0166-2236(26)00014-7. [Epub ahead of print]
    The impact of dendritic mitochondrial heterogeneity on synapse function.
    Mikel L Cawley, Shannon Farris.
      Mitochondria are energy- and metabolite-producing organelles that are differentially distributed throughout neuronal axons and dendrites to meet unique energy demands. Emerging evidence indicates that mitochondria in dendrites can be molecularly, structurally, and functionally distinct depending on cell types or even nearby synaptic inputs. This suggests that mitochondrial heterogeneity not only serves individual cell types but also plays a role in supporting the diversity of synaptic functions and connectivity patterns across different brain areas. This review highlights recent studies that contribute to our understanding of how heterogeneity in dendritic mitochondrial morphology, dynamics, and function converges to support cell- and compartment-specific metabolic demands and diverse postsynaptic properties.
    Keywords:  bioenergetics; brain; local translation; neuron; plasticity; postsynapse
    DOI:  https://doi.org/10.1016/j.tins.2026.01.011
  10. Int J Nanomedicine. 2026 ;21 589123
    The Dual Role of Extracellular Vesicles in Aging and Age-Related Diseases: Pathophysiology and Therapeutic Potential.
    Yifan Zhu, Xiansong Fang, Shuli Zhang, Yiqun Liao, Haihong Lin, Puwen Chen, Mei Yang, Junyun Huang, Xiaoling Wang.
      Aging is a complex biological process characterized by progressive loss of physiological integrityand represents the primary risk factor for numerous chronic disorders, including neurodegenerative diseases, diabetes mellitus, cardiovascular disease, and stroke. Increasing evidence indicates that chronic low-grade inflammation ("inflammaging"), genomic instability, mitochondrial dysfunction, deregulated nutrient sensing, cellular senescence, and impaired intercellular communication collectively drive aging and age-related pathologies. Extracellular vesicles (EVs), a heterogeneous population of lipid bilayer-enclosed nanoparticles released by nearly all cell types, have emerged as critical regulators of these processes by mediating intercellular transfer of proteins, lipids, metabolites, and nucleic acids. In this review, we systematically synthesize current advances in EV biology within the context of aging and major age-related diseases, emphasizing their double-edged roles in disease pathogenesis and therapy. We discuss how senescent or diseased cell-derived EVs propagate inflammation, oxidative stress, genomic damage, mitochondrial dysfunction, and maladaptive immune responses, thereby accelerating tissue degeneration. Conversely, EVs derived from stem cells or young, healthy tissues exert therapeutic and rejuvenating effects by restoring redox balance, modulating immune polarization, enhancing mitochondrial function, regulating nutrient-sensing pathways, and promoting tissue repair and regeneration. Finally, we highlight the therapeutic potential of native and engineered EVs as diagnostic biomarkers and treatment modalities for aging and age-related diseases, while discussing key limitations, including rapid systemic clearance and targeting efficiency. Collectively, this review provides a comprehensive and therapy-oriented framework for understanding EVs as both drivers of aging-associated pathology and promising tools for anti-aging and regenerative medicine.
    Keywords:  aging; cardiovascular disease; diabetes; extracellular vesicles; neurodegenerative diseases; stroke
    DOI:  https://doi.org/10.2147/IJN.S589123
  11. Mol Neurobiol. 2026 Mar 11. pii: 493. [Epub ahead of print]63(1):
    Amyloid-β and Mitochondrial Membranes: A Missing Link in Alzheimer's Pathogenesis.
    Aneta Houfkova, Monika Schmidt.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline, predominantly in the elderly (Alzheimer Disease International et al., 2015). Although amyloid-β peptide (Aβ), particularly in its oligomeric forms, has long been linked to AD pathogenesis (Chen 9:1205-1235 2017, Gaspar 2 394-400 2010), the mechanisms underlying its cellular toxicity remain unclear. Mitochondrial dysfunction is a consistent feature of AD (D'Alessandro 107:102713 2025), yet how Aβ drives these alterations is not fully understood. This review integrates recent evidence showing that Aβ accumulates on mitochondrial membranes (Cenini 21:3257-3272 2016, Manczak 23:5131-5146 2006, Sirk 5:1989-2003 2007), providing a mechanistic link between amyloid pathology and mitochondrial damage. We discuss how membrane-associated Aβ disrupts mitochondrial protein import by impairing the translocase of the outer membrane (TOM) complex (Cenini 21:3257-3272 2016, Sirk 5:1989-2003 2007) and interferes with voltage-dependent anion channel 1 (VDAC1) (Smilansky 52:30670-30683 2015), a key regulator of metabolite exchange and apoptosis. We further emphasize the role of mitochondria-associated membranes (MAMs) as critical sites for Aβ generation and transfer to mitochondria, where dysregulated cholesterol metabolism may amplify MAM activity and Aβ accumulation (Area-Gomez and Schon 38:90-96 2017, Monaghan 2:240287 2025). Altogether, we propose that mitochondrial membrane localization of Aβ is a central mechanism linking amyloid pathology to mitochondrial dysfunction in aging, highlighting new directions for mitochondria-targeted therapeutic strategies in AD.
    Keywords:  Amyloid-β; Cholesterol; Mitochondria; Mitochondria-associated membranes; Proteostasis; Translocase of outer membrane; Voltage-dependent anion channel
    DOI:  https://doi.org/10.1007/s12035-026-05786-z
  12. BMB Rep. 2026 Mar 09. pii: 6743. [Epub ahead of print]
    Mitochondrial Quantity-Quality Imbalance in Cellular Senescence: Practical Readouts and Minimal Assay Bundles.
    Myeongwoo Jung, Seongho Cha, Eun Kyung Lee.
      Cellular senescence is an irreversible program of cell-cycle arrest that accumulates with age, contributing to chronic inflammation and various age-related diseases. A key feature of senescence paradigms is mitochondrial dysfunction, which involves not just a single defect but a series of coordinated changes in bioenergetics, redox homeostasis, mitochondrial quality control, and organelle interaction. Senescent cells often display a "quantity-quality imbalance" in their mitochondria: while the mitochondrial mass may increase, their efficiency in oxidative phosphorylation decreases, leading to a destabilized membrane potential (ΔΨm) and elevated levels of mitochondrial reactive oxygen species (mtROS). These interrelated changes can exacerbate senescence through persistent stress signaling, impaired turnover of damaged mitochondrial components, and alterations in organelle contacts, such as those between endoplasmic reticulum (ER) and mitochondria, and between mitochondria and lysosomes. Given that these phenotypes differ depending on cell type, triggering factors, and timing, no single assay can adequately define senescence-associated mitochondrial dysfunction. In this review, we present practical, complementary strategies that include extracellular flux-based respiration profiling, ATP output measurement, ΔΨm and ROS assessments, flux-based mitophagy reporters, quantitative network imaging, and contact-site assays. We propose minimal assay bundles that allow for a thorough multidimensional analysis. By establishing standardized, orthogonal measures of mitochondrial quantity and quality, we aim to enhance mechanistic understanding and facilitate the rational evaluation of mitochondria-targeted senolytic and senomorphic therapies.
  13. PLoS Genet. 2026 Mar;22(3): e1012076
    COG5 deficiency disrupts cellular copper homeostasis and underlies the impaired mitochondrial OXPHOS function.
    Yuwei Zhou, Keyi Li, Ruowei Zhu, Xue Ma, Xinfei Ye, Mengqing Mao, Ding Li, Xiaofei Zeng, Zhehui Chen, Jing Wu, Liqin Jin, Xiaohua Tang, Yanling Yang, Jianxin Lyu, Xiaoting Lou.
      COG5, a subunit of the conserved oligomeric Golgi (COG) complex, plays a critical role in retrograde trafficking within the Golgi apparatus. Dysfunction of COG5 is associated with various human disorders, yet the underlying pathogenic mechanisms remain poorly understood. To investigate the mechanisms, we conducted proteomic analyses using COG5-deficient and rescue cell models, which revealed a potential link between COG5 dysfunction and mitochondrial oxidative phosphorylation (OXPHOS) deficiency. Using COG5-deficient cell models and patient-derived cells harboring COG5 variants, we biochemically validated the involvement of COG5 in mitochondrial OXPHOS, particularly in the regulation of complex I content. These models also exhibited elevated cellular copper levels. Notably, the significant reduction in OXPHOS complexes could be rescued by either restoring COG5 expression or administering a copper chelator. We further demonstrated that excessive cellular copper disrupts the function of mitochondrial iron-sulfur clusters, potentially leading to complex I assembly defects. Additionally, we identified a patient with biallelic COG5 variants presenting with a distinct subtype of mitochondrial disease (Leigh syndrome), a phenotype not previously associated with COG5-related disorders. These findings provide novel mechanistic insights into the role of COG5, extending beyond its established function in Golgi-mediated glycosylation modifications. Our results underscore the importance of COG5 in mitochondrial function through a copper-dependent pathway, offering new perspectives on its contribution to cellular homeostasis and disease pathogenesis.
