bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–05–24
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Nucleoside therapy for thymidine kinase 2 deficiency: Long-term outcomes from a Brazilian cohort.
  2. Targeting competitive Fe-S regulation to treat Friedreich's ataxia.
  3. Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
  4. Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.
  5. Melas mimicking hydrocephalus.
  6. Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.
  7. A Novel Combination of Biallelic Variants in the VARS2 Gene: A Severe Phenotype.
  8. "SelO"ective NAD+ hydrolysis regulates mitochondrial NAD+ and homeostasis.
  9. The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
  10. Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.
  11. Mitochondrial Dynamics and Transfer in Mesenchymal Stromal Cells: Redox Regulation, Therapeutic Mechanisms, and Engineering Strategies.
  12. Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.
  13. Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.
  14. Metabolic Plasticity in Embryogenesis Throughout the Lens of NAD.
  15. Development of a secretable frataxin for enhanced efficacy in treating Friedreich's Ataxia.
  16. Early-life mitochondrial impact of prenatal DL-PCB exposure: A signal from cord blood mtDNA.
  17. Role of oxidative stress in the susceptibility to mitophagy of the skin fibroblasts and iPSC-derived neurons of patients with MERRF syndrome.
  18. Xenogeneic Mitochondrial Transplantation Improves Selected Age-Associated Phenotypes in Mice.
  19. Directed evolution of small RNA-stabilizing motifs that improve prime-editing efficiency.
  20. Progressive short stature in Pearson syndrome and the impact of organ failure.
  21. Mitochondria and polycystic ovary syndrome: The role of ferroptosis, inflammasomes, and endoplasmic reticulum stress.
  22. SIRT2 mediates integrated stress response by deacetylating and stabilizing 4E-BP1 to suppress translation.
  23. Environmental cadmium drives placental senescence and fetal growth restriction via activating CLPP-dependent mitochondrial stress.
  24. Optimized lentivirus-derived virus-like particles for efficient delivery of Cas9-based genome editors.
  1. J Neuromuscul Dis. 2026 May 20. 22143602261432401
    Nucleoside therapy for thymidine kinase 2 deficiency: Long-term outcomes from a Brazilian cohort.
    Cristiane Araujo Martins Moreno, Tatiana Ribeiro Fernandes, Clara Gontijo Camelo, Gabriel Keller, Filipe Di Pace, Gabriella Corrêa Dousseau, Alulin Tácio Quadros Santos Monteiro Fonseca, Eliene Dutra Campos, Ana Paula Dos Anjos Lança, Mariana Cunha Artilheiro, André Macedo Serafim da Silva, Michelle Abdo Paiva, Andres Nascimento, Edmar Zanoteli.
      BackgroundThymidine Kinase 2 deficiency (TK2d) is a rare, mitochondrial DNA (mtDNA) depletion/deletions syndrome leading to a severe and progressive myopathic disorder. Nucleoside supplementation (deoxythymidine and deoxycytidine) has been shown to favorably alter the disease's course, particularly in severe infantile-onset cases. Long-term data on efficacy and safety, especially in the adult patient population, remain limited.MethodsThis is a retrospective, long-term follow-up study of 14 TK2d patients (five children and nine adults with childhood-onset disease) treated with nucleosides. Patients were systematically evaluated over a period ranging from 9 to 36 months, with assessments conducted every 3 months during the first year of treatment, and every 6 months thereafter. Comprehensive functional assessments of motor, respiratory, and bulbar function were performed. Periodic measurements of liver and pancreatic function monitored safety and tolerability.ResultsAll 14 TK2d patients showed beneficial effects across motor, respiratory, and bulbar function domains. Among pediatric patients, a rapid treatment response was observed early on, with functional gains sustained and continuing beyond 12 months of therapy. Adults experienced substantial improvements in motor and respiratory capacity but most of them reported severe gastrointestinal symptoms. Liver and pancreatic enzymes abnormalities were noticed mainly in adults.ConclusionsDeoxythymidine and deoxycytidine were found to be safe and beneficial in this long-term cohort of TK2d patients, but elevation in liver and pancreatic enzymes were present and required regular monitorization. This study provided valuable evidence supporting this therapy as an effective and safe, long-term disease-modifying treatment option for both pediatric and adult patients.
    Keywords:  Mitochondrial Myopahty; TK2 deficiency; deoxythymidine and deoxycytidine; mtDNA depletion syndrome; nucleosides therapy
    DOI:  https://doi.org/10.1177/22143602261432401
  2. Trends Pharmacol Sci. 2026 May 18. pii: S0165-6147(26)00108-2. [Epub ahead of print]
    Targeting competitive Fe-S regulation to treat Friedreich's ataxia.
    Juliane C Campos, Julio C B Ferreira.
      Recent discoveries reveal that frataxin (FXN) and ferredoxin 2 (FDX2) competitively regulate mitochondrial iron-sulfur (Fe-S) cluster biosynthesis through their binding to the cysteine desulfurase NFS1 and the iron-sulfur cluster scaffold protein ISCU2 complex. Here, we discuss the potential of rationally designed peptide inhibitors targeting the FDX2-NFS1 interaction as a strategy to mitigate FXN deficiency and restore Fe-S cluster biosynthesis.
    Keywords:  genetic disease; mitochondria; neurodegeneration; pharmacology; protein–protein interaction
    DOI:  https://doi.org/10.1016/j.tips.2026.04.010
  3. Sci Immunol. 2026 May 29. 11(119): eaef0098
    Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
    Sofía C Khouili, Elena Priego, Ignacio Heras-Murillo, Gillian Dunphy, Annalaura Mastrangelo, Sarai Martínez-Cano, Vanessa Nuñez, Manuel Rodrigo-Tapias, Adrián Belinchón-García, Johan Garaude, Salvador Iborra, Navdeep S Chandel, Patricia González-Rodríguez, Michel Enamorado, David Sancho.