    DOI:  https://doi.org/10.1371/journal.pgen.1012076
  14. Int J Biol Sci. 2026 ;22(5): 2435-2451
    DNA Polymerase Gamma Acetylation Governs Mitochondrial Homeostasis and Vascular Cell Senescence.
    Pengbo Wang, Liming Yu, Kexin Cao, Xiaofan Guo, Lufan Sun, Shu Zhang, Tong Zhao, Yao Yu, Mengyao Xiong, Chang Liu, Naijin Zhang, Yingxian Sun, Guozhe Sun, Liu Cao.
      DNA polymerase gamma (Polγ), the sole polymerase for mitochondrial DNA (mtDNA), emerges as a critical regulator of metabolism-associated senescence. While lysine acetylation represents a key post-translational modification (PTM) influencing mitochondrial function, its mechanistic role in Polγ-mediated vascular aging remains undefined. Through combinatorial approaches employing in vitro acetylation models and POLG D257A/D257A mice, a validated model of mitochondrial dysfunction and senescence, we identify Lys 1039 (K1039) as a novel acetylation site which was dynamically regulated during aging process. Both D257A mutation-driven hyper-acetylation of Polγ K1039 reduced human aortic smooth muscle cell (HASMC) contractility, triggering pathological hyperproliferation and mitochondrial dysfunction, collectively culminating in premature cellular senescence. Pathological stimulation or genetic manipulation inducing hyperacetylation at K1039 disrupts Polγ's binding capacity with mtDNA. This molecular deficiency manifested functionally as compromised contractile performance in HASMCs and accelerated senescence phenotypes. Based on the above foundation and POLG D257A/D257A mice model, we demonstrated that D257A mutation reduced Sirt3-Polγ complex formation constituted the pathologically relevant molecular pathway driving aberrant acetylation homeostasis and leading to the senescence. Our findings establish a previously unrecognized regulatory axis wherein Polγ acetylation status at K1039 serves as a molecular switch coordinating mtDNA homeostasis, HASMCs functionality, and senescence progression. This mechanism might explain the remarkably consistent phenotypic manifestations of Polγ-induced dysfunction across diverse tissues and aging models. This work provides fundamental insights into the epigenetic-metabolic crosstalk governing vascular aging processes, providing a unifying framework for age-related vascular pathologies.
    Keywords:  Acetylation; DNA polymerase gamma; human aortic smooth muscle cells; mitochondrial homeostasis; senescence
    DOI:  https://doi.org/10.7150/ijbs.122298
  15. Trends Endocrinol Metab. 2026 Mar 07. pii: S1043-2760(26)00034-2. [Epub ahead of print]
    Targeting mitochondrial metabolism with combined metabolic activators.
    Hong Yang, Xiangtai Kong, Xinmeng Liao, Hasan Turkez, Jan Boren, Mathias Uhlen, Ozlem Altay, Adil Mardinoglu.
      Mitochondria play a central role in energy metabolism, redox balance, and cellular homeostasis, and their dysfunction has been implicated in the pathogenesis of complex human diseases. Advances in systems biology and omics technologies have elucidated the mechanisms underlying these conditions, including metabolic dysfunction, mitochondrial impairment, inflammation, and redox imbalance. Preclinical and early clinical studies of combined metabolic activators (CMA), a formulation of bioactive metabolites, have demonstrated improvements in mitochondrial function and systemic metabolic profiles across multiple diseases. In this review, we provide a comprehensive overview of the mechanistic rationale for CMA, summarize evidence from preclinical models and clinical studies investigating CMA and its components, and evaluate its translational potential and challenges as a mitochondrial-targeted therapeutic strategy for complex human diseases.
    Keywords:  NAD(+); combined metabolic activators; glutathione; l-carnitine tartrate; metabolic diseases; mitochondrial dysfunction; serine
    DOI:  https://doi.org/10.1016/j.tem.2026.01.018
  16. Int J Biol Sci. 2026 ;22(5): 2720-2735
    APP Deficiency Ameliorates FAD Presenilin 1 F105C and A246E Mutations-induced Mitochondrial Dysfunction in Human Cortical Neurons.
    Yu-Hsin Yen, Fang Yuan, Daijiao Tang, Jing-Fang Luo, Chen Ming, Phil-Jun Kang, Huanxing Su, Cheong-Meng Chong, Su-Chun Zhang.
       Background: Mitochondrial dysfunction is widely regarded as a central and early feature of Alzheimer's disease (AD) pathology. Prior studies suggest that the accumulation of amyloid precursor protein (APP) within mitochondria contributes to this dysfunction. Mutations in presenilin-1 (PS1), which account for most cases of early-onset familial AD (FAD), have also been shown to impair mitochondrial function. In this study, we investigated how APP influences PS1 mutation-induced mitochondrial dysfunction in human cortical neurons derived from patient induced pluripotent stem cells (iPSCs).
    Methods: We analyzed transcriptomic and proteomic datasets from postmortem sporadic AD cortex to identify key dysregulated pathways. To functionally interrogate selected mechanisms, we established a panel of CRISPR/Cas9-engineered human iPSC lines, including PS1 mutant lines (PS1+/F105C and PS1+/A246E), an APP knockout derivative (APP-/-_PS1+/F105C), and their isogenic wild-type controls. These iPSCs were differentiated into cortical neurons for functional studies. Following directed differentiation into cortical neurons, biochemical analyses and super-resolution imaging were conducted to evaluate mitochondrial and neuronal phenotypes.
    Results: Analyses of sporadic AD cortical transcriptomes and proteomes identified mitochondrial dysfunction as a prominently altered pathway. In agreement, cortical neurons differentiated from FAD PS1 mutant (F105C and A246E) iPSCs displayed mitochondrial defects and AD-related phenotypes, both of which were mitigated by APP knockout.
    Conclusions: These findings provide critical insights into the bridging role of APP in FAD PS1 mutant-mediated mitochondrial dysfunction, advancing our understanding of the cellular mechanisms underlying AD.
    Keywords:  Alzheimer's disease; CRISPR; amyloid precursor protein; iPSCs; mitochondrial dysfunction; presenilin 1
    DOI:  https://doi.org/10.7150/ijbs.120062
  17. ArXiv. 2026 Mar 05. pii: arXiv:2511.02263v4. [Epub ahead of print]
    LA-MARRVEL: A Knowledge-Grounded, Language-Aware LLM Framework for Clinically Robust Rare Disease Gene Prioritization.
    Jaeyeon Lee, Lin Yao, Hyun-Hwan Jeong, Zhandong Liu.
      Rare disease diagnosis requires matching variant-bearing genes to complex patient phenotypes across large and heterogeneous evidence sources. This process remains time-intensive in current clinical interpretation pipelines. To overcome these limitations, We present LA-MARRVEL, a knowledge-grounded, language-aware LLM framework and designed for clinical robustness and practical deployment. LA-MARRVEL delivers a 12-15 percentage-point absolute improvement in Recall@1 over established gene prioritization approaches, showing that architectural design can drive substantial accuracy gains. We found that the central contributor is structured, phenotype-rich prompt construction that explicitly encodes patient and disease phenotypes, preserving clinically meaningful context more effectively than disease labels alone. Across three real-world cohorts, LA-MARRVEL consistently improves gene-ranking performance, including in challenging cases where the causal gene was initially ranked lower by first-stage prioritization. For each candidate gene, the system delivers clinically relevant, ACMG-aligned reasoning that integrates phenotype concordance, inheritance patterns, and variant-level evidence into auditable explanations, enabling streamlined clinical review. These findings suggest that knowledge-grounded LLM layer can enhance existing rare-disease gene prioritization workflows without altering established diagnostic pipelines.
  18. Mech Ageing Dev. 2026 Mar 09. pii: S0047-6374(26)00026-6. [Epub ahead of print]231 112174
    NAD⁺ as a central metabolic hub Regulating the hallmarks of aging: Mechanisms and therapeutic implications.
    Zerong Pei, Fengni Liang, Xuemei Wang, Hui Li.
      The increasing global burden of age-related diseases necessitates interventions that target the unified biological processes of aging, as outlined by the expanding framework of fourteen interconnected hallmarks. This review establishes nicotinamide adenine dinucleotide (NAD⁺) as the central metabolic hub that coordinately regulates this entire network. We systematically elucidate the bidirectional mechanistic links between NAD⁺ metabolism and each hallmark, demonstrating how its age-related decline-driven by impaired biosynthesis and heightened consumption-propagates dysfunction across genomic, epigenetic, mitochondrial, proteostatic, and communicative processes. A large body of evidence supports that NAD⁺ can counter functional decline in models of neurodegenerative diseases, cardiometabolic diseases, and musculoskeletal aging However, a critical synthesis of evidence reveals a paradoxical, context-dependent role for NAD⁺, particularly in oncology, where it can sustain the pro-tumorigenic senescence-associated secretory phenotype (SASP) and fuel established cancers. This duality, along with tissue-specific metabolic nuances, underscores the fundamental limitation of indiscriminate "blind supplementation." Consequently, we advocate for a necessary paradigm shift towards "precision NAD⁺ modulation." Building on the integrated mechanistic analysis, we critically examine the therapeutic implications and challenges across major age-related diseases. Looking ahead, we propose that advancing the field requires embracing a "NAD⁺ systems biology" perspective. Design next-generation interventions that precisely balance tissue-specific NAD⁺ synthesis and consumption. This paradigm is essential for translating the promise of NAD⁺ biology into safe and effective strategies for extending human healthspan.
    Keywords:  Aging hallmarks; Healthspan; Metabolic regulation; NAD⁺; Precision geroscience; Sirtuins
    DOI:  https://doi.org/10.1016/j.mad.2026.112174
  19. Int J Mol Sci. 2026 Mar 09. pii: 2505. [Epub ahead of print]27(5):
    Morphological and Molecular Characteristics of Choroid Plexus Epithelium in Aged Brains.
    Ryuta Murakami, Masaki Ueno.
      The choroid plexus (CP) has traditionally been regarded as a cerebrospinal fluid-producing structure; however, increasing evidence indicates that it functions as a dynamic regulatory interface involved in immune surveillance, metabolic homeostasis, and brain clearance. Neuroimaging studies consistently report CP enlargement across aging and diverse neurological and neuropsychiatric disorders, yet the underlying cellular mechanisms remain poorly integrated. In this review, we synthesize morphological, molecular, and imaging evidence to propose a sequential degenerative model of the CP epithelium. This model comprises: (1) regulated epithelial cell loss via apical extrusion, (2) compensatory hypertrophy of residual cells, (3) mitochondrial remodeling with oncocytic-like change, and (4) progressive blood-cerebrospinal fluid barrier dysfunction. At the molecular level, alterations in epithelial adhesion systems-particularly SPINT1-mediated protease regulation and E-cadherin-based adherens junction stability-may initiate epithelial instability. Hypertrophic epithelial cells exhibit increased mitochondrial burden, reflected by Tom20 expression, which may initially support metabolic adaptation but ultimately contribute to oxidative stress and functional decline. At the macroscopic level, the cumulative effects of cell loss, hypertrophy, and mitochondrial remodeling likely underlie CP enlargement detectable by magnetic resonance imaging. This framework positions CP enlargement as an imaging-visible manifestation of epithelial stress and provides a structural-molecular basis for interpreting CP alterations in brain aging and neurodegenerative disorders.
    Keywords:  E-cadherin; SPINT1; choroid plexus; epithelial cells; mitochondria
    DOI:  https://doi.org/10.3390/ijms27052505
  20. Mol Genet Metab. 2026 Mar 03. pii: S1096-7192(26)00158-7. [Epub ahead of print]148(2): 109875
    The goal attainment scale in primary mitochondrial disease: Construct validity and lessons learned from a randomized controlled trial.
    Kristofoor E Leeuwenberg, Joanna IntHout, Jan T Groothuis, Edith Cup, Jan Smeitink, Karlien Mul, Mirian C H Janssen.
       BACKGROUND: Primary mitochondrial diseases (PMD) are rare heterogeneous disorders caused by defective oxidative phosphorylation, with symptoms varying widely between individuals with PMD. Despite extensive research, no consensus exists on outcome measures that adequately reflect function, activities, and participation for adults with mitochondrial diseases. The Goal Attainment Scale (GAS) offers a personalized, patient-centered way to capture these outcomes. However, its validity and standardized use in trials remain unclear. This study assessed GAS construct validity in a PMD trial, including comparison with the Canadian Occupational Performance Measure (COPM), and provides guidance for future application.
    METHODS: Data from a double-blind, randomized, placebo-controlled, exploratory Phase IIA cross-over trial on the safety and efficacy of sonlicromanol (KH176) in 18 adult m.3243 A>G patients, were retrospectively analyzed. GAS goals were categorized using the World Health Organization International Classification of Functioning, Disability and Health. Additional outcome measures with overlapping content were selected to evaluate GAS validity. Implementation quality was evaluated using 17 GAS appraisal criteria.
    RESULTS: Most goals addressed fatigue or lack of energy (85%, 22/26). GAS showed weak to moderate negative correlations with the Checklist Individual Strength (CC = -0.40) and Beck Depression Inventory-II scores (CC = -0.37), indicating higher GAS scores were associated with reductions in fatigue and depressive symptoms. Moderate correlations were observed between GAS and COPM scores (CC = 0.50-0.55). No significant correlations were found with the 6-min walk test, 36-item Short Form Health Survey or Newcastle Mitochondrial Disease Scale for Adults. Only 6 out of 17 (35%) implementation criteria were fully met.
    CONCLUSIONS: GAS demonstrated some construct validity in relation to fatigue and depressive symptoms, showed limited overlap with conventional outcome measures and suffered from suboptimal implementation. Although exploratory, these findings suggest GAS may capture patient-relevant change in individuals with PMD. To realize its potential, standardized methodology and further validation are essential for its use as a robust outcome measure in future PMD trials.
    Keywords:  Construct validity; Goal attainment scale; Mitochondrial disease; Outcome measure
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109875
  21. Int J Mol Sci. 2026 Feb 26. pii: 2206. [Epub ahead of print]27(5):
    Potential Links Between Aging, Mitochondrial Dysfunction, and Drug Transporter Function-Molecular Mechanisms and Pharmacokinetic Implications.
    Patryk Rzeczycki, Oliwia Pęciak, Martyna Plust, Marek Droździk.
      Aging is associated with complex physiological changes that influence drug pharmacokinetics, including alterations in mitochondrial function and gastrointestinal (GI) drug transporter activity. Mitochondrial dysfunction-characterized by reduced oxidative phosphorylation, mitochondrial DNA damage, and increased reactive oxygen species-is a hallmark of aging and may affect energy- and redox-dependent cellular processes in the gut. At the same time, aging can modulate the expression and function of key intestinal drug transporters from the ATP-binding cassette (ABC) and solute carrier (SLC) families, which play a central role in oral drug absorption and bioavailability. This review examines the molecular links between age-related mitochondrial dysfunction and regulation of GI drug transporters, with a focus on their pharmacokinetic consequences in older adults. We summarize evidence of mitochondrial decline in the aging intestine and discuss how mitochondrial signals-such as cellular energy status and oxidative stress-regulate transporter expression and activity via pathways including AMPK (AMP-Activated Protein Kinase), Sirtuin-FOXO (Forkhead box O transcription factors), Nrf2 (Nuclear factor erythroid 2-related factor 2), and NF-κB (Nuclear Factor kappa B). We highlight clinical examples of drugs showing age-related changes in bioavailability that may be attributable to transporter dysfunction. Finally, we discuss therapeutic implications for geriatric pharmacotherapy, including dose adjustment, management of transporter-mediated drug-drug interactions, and strategies aimed at preserving mitochondrial health.
    Keywords:  ABCG2; P-glycoprotein (ABCB1); aging; bioavailability; drug–drug interactions; elderly patients; energy metabolism; gastrointestinal tract; geriatric pharmacotherapy; intestinal drug absorption; mitochondrial dysfunction; oxidative stress; pharmacokinetics; polypharmacy
    DOI:  https://doi.org/10.3390/ijms27052206
  22. ACS Chem Neurosci. 2026 Mar 12.
    Energy Compensation Strategy: The Frontier of Neurodegenerative Disease Treatment.
    Junyue Tang, Yuning Sun, Xingyu Lin, Xinhui Zhao, Chun Mao, Mimi Wan, Jianying Li, Ya Guan.
      Neurodegenerative diseases are a major threat to global public health. Recent studies have revealed that mitochondrial DNA damage and the imbalance of protein homeostasis during aging constitute the core pathological basis of neurodegeneration. The resulting energy metabolism disorders are the common pathogenic hubs of multiple neurodegenerative diseases. In this review, we focus on representative neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's disease, and systematically discuss their pathology related to metabolic disorders. We introduce various energy compensation strategies: (1) rebuilding the energy supply by enhancing mitochondrial function; (2) implementing systemic metabolic remodeling; (3) supplementing alternative energy substrates; (4) utilizing direct energy delivery technology. This review also highlights the technical bottlenecks of existing energy compensation strategies, guiding future research on neurodegenerative diseases.
    Keywords:  eirect energy delivery; energy compensation; energy substrate supplementation; metabolic reprogramming; mitochondria-targeted therapies; neurodegenerative diseases
    DOI:  https://doi.org/10.1021/acschemneuro.5c00964
  23. J Bioeth Inq. 2026 Mar 13.
    From Prohibition to Prudent Opening : Exploring the Legalization of Human Germline Gene Editing for Correcting Genetic Diseases.
    Lijie Wang, Shunbin Zhang, Wei Zhong, Kainan Zhu, Quan Yang, Zichuan Ma, Jianzhen Li.
      The rapid advancement of human germline gene editing (HGGE) technology has brought opportunities for gene therapy in patients with rare diseases. However, due to risks related to technical safety, ethics, and societal concerns, some countries have explicitly prohibited the application of germline gene editing. In reality, the use of HGGE for correcting genetic diseases contributes to safeguarding the fundamental rights of patients with rare genetic disorders and their offspring. The off-target effects of CRISPR/Cas9 gene editing technology are controllable, and preliminary clinical successes have been achieved, with a low probability of substantial harm. Moreover, the expected number of actual applications is minimal, meaning it will not significantly alter the human gene pool in the short term. When applied reasonably, HGGE for correcting genetic diseases does not pose the aforementioned ethical or social risks. Its application is ethically justified, and by implementing matching safety safeguards and regulatory frameworks, the legalization of HGGE for genetic disease correction can be achieved, thereby balancing technological innovation with human rights protection.
    Keywords:  Genetic diseases; Human germline gene editing; Legalization; Prudent opening
    DOI:  https://doi.org/10.1007/s11673-025-10521-9
  24. Forensic Sci Int Genet. 2026 Mar 01. pii: S1872-4973(26)00058-X. [Epub ahead of print]84 103477
    MitoMetrics: Incorporation of mtDNA profile discrepancies in likelihood ratio calculations.
    Floor Claessens, Mikkel Meyer Andersen, Christina Amory, Cristina Arévalo, Stijn Desmyter, Sophie Dognaux, Kristiaan J van der Gaag, Tomasz Grzybowski, Gabriela Huber, Filomena Melchionda, Hiroaki Nakanishi, Tóra Olsen, Cristina Pie, Lourdes Prieto, Katarzyna Skonieczna, Chiara Turchi, Walther Parson, Vania Pereira.
      Interpretation of mitochondrial DNA (mtDNA) evidence in a forensic context faces challenges, particularly when evaluating mtDNA profiles from different tissues. In hair, for example, the segregation of mtDNA shows tight bottlenecks that can result in different mtDNA profiles between and along hair shafts, and between hair and other reference tissues of the same donor. Current forensic interpretation guidelines for mtDNA are based on conventions on the number of discrepant positions observed between the two compared profiles. Most legislations consider two discrepancies between samples as an exclusion, and one discrepancy as an inclusion or as an inconclusive result. More data are needed to understand the variation and occurrence of discrepancies in samples from the same donor, to be able to incorporate this knowledge into a mathematical approach that effectively quantifies the probability of these events. This study reports the first project of the MitoMetrics collaborative initiative. In this study, data were generated from several participating laboratories, and previously published data, along with data generated from casework. mtDNA profiles from blood/buccal reference samples were compared to those from hair shafts from the same individuals. Results report the levels of heteroplasmy detected in the different tissues, the number of differences observed between the tissue comparisons, and the number of discrepant positions observed. We suggest a preliminary model for calculating the evidential value of mtDNA-based evidence using a likelihood ratio approach, that takes into consideration the occurrence of discrepancies between profiles from the same donor. This work represents the first attempt to quantify the probability of finding discrepant events between tissues and to incorporate these when reporting mtDNA in a forensic context.
    Keywords:  Forensic interpretation; Heteroplasmy; Mitochondrial DNA; Weight of the evidence
    DOI:  https://doi.org/10.1016/j.fsigen.2026.103477
  25. J Affect Disord. 2026 Mar 06. pii: S0165-0327(26)00439-8. [Epub ahead of print] 121588
    Sex-specific mitochondrial alterations in cognitively unimpaired older depressed individuals.
    Brandi Quintanilla, Chelsea Reichert Plaska, Ashutosh Tripathi, Amit Kumar Madeshiya, María Torres Carrizalez, Buno P Imbimbo, Nunzio Pomara, Anilkumar Pillai.
      Major depressive disorder (MDD) is a leading cause of disability worldwide, and depression in older adults is an increasingly urgent public health concern. While psychosocial contributors to late-life depression have been extensively studied, the underlying biochemical mechanisms remain less well understood. Mitochondria, critical for neuronal energy production, function, and survival, have been implicated in depression, and mitochondrial alterations have also been linked to changes in sex hormone levels. This is a secondary analysis of an observational study of cognitively unimpaired older adults with and without MDD (N = 112) who were followed for three years. We analyzed the baseline data of an observational study to examine the relationship between depression status and mitochondrial function, using plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) and mitochondrial DNA encapsulated in extracellular vesicles (EV-mtDNA). We also examined the association between mitochondrial function and biological sex as well as interactions with depression status. Across all participants, we observed moderately strong correlations (r = 0.42-0.53) between plasma levels of ccf-mtDNA and EV-mtDNA. Group-level analyses showed elevated levels of both EV-mtDNA and ccf-mtDNA in the depressed group, with depression severity positively associated with both measures in a sex-specific manner. Importantly, older depressed females exhibited higher EV-mtDNA levels compared to older depressed males, while older depressed males showed higher ccf-mtDNA levels compared to their female counterparts. These findings suggest that mitochondrial alterations in depression may be shaped by sex-specific biological pathways in the aging population.
    Keywords:  Depression; Mitochondrial DNA; Mitochondrial function
    DOI:  https://doi.org/10.1016/j.jad.2026.121588
  26. Int J Mol Sci. 2026 Mar 03. pii: 2361. [Epub ahead of print]27(5):
    From Microscopy to Nanoscopy: Contemporary Physical Methods in Mitochondrial Structural Biology.
    Semen V Nesterov, Anton G Rogov, Raif G Vasilov.
      Mitochondria play a crucial role in cellular bioenergetics, signaling, and metabolism; yet, many fundamental mechanisms such as the proton transfer along the membranes, the link between membrane curvature and oxidative phosphorylation, and the nanoscale organization of enzyme supercomplexes remain poorly understood due to the limitations of classical biochemical approaches. This review addresses this gap by systematically analyzing the contemporary physical methods used to investigate the mitochondrial structure and function from the micro to nano scale. It covers advanced fluorescence and super-resolution microscopy, electron and volume electron microscopy, and scanning probe techniques, as well as cryo-electron tomography for resolving supramolecular assemblies in near-native conditions. The review highlights the applications of the modern fluorescent probes, expansion and phase microscopy, and machine-learning-based image analysis for a quantitative assessment of the mitochondrial morphology, membrane potential, and dynamics in living cells and tissues. Complementary spectroscopic and scattering methods, including Raman spectroscopy, NMR, and X-ray and neutron scattering, are discussed as tools for probing the redox state, metabolite composition, and membrane organization. Emphasis is placed on integrating high-resolution experimental data with advanced computational frameworks to test competing models of mitochondrial function and pathology, and to guide the development of biomimetic and biomedical technologies.
    Keywords:  bioenergetics; cryo-electron tomography; fluorescent markers; mitochondria; mitochondrial morphology; spectroscopy; super-resolution
    DOI:  https://doi.org/10.3390/ijms27052361
  27. Int J Mol Sci. 2026 Feb 27. pii: 2232. [Epub ahead of print]27(5):
    Mitochondrial Iron Handling and Lipid Peroxidation as Drivers of Ferroptosis.
    José Luis Bucarey, Mariana Casas, Alejandra Espinosa.
      Mitochondria are a key organelle in maintaining metabolic homeostasis. It not only generates most of the cell's energy through oxidative phosphorylation but also acts as a complex sensor of the redox state and oxygen in the cell. This review thoroughly analyzes the interactions among mitochondrial iron metabolism, mitochondrial reactive oxygen species (mtROS), and lipid peroxidation (LPO), the triggering factors of ferroptosis, an iron-dependent form of programmed cell death. We point out research showing that intrinsic mitochondrial machinery, such as iron-sulfur (Fe-S) cluster assembly and heme metabolism, is both an important cofactor and a master regulator. If these processes are disrupted, they can lead to ferroptosis. Unlike views that focus on the cytosol, we explain that the stability of Fe-S clusters in complexes such as aconitase and respiratory Complex I is crucial for preventing electron leakage and excessive mtROS formation. The Fenton reaction and its direct effect on cardiolipin (CL) oxidation in the inner membrane of mitochondria is a central event in cardiometabolic diseases. Its peroxidation and breakdown make the organelle very unstable and lead to cell death though Ca2+ overload and a significantly decreased reduced/oxidized glutathione ratio. Additionally, the functions of essential iron transporters and glutathione homeostasis are examined, and their dysregulation is correlated with ferroptosis-associated progression of cardiometabolic and neurodegenerative disorders, such as obesity and Alzheimer's disease. This review focused on the need to revisit the classic bioenergetic core of the mitochondria as a key player in the pathophysiology of metabolic and neurodegenerative diseases.
    Keywords:  cardiolipin; complex I; ferroptosis; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/ijms27052232
  28. Theranostics. 2026 ;16(9): 5044-5064
    From bench to bedside: the promise and roadblocks of extracellular vesicle therapeutics.
    Jing Zhang, Yuanwei Pan, Peng She, Lang Rao.
      Extracellular vesicles (EVs) have transformed the landscape of precision therapeutics, owing to their intrinsic biocompatibility, capacity to transport biomolecules, and ability to cross biological barriers. Benefiting from these advantages, several EV-based therapeutic applications are currently under active development. However, most products remain at the preclinical stage due to significant translational challenges. In this review, we systematically outline these obstacles and highlight opportunities that can accelerate the clinical translation of EVs. We first identify core issues impeding clinical progress, such as difficulties in isolation, storage stability, precise characterization, biosafety evaluation, and quality control. After that, we examine emerging technologies designed to overcome these bottlenecks, including advanced bioreactors for large-scale production, microfluidic systems for high-purity separation, single-vesicle analysis technologies to address heterogeneity, and machine learning approaches that enhance standardization and support clinical decision-making. Finally, we discuss future directions focused on standardizing EV production, improving safety assessment, and ensuring regulatory compliance. By addressing current challenges and identifying promising pathways, this review aims to facilitate the translation of EV-based therapies from bench to bedside.
    Keywords:  analytical techniques; clinical translation; extracellular vesicles (EVs); machine learning; single EV analysis
    DOI:  https://doi.org/10.7150/thno.131621
  29. Cells. 2026 Feb 27. pii: 414. [Epub ahead of print]15(5):
    Network Rewiring in the Aging Immune System: From Chronic Inflammation to Age-Related Pathologies.
    Ludmila Müller, Svetlana Di Benedetto.
      Aging is accompanied by profound alterations in immune function that collectively drive increased susceptibility to infection, reduced vaccine efficacy, impaired tissue repair, and heightened risk of age-related diseases (ARDs). These alterations are characterized by the coexistence of immunosenescence and inflammaging. Rather than reflecting isolated cellular defects, immune aging emerges as a systems-level reprogramming of immune networks that disrupts the initiation, resolution, and regenerative phases of inflammatory responses. In particular, aging is associated with impaired resolution of inflammation, defective efferocytosis, reduced responsiveness to pro-resolving signals, and diminished regenerative capacity, leading to persistent inflammatory milieus and tissue damage. This review summarizes recent advances in the mechanisms underlying immune dysfunction in aging, with a focus on how chronic inflammation, failed resolution, and defective repair reinforce one another. We discuss how alterations in innate and adaptive immunity, immunometabolism, cellular senescence, and immune-tissue interactions drive inflammaging and contribute to major ARDs, including cancer, neurodegenerative, and cardiometabolic diseases. Finally, we highlight emerging therapeutic strategies aimed at restoring immune balance and resolution. By adopting a systems-level and network-based perspective, this review underscores immune aging as a modifiable driver of ARDs and identifies key knowledge gaps and future directions toward interventions that promote healthy aging and extended healthspan.
    Keywords:  age-related diseases; immunosenescence; impaired resolution of inflammation; inflammaging; pro-resolving lipid mediators; systems-level and network-based perspective; therapy
    DOI:  https://doi.org/10.3390/cells15050414
  30. Ann Neurol. 2026 Mar 11.
    Astrocytic Mitochondria Transplantation Rescues Neuron Loss and Dendritic Injuries in Acute Cerebral Ischemic Stroke Mouse Model by Flexibly Regulating Mitochondria Dynamics.
    Ning Bian, Jianing Shen, Linwei Tian, Jinghui Li, Lu Yang, Bo Yuan, Shulin Li, Yuyu Niu, Lu Zhao, Jingkuan Wei.
       OBJECTIVE: Cerebral ischemic stroke causes neuronal oxygen/energy deprivation, disrupting mitochondrial function including reduced membrane potential and bioenergetics, exacerbating neuronal injury. Mitochondrial defects are, therefore, a central neuropathological node and potential therapeutic target. Previous studies have shown that mitochondria transplantation rescued infarction in cerebral ischemic stroke. However, interactions between transplanted and endogenous mitochondria remain unclear. Here, we proposed astrocytic mitochondria as the optional donor for mitochondria transplantation in ischemic stroke treatment because of their ischemic resistance.
    METHODS: We transplanted mitochondria derived from astrocytes into an ischemic stroke cell and mouse model to investigate the feasibility and mechanisms of astrocytic mitochondria transplantation for ischemic cerebral stroke. We assessed the uptake of transplanted mitochondria by neurons, their impact on endogenous mitochondrial dynamics (fusion/fission), mitochondrial functions, neuronal dendritic structure, neuronal survival, and mice motor function.
    RESULTS: Transplanted astrocytic mitochondria were successfully taken up by neurons, and within neurons, they flexibly regulated endogenous mitochondrial dynamics. This intervention rescued the stroke-induced reduction in mitochondrial membrane potential and oxidative phosphorylation capacity. Consequently, it significantly decreased neuronal dendritic injuries and cell death. These cellular improvements translated into alleviated motor deficits in the stroke model.
    INTERPRETATION: Astrocytic mitochondria transplantation is an effective therapeutic strategy for ischemic stroke. Its neuroprotective effects stem from the internalization of functional mitochondria into neurons and the subsequent flexibly regulation of endogenous mitochondrial dynamics, restoring bioenergetics and promoting neuronal survival. This approach holds significant promise for treating ischemic stroke and potentially other brain disorders involving mitochondrial dysfunction. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78197
  31. Cureus. 2026 Feb;18(2): e103261
    Leber Hereditary Optic Neuropathy Caused by the Rare MT-ND1 m.3394T>C Mutation: A Case With Favorable Visual Prognosis and a Literature Review.
    Paulina Mikulenaite, Alvita Vilkeviciute, Almina Stramkauskaite, Ieva Povilaityte, Neringa Jurkute, Rasa Liutkeviciene.
      Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial optic neuropathy characterized by acute or subacute painless central visual loss. Most cases are associated with three primary mitochondrial DNA mutations; however, rare variants remain incompletely characterized. Early diagnosis is essential for appropriate management and genetic counseling. We report the case of a 51-year-old Lithuanian woman who presented with painless, progressive central visual loss. Initial neurological and ophthalmological investigations were unremarkable, and corticosteroid therapy was ineffective. Genetic testing revealed a rare homoplasmic m.3394T>C mutation in the MT-ND1 gene. The patient was subsequently treated with idebenone and followed for six years. Following initiation of idebenone therapy, the patient demonstrated gradual and sustained improvement in best-corrected visual acuity, reaching 1.0 in both eyes. Visual fields stabilized, and long-term follow-up showed preserved visual function. Optical coherence tomography revealed persistent but stable structural changes, including retinal nerve fiber layer and ganglion cell layer thinning in the affected eye. This case highlights the potential for favorable long-term visual outcomes in patients with LHON associated with rare mitochondrial variants. It underscores the importance of considering hereditary optic neuropathy in patients with painless visual loss and poor response to corticosteroids. Further studies are needed to clarify genotype-phenotype correlations and treatment responsiveness in rare LHON-associated mutations.
    Keywords:  aetiology; diagnosis; leber hereditary optic neuropathy; mt-nd1 gene (m.3394t>c); treatment
    DOI:  https://doi.org/10.7759/cureus.103261
  32. Immunol Rev. 2026 Mar;338(1): e70114
    Sex Differences in Metabolite-Immune Circuits of Neuroinflammation.
    Priyanka Saminathan, Maija Corey, Alicia Gibbons, Mahati Rayadurgam, Neha Reddy, Pavithra Ramesh, Sonia Sharma.
      Sex is a fundamental yet underexplored determinant of human neuroinflammation. Across autoimmune, neurodegenerative, and post-infectious neurological syndromes, males and females exhibit consistent differences in disease vulnerability, progression, and immune tone. While sex hormones and chromosomes strongly shape immune development and function in health and disease, they do not fully explain the magnitude or disease-specific patterns of these disparities, nor do they provide sufficient mechanistic information for developing novel therapeutics. Emerging evidence suggests that sex-defining factors interact with age and environment to shape downstream metabolite-immune circuits, networks in which metabolic enzymes, metabolites, and immune cells tune inflammatory set points. Pathways spanning purine metabolism, glycolytic remodeling, lipid sensing, mitochondrial stress, and nucleic-acid sensing can recalibrate microglial activation thresholds, T-cell cytokine programs, innate type I interferon antiviral responses, and shape overall CNS resilience in a sex-dependent manner. Here, we synthesize mechanistic and human systems-level studies to propose an integrated framework in which sex-biased immunometabolism serves as a mechanistic bridge between biological sex and neuroimmune disease risk, progression, and responses to injury. We highlight key knowledge gaps and discuss how targeting metabolite-immune pathways may enable sex-informed biomarkers and therapeutic strategies in neuroinflammatory disease.
    Keywords:  bio‐active lipids; immunometabolism; microglia; neuroinflammation; purine metabolism; sex differences
    DOI:  https://doi.org/10.1111/imr.70114
  33. Interact J Med Res. 2026 Mar 09. 15 e83709
    Global Research Trends and Hotspots in Gene Editing and Stem Cell Therapies for Neurodegenerative Diseases: Bibliometric and Visualization Analysis.
    Lijun Xiang, Yun Xiao, Ming Cai, Jing Qin, Ting Wang, Xueming Xiang, Jun Ke, Ganlin Peng.
       Background: Neurodegenerative diseases are a major and growing global health burden. Their pathogenesis is complex, and effective therapies remain limited. Gene editing and stem cell-based strategies are reshaping the therapeutic landscape. However, the field has not been systematically examined through bibliometric analysis.
    Objective: We aimed to define the intellectual landscape of global research on gene editing and stem cell therapy for neurodegenerative diseases from 2005 to 2024, highlight evolving hotspots, track the field's evolution, and identify major bottlenecks limiting clinical translation.
    Methods: We retrieved 1821 publications from the Web of Science Core Collection (2005-2024). We performed a multidimensional bibliometric analysis using CiteSpace and VOSviewer. We assessed publication output, country and institutional contributions, key authors and journals, co-cited references, and keyword networks. These analyses were used to track the field's evolution and pinpoint emerging themes.
    Results: In total, 9978 researchers from 90 countries and 2515 institutions contributed to this literature. Annual publications increased from 28 in 2005 to 179 in 2024, with stepwise growth over time. The United States ranked first in output (n=780) and in citation impact (total local citation score=2784; total global citation score=40,009). China and India ranked second and fifth in output, respectively, but their average citation impact was lower than that of the leading countries. The University of California, San Francisco, and Johns Hopkins University remained consistently influential. Boulis NM, Bankiewicz KS, and Feldman EL were among the most prominent contributors. Molecular Therapy was the leading journal in this area. Keyword analyses pointed to a growing intersection between genetics and immunology. Major topics included nanotechnology-based delivery, adeno-associated virus vectors, small interfering RNA, intrathecal microsphere injection, autophagy, blood-brain barrier (BBB) targeting, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), and induced pluripotent stem cells. Burst detection highlighted "open label" as a recent hotspot. This likely reflects rising translational activity and early clinical testing.
    Conclusions: The field is moving from technology development toward clinical translation. Anglo-American countries currently drive both productivity and influence. China and India contribute heavily to volume but need a stronger impact. CRISPR/induced pluripotent stem cell platforms and BBB-focused delivery remain central frontiers. The rise of "open-label" studies suggests accelerating clinical momentum. Future progress will require safer and more efficient delivery, clearer standards, and larger global consortia to harmonize protocols and speed translation.
    Keywords:  bibliometric analysis; clinical translation; gene editing technology; neurodegenerative diseases; stem cell therapy
    DOI:  https://doi.org/10.2196/83709
  34. Cell Stem Cell. 2026 Mar 05. pii: S1934-5909(26)00073-1. [Epub ahead of print]33(3): 372-381
    Two decades of induced pluripotent stem cell research: From discovery to diverse applications.
    Shinya Yamanaka.
      Twenty years have passed since the first demonstration of mouse induced pluripotent stem cells (iPSCs). What began as an unexpected observation in Kyoto quickly transformed stem cell biology and regenerative medicine worldwide. Over the past two decades, we have gained profound insights into the molecular mechanisms underlying cellular reprogramming and pluripotency. The technology has continued to evolve-becoming safer, more efficient, and more versatile. Today, iPSCs serve as a foundation for wide-ranging applications, from disease modeling and drug discovery to regenerative therapies and rejuvenation research. In this review, I reflect on the scientific journey of iPSCs, highlight key milestones in our understanding of reprogramming, and discuss the expanding clinical and societal impact of iPSCs.
    Keywords:  iPS cells; medical application; reprogramming
    DOI:  https://doi.org/10.1016/j.stem.2026.02.003
  35. J Leukoc Biol. 2026 Mar 11. pii: qiag034. [Epub ahead of print]
    Mitochondrial Electron Transport Chain Modulation Orchestrates Divergent TLR3 and TLR7 Responses.
    Mary-Elizabeth Sheridan, Duale Ahmed, Malak Al Daraawi, Nikki Kovac, Edana Cassol.
      Macrophages are on the front lines against viral infections and play a central role in initiating antiviral immune responses. They do this by sensing viral ligands through their arsenal of pattern recognition receptors, which fine-tune and determine the specificity of the immune response. Cellular metabolism has emerged as a central regulator of this specificity, driven in part by alterations in mitochondrial function. Yet, we are only starting to elucidate the specific mitochondrial dynamics that contribute to this differential modulation. Here, we report that TLR3 vs. TLR7 engagement results in divergent metabolic reprogramming that regulates their specific responses and that PKM2 dimerization and nuclear translocation serve as regulators of the balance in type I IFN, pro-inflammatory and anti-inflammatory programming. Furthermore, we found chemical modulation of ETC complexes I and II activity can selectively alter PKM2-dependent signalling, enabling a fine-tuning of macrophage effector response. Given that TLR3 and TLR7 ligands are utilized as vaccine adjuvants and have demonstrated potential as cancer immunotherapies, our findings suggest that specific targeting of mitochondrial function can be used to manipulate macrophage responses and to improve the efficacy and limit the off-target effects of these therapeutics.
    Keywords:  Antiviral Responses; Immunometabolism; Macrophage; Mitochondria; Toll-like receptors
    DOI:  https://doi.org/10.1093/jleuko/qiag034
  36. Cell. 2026 Mar 11. pii: S0092-8674(26)00173-X. [Epub ahead of print]
    Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy.
    Annika Zink, Dao-Fu Dai, Annika Wittich, Marie-Thérèse Henke, Giulia Pedrotti, Sonja Heiduschka, Guillem Santamaria, Tancredi Massimo Pentimalli, Christian Brueser, Sofia Notopoulou, Abdul Rahim Umar, Aleksandra Zhaivoron, Laura Petersilie, Caleb Jerred, Jesper Bergmans, Louis Anton Neu, Fabian Schumacher, Jan Keller-Findeisen, Agnieszka Rybak-Wolf, Daniel Stach, Jeanette Reinshagen, Undine Haferkamp, Kim Krieg, Andrea Zaliani, Liliya Euro, Alessia Di Donfrancesco, Chiara Santanatoglia, Enrica Cappellozza, Marta Suarez Cubero, Mario Pavez-Giani, Oleh Bakumenko, David Meierhofer, Alan Foley, Susanne Morales-Gonzalez, Isabella Tolle, Diran Herebian, Daniele Bonesso, Giulia Cecchetto, Sakurako Nagumo Wong, Monica Moresco, Alessandra Maresca, Ilaria Decimo, Francesco De Sanctis, Annalisa Adamo, Merel J W Adjobo-Hermans, Roberto Duchi, Maria Barandalla, Marco Scaglia, Andrea Perota, Cesare Galli, Burkhard Kleuser, Lukas Cyganek, Chris Mühlhausen, Lars Schlotawa, Valeria Tiranti, Ertan Mayatepek, Ildiko Szabo, Chiara La Morgia, Thomas Klopstock, Valerio Carelli, Felix Distelmaier, Andrea Rossi, Nikolaus Rajewsky, Ghanim Ullah, Stefan Jakobs, Christine R Rose, Spyros Petrakis, Frank Edenhofer, Werner J H Koopman, Pawel Lisowski, Anu Suomalainen, Dario Brunetti, Antonio Del Sol, Emanuela Bottani, Ole Pless, Markus Schuelke, Alessandro Prigione.
      Mitochondrial disease encompasses inherited disorders affecting mitochondrial function. A severe and untreatable form of mitochondrial disease is Leigh syndrome (LS), causing psychomotor regression and metabolic crises. To accelerate drug discovery for LS, we screen a library of 5,632 repurposable compounds in neural cells from LS-patient-derived induced pluripotent stem cells (iPSCs). We identify phosphodiesterase type 5 (PDE5) inhibitors as leads and prioritize sildenafil for its clinical safety. Sildenafil corrects mitochondrial membrane potential defects, restores neurodevelopmental pathways, and normalizes calcium responses in LS brain organoids. In small and large mammalian models of LS, sildenafil extends lifespan and ameliorates disease phenotypes. Off-label treatment on an individual basis with sildenafil in six LS patients improves their motor function and resistance to metabolic crises. Collectively, the findings highlight the potential of iPSC-driven drug discovery and position sildenafil as a promising drug candidate for mitochondrial disease.
    Keywords:  Leigh syndrome; PDE5 inhibitors; PRKG1; brain organoids; drug repurposing; drug screening; high-content analysis; iPSCs; mitochondrial diseases; sildenafil
    DOI:  https://doi.org/10.1016/j.cell.2026.02.008
  37. Biol Pharm Bull. 2026 ;49(3): 457-466
    Structural and Functional Diversity of Mitochondria Isolated from Different Cell Types.
    Yusei Endo, Mai Kanai, Masaki Kobayashi, Yoshikazu Higami, Shoko Itakura, Makiya Nishikawa, Kosuke Kusamori.
      Mitochondria are essential organelles responsible for energy production, autophagy, and apoptosis, and mitochondrial dysfunction has been implicated in various diseases affecting the heart, liver, and kidneys. Mitochondrial transplantation, wherein isolated mitochondria are administered into cells or tissues, has recently emerged as a promising therapeutic approach for restoring cellular functions by enhancing ATP generation and reducing oxidative stress. However, the characteristics and functional diversity of the mitochondria isolated from different cell types remain poorly understood. Here, we aimed to identify the optimal mitochondrial source for transplantation therapy by comparing mitochondria isolated from several mammalian cell types, including mesenchymal stromal, hepatic, muscular, and pluripotent stem cells. Mitochondria were isolated using a streptolysin O-based isolation method and characterized through particle size, zeta potential, protein content, and ATP content. The isolated mitochondria exhibited uniform morphology, negative surface charge, sufficient protein yield, and ATP content, indicating successful preparation of functionally competent organelles suitable for comparative analysis. The mitochondria derived from mesenchymal stromal cells exhibited the highest bioenergetic activity. Adding these mitochondria enhanced cellular proliferation, oxygen consumption, and resistance to oxidative stress in recipient cells. Collectively, these findings demonstrate that mitochondria isolated from autologous mesenchymal stromal cells possess superior bioenergetic properties, highlighting their potential as an optimal source for mitochondrial transplantation therapy and providing new insights into the design of mitochondria-based therapeutics.
    Keywords:  ATP production; cellular bioactivity; mesenchymal stromal cell; mitochondrial transplantation; oxidative stress
    DOI:  https://doi.org/10.1248/bpb.b25-00716
  38. medRxiv. 2026 Mar 06. pii: 2026.03.05.26347086. [Epub ahead of print]
    Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification.
    Tobias Brünger, Ilona Krey, Suyeon Kim, Chiara Klöckner, Scott J Myers, Katrine M Johannesen, Arthur Stefanski, Gary Taylor, Eduardo Perez-Palma, Marie Macnee, Stephanie Schorge, Rebekka S Dahl, Hongjie Yuan, Riley E Perszyk, Sukhan Kim, Sunanjay Bajaj, Ingo Helbig, Jen Q Pan, Mark Farrant, Lonnie Wollmuth, David J A Wyllie, Erkin Kurganov, David Baez, Sameer Zuberi, Christian M Boßelmann, Holger Lerche, Massimo Mantegazza, Sandrine Cestèle, Patrick May, Alina Ivaniuk, Mary Anne Meskis, Veronica Hood, Leah Schust, Kimberly Goodspeed, Jing-Qiong Kang, Amber Freed, Cornelius Gati, Ludovica Montanucci, Arthur Wuster, Marena Trinidad, Steven Froelich, Alexander T Deng, Ángel Aledo-Serrano, Artem Borovikov, Artem Sharkov, Arjan Bouman, M J Hajianpour, Deb K Pal, Leslie Danvoye, Damien Lederer, Tugce R Balci, Eveline E O Hagebeuk, Alexis Heidlebaugh, Kathryn Oetjens, Trevor L Hoffman, Pasquale Striano, Sarah Drewes Williams, Kalene van Engelen, Katherine B Howell, Jean Khoury, Tim A Benke, Vincent Strehlow, Konrad Platzer, Amy Ramsey, Lisa Manaster, Sunitha Malepati, Pangkong Fox, Jeffrey Noebels, Wendy Chung, Annapurna Poduri, Laina Lusk Stripe, Sarah M Ruggiero, Stacey Cohen, Lacey Smith, Sylvia Boesch, Olivia Wilmarth, Anna Jenne Prentice, Esther Cha, Nikita Budnik, Marina P Hommersom, Audra Kramer, Carlos G Vanoye, Guo-Qiang Zhang, Michael Nothnagel, Aarno Palotie, Mark J Daly, Alfred L George, Yuri A Zarate, Andreas Brunklaus, Stephen F Traynelis, Rikke S Møller, Johannes R Lemke, Dennis Lal.
      Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework's utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.
    DOI:  https://doi.org/10.64898/2026.03.05.26347086
  39. Gene Ther. 2026 Mar 13.
    Building a gene editing lexicon: a model for rare and inherited disorders.
    Leonard A Valentino, Cedric Hermans, Donna Coffin, Wolfgang Miesbach, Maria Elisa Mancuso, Carmen Unzu, Micheala Jones, David E Gutstein, William McKeown, Craig M Kessler.
      As more advanced cell and gene therapies, including gene editing technologies, progress through drug development, there is increased emphasis on the importance of stakeholders, including people living with disease, caregivers, and healthcare professionals, to communicate using clear, accurate, and consistent language. Lexicons explaining advanced gene therapies will support patients' and clinicians' understanding, enabling shared decision-making and informed consent for clinical trial participation and, in the future, healthcare choice. Early lexicon development is crucial for standardizing communication across clinical sites, geographies, clinicians, and patients. A lexicon for clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) gene editing for hemophilia was developed using comprehensive methodologies, gathering insight through qualitative research and in-depth interviews, language audits, and workshops, with input from lived experience experts, leading clinicians in hemophilia, gene therapy experts, and scientific and patient organizations. This lexicon serves as a gold standard template for future comprehensive patient lexicon development strategy and could be applied to other therapeutic areas where treatments are being developed and standardized, or where accessible vocabulary for patients, healthcare professionals, and the affected community is lacking. This communication highlights the need for lexicon development for advanced gene editing treatments across therapeutic areas to support standardized understanding and enhance communication.
    DOI:  https://doi.org/10.1038/s41434-026-00596-3
  40. Redox Biol. 2026 Mar 02. pii: S2213-2317(26)00104-7. [Epub ahead of print]92 104106
    hUCMSC mitochondrial EVs confer neuroprotection after ischemia by Tom1l2-mediated mitochondrial fusion and Crls1-cardiolipin axis reprogramming.
    Ziheng Li, Xingjia Zhu, Weiquan Liao, Rui Jiang, Enze Sang, Jue Zhu, Gaojia Sun, Zhichao Lu, Chenxing Wang, Yi Jiang, Jian Chen, Peipei Gong, Qianqian Liu.
      Mitochondrial dysfunction is a central driver of irreversible neuronal injury following ischemic stroke (IS); yet effective strategies to restore mitochondrial function and promote long-term neurological recovery remain limited. In this study, we demonstrate that mitochondrial extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUCMSC Mito-EVs) serve as a novel biotherapeutic vehicle capable of delivering functional mitochondria to damaged neurons. This process involves Target of Myb1-like 2 membrane trafficking protein (Tom1l2)-dependent membrane fusion between hUCMSC Mito-EVs and neuronal mitochondria, leading to the restoration of mitochondrial membrane potential and mitochondrial function. Mechanistically, Mito-EVs-mediated mitochondrial transfer upregulates cardiolipin synthase 1 (CRLS1), which preserves the inner mitochondrial membrane integrity and stabilizes respiratory chain complexes. The restoration of mitochondrial structure and function subsequently reduces reactive oxygen species production, suppresses pyroptosis, and promotes the recovery of neuronal metabolic and functional homeostasis. Collectively, these findings suggest that the Tom1l2-Crls1 axis serves as a key mediator of mitochondrial repair in hUCMSC Mito-EVs therapy, highlighting its promising potential as a targeted therapeutic strategy for neuronal protection following IS.
    Keywords:  Human umbilical cord mesenchymal stem cells; Ischemic stroke; Mitochondria; Mitochondrial extracellular vesicles; Neuron
    DOI:  https://doi.org/10.1016/j.redox.2026.104106
  41. J Alzheimers Dis. 2026 Mar 10. 13872877261424276
    Modulation of mitochondrial quality by exercise mimetics: A potential strategy for the prevention and treatment of Alzheimer's disease.
    Zhiwei Ke, Bo Wang, Rongxiang Liang.
      Decline in mitochondrial quality is a prominent pathological feature of Alzheimer's disease (AD), manifested by impaired energy metabolism, disrupted mitochondrial biogenesis, abnormal mitochondrial dynamics, and defective mitophagy. Increasing evidence indicates that mitochondrial dysfunction contributes to the exacerbation of amyloid-β (Aβ) deposition and tau protein hyperphosphorylation, thereby accelerating AD pathogenesis. Of particular interest, physical exercise has been shown to effectively enhance mitochondrial quality and help prevent or slow the progression of AD, largely through the activation of key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). However, regular physical activity may not be feasible for individuals in the prodromal or clinical stages of AD. In this context, exercise mimetics-compounds that pharmacologically simulate the molecular effects of exercise-have emerged as a promising alternative intervention. This review analyzes the mechanistic roles of exercise mimetics in improving mitochondrial quality under AD conditions, with a focus on their regulation of mitochondrial homeostasis via key signaling pathways. It further aims to provide theoretical insight for the development of mitochondria-targeted exercise mimetics and offer a potential strategy for addressing the growing global burden of AD.
    Keywords:  Alzheimer's disease; brain-derived neurotrophic factor; exercise mimetics; irisin; metformin; mitochondrion; resveratrol
    DOI:  https://doi.org/10.1177/13872877261424276
  42. Nutrients. 2026 Mar 07. pii: 863. [Epub ahead of print]18(5):
    Mechanistic Modulation of Autophagy by Bioactive Natural Products: Implications for Human Aging and Longevity.
    Maroua Jalouli, Abdel Halim Harrath, Mohammed Al-Zharani, Md Ataur Rahman.
      Autophagy is an evolutionarily preserved intracellular degradation process pivotal in maintaining proteostasis, mitochondrial homeostasis, and metabolic equilibrium, all of which are dysregulated with aging. Aberrant autophagy has been recognized as a hallmark of human aging and age-related diseases, including neurodegeneration, metabolic dysfunction, cardiovascular diseases, and cancer. Bioactive natural compounds derived from plants, foods, and marine organisms have emerged as potent modulators of autophagy, offering a promising strategy to counteract aging and promote healthy lifespan. Mechanistically, these compounds regulate autophagy by modulating key signaling pathways, such as AMPK, PI3K/AKT/mTOR, SIRT1, and FOXO, while also alleviating oxidative stress, inflammation, and mitochondrial dysfunction. Natural compounds like polyphenols, flavonoids, alkaloids, terpenoids, and carotenoids exhibit dual roles by restoring age-related suppressed autophagic flux and inhibiting excessive autophagy-induced cell death. In this review, we provide a comprehensive overview of the molecular mechanisms through which bioactive natural compounds modulate autophagy and impact human aging and longevity. We discuss both experimental and clinical evidence supporting their geroprotective effects, limitations regarding bioavailability and dose-dependent effects, and prospects for the utilization of autophagy-targeting natural products in aging intervention strategies.
    Keywords:  autophagy modulation; bioactive natural products; cellular homeostasis; human aging; longevity; oxidative stress
    DOI:  https://doi.org/10.3390/nu18050863
  43. Biochem Soc Trans. 2026 Mar 25. pii: BST20253120. [Epub ahead of print]54(3):
    The segregation of organelles and organellar genomes across eukaryotic biology.
    Clirim Jetishi, Markus Gerber, Torsten Ochsenreiter.
      Eukaryotic cells are characterized by the presence of organelles such as mitochondria and, in the case of plants and certain protists, plastids, both of which often contain their own genomes. Accurate distribution of replicated organelles and their genomes to daughter cells is crucial for cell survival and propagation across all eukaryotic organisms. Unlike nuclear DNA, which follows a well-characterized segregation process via the mitotic spindle, organelle genomes are inherited through more diverse and less-understood mechanisms. Ensuring proper organelle genome inheritance is essential for maintaining cellular energy production, metabolic functions, and overall viability. Because organelle and organelle genome segregation lack a universal mechanism, different organisms employ various strategies that include stochastic distribution and active cytoskeletal transport and membrane tethering to prevent the loss of essential genetic material while supporting organelle division and turnover. This review provides an overview of organelle and organellar DNA segregation mechanisms in diverse eukaryotic systems before focusing on the tripartite attachment complex as a specialized adaptation in kinetoplastid parasites.
    Keywords:  DNA segregation; apicoplast; chloroplast; membrane tethering; mitochondrion; mitosomes; organellar DNA; tripartite attachment complex
    DOI:  https://doi.org/10.1042/BST20253120
  44. EPMA J. 2026 Mar;17(1): 1-19
    Innovative mitochondria-based holistic 3PM approach to female health status: Facts and outlook.
    Martin Pesta, Vadim Goncharenko, Vlastimil Kulda, Jiri Polivka, Jasur Rizaev, Olga Golubnitschaja.
      Throughout a woman's life, energy metabolism faces more volatile demands compared to men, driven by major hormonal transitions like puberty, the menstrual cycle, pregnancy, and menopause. Mitochondria, as central organelles for energy production and vital cellular biosensors, are consequently subjected to substantial physiological stress. When the body's compensatory mechanisms are overwhelmed, particularly in states of suboptimal health, compromised mitochondrial functionality is characterised by increased generation of reactive oxygen species (ROS) frequently associated with a chronification of the low-grade inflammation and development of follow-up pathologies. Compromised health and shifted homeostasis of mitochondria are crucial for development and progression of a broad spectrum of disorders in female subpopulations which can be exemplified by chronic fatigue, gestational diabetes mellitus, preeclampsia, polycystic ovary syndrome, and gynaecologic cancers, amongst others. This article strongly advocates for the implementation of an innovative, mitochondria-based holistic approach within the framework of Predictive, Preventive, and Personalised Medicine (3PM). 3PM-guided strategy focuses on the early detection of reversible health damage shifting care from reactive treatment to individualised proactive, risk-adapted management of the health conditions. The integration and interpretation of the multimodal data, supported by artificial intelligence, enable the stratification of individuals in suboptimal health conditions and affected patients for cost-effective protective measures tailored to individualised patient profiles, therapeutic interventions, and personalised pre- and rehabilitation programmes. In summary, by utilising mitochondrial biosensorics for monitoring systemic effects in a holistic manner, the presented 3PM-guided innovation offers a robust model for protecting individuals against health-to-disease transition and disease progression in affected patient cohorts.
    Keywords:  AI; Chronic fatigue; Chronic inflammation; Expert recommendations; Female cancers; Flammer syndrome phenotype; Gestational diabetes; Health risk assessment; Homeostasis; Hormonal stress; Individualised protection against health-to-disease transition; Individualised rehabilitation programme; Life quality; Mitochondrial health; Patient phenotyping and stratification; Patient-friendly non-invasive approach; Predictive preventive personalised medicine (PPPM / 3PM); Pregnancy; Sympathetic overdrive; Tear fluid analysis
    DOI:  https://doi.org/10.1007/s13167-026-00438-7
  45. Mol Biol Cell. 2026 Mar 11. mbcE25070334
    ATG9B Regulates Mitochondrial Integrity and Apoptotic Tumor Cell Death.
    Hong Cao, Lixia Guo, Jing Chen, Eugene Krueger, Gina Razidlo, Mark A McNiven.
      It is well established that many tumor types possess defective autophagic pathways. Several studies have reported that the transmembrane, autophagic lipid scramblase ATG9B is altered in multiple cancers, suggesting that this dysregulation could contribute to oncogenesis. Therefore, the goal of this study was to define the cellular distribution of ATG9B in two different tumor cell types and to provide insights into its cellular function. Surprisingly, we found that ATG9B shows a modest association with autophagic structures and exhibits a unique and prominent localization to mitochondria, in contrast to its related form ATG9A. Upon expression of tagged ATG9B forms, this mitochondrial distribution was accompanied by aberrant changes in mitochondrial morphology as well as a reduction in the mitochondrial membrane potential and the release of mtDNA. Few indicators for ATG9B-dependent mitophagy were noted. Instead, ATG9B overexpression led to pronounced apoptotic cell death as assessed by a variety of indicators. Further, we find that the N-terminal sequence of ATG9B acts as a mitochondrial targeting domain and that expression of this peptide alone can induce apoptotic cell death. These findings provide new insights into a putative cellular localization and function for ATG9B. [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-07-0334
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