      Mitochondrial metabolism modulates immune cell signaling, yet how individual electron transport chain complexes fine-tune dendritic cell (DC) function remains unclear. Here, we identify mitochondrial complex I (CI) as a critical metabolic checkpoint controlling antigen cross-presentation by DCs in mice. Deficiency of the CI subunit NDUFS4 in DCs led to the formation of a nonfunctional CI subcomplex, resulting in mildly impaired mitochondrial respiration without triggering a compensatory glycolytic shift. NDUFS4 deficiency limited endosomal escape of internalized antigens, thereby impairing antigen cross-presentation while largely preserving direct presentation. CI dysfunction lowered the NAD+/NADH ratio, concomitant with decreased ATP levels, and diminished neutral lipid storage and lipid peroxidation. Restoration of the NAD+/NADH ratio rescued cross-presentation in NDUFS4-deficient DCs. NDUFS2-deficient DCs showed similar defects in cross-presentation, which were also rescued by rebalancing the NAD+/NADH ratio. Together, these findings reveal a link between mitochondrial CI integrity, NAD+-driven redox metabolism, and antigen cross-presentation.
    DOI:  https://doi.org/10.1126/sciimmunol.aef0098
  4. Nature. 2026 May 20.
    Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.
    Ram P Chakrabarty, Jonathan G Van Vranken, Yuki Aoi, Taylor A Poor, Gregory S McElroy, Karthik Vasan, Shimaa H A Soliman, Marta Iwanaszko, Rogan A Grant, Benjamin C Howard, Colleen R Reczek, Anjali D Chandel, Michael Kahl, Zhaofa Xu, Kathryn A Helmin, Qiushi Jin, Dongmei Wang, Peng Gao, Jenna L E Blum, Zachary L Sebo, Feng Yue, Yongchao C Ma, Shawn M Davidson, Steven P Gygi, Samuel E Weinberg, Benjamin D Singer, SeungHye Han, Ali Shilatifard, Navdeep S Chandel.
      L-2-Hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals because the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH) oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation1. In humans, a lack of L2HGDH activity leads to L-2-HG accumulation and causes L-2-hydroxyglutaric aciduria2. Thus, L-2-HG is often classified as a toxic metabolite2-5. However, whether L-2-HG has any physiological function is unclear. Here we investigate whether L-2-HG qualifies as a physiological signalling metabolite by testing three criteria: regulated levels, defined molecular targets and a measurable physiological function. We report that an increase in mitochondrial NADH/NAD+ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG. Moreover, L2HGDH oxidizes L-2-HG back to 2-OG in the mitochondrial matrix without requiring a functional electron transport chain. Through proteome integral solubility alteration assays, we show that the KDM4 family of H3K9 demethylases are L-2-HG-responsive targets. L-2-HG represses the nascent transcription of specific genes in mouse embryonic stem cells and increases H3K9me3 (a repressive histone mark) at these loci. In vivo, early embryonic L2HGDH overexpression in mice systemically reduces L-2-HG levels, impairs postnatal growth, causes mortality and produces selective functional and histological renal vulnerabilities. In postnatal kidneys, this reduction in L-2-HG causes H3K9me3 loss at L1MdTf retrotransposons and their derepression, which coincides with the activation of the integrated stress response and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiological signalling metabolite and indicate that metabolites previously regarded as toxic may also have crucial physiological functions.
    DOI:  https://doi.org/10.1038/s41586-026-10564-x
  5. Neurol Sci. 2026 May 20. pii: 506. [Epub ahead of print]47(6):
    Melas mimicking hydrocephalus.
    Matthieu Labriffe, Patrizia Amati-Bonneau, Marco Spinazzi.
      
    Keywords:  Dementia; Hydrocephalus; MELAS; Mitochondrial disease; Neurodegeneration; Ventricular enlargement
    DOI:  https://doi.org/10.1007/s10072-026-09113-1
  6. Sci Rep. 2026 May 18.
    Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.
    Renae J Stefanetti, Chiara Pizzamiglio, Alasdair P Blain, Oliver M Russell, Lisa Alcock, Gavin Hudson, Jane Newman, Naomi Thomas, Charlotte Warren, Huizhong Su, Helen A L Tuppen, Philip Brown, David Houghton, Heather Hunter, Albert Z Lim, Yi Shiau Ng, Catherine Feeney, Iwona Skorupinska, Louise Germain, Enrico Bugiardini, Michael G Hanna, Robert McFarland, Robert D S Pitceathly, Gráinne S Gorman.
      Primary mitochondrial myopathies (PMM) are rare, genetically-defined disorders characterised by defects of oxidative phosphorylation, predominantly affecting skeletal muscle. This Phase 1b open-label trial evaluated mavodelpar, a selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, over 12 weeks (Part A), with an optional 36 week extension (Part B) in adults with PMM. The primary objective was to assess safety and tolerability, with secondary assessments of pharmacokinetics, pharmacodynamics, and exploratory performance, patient-reported, and muscle biopsy outcomes. Of the 23 participants who received mavodelpar, 17 completed Part A; none completed Part B due to premature study termination during the COVID-19 pandemic. Adverse events were mild-moderate severity, with headache and constipation most common (4/23 participants; 17.4% each). Exploratory measures showed a mean increase of 104 m in the twelve minute walk test (95% CI: 53 to 156) and a mean reduction of -10.5 points in patient-reported fatigue (95% CI: -16.3 to -4.6). No consistent changes in mitochondrial function were detected in muscle biopsies (n = 10), while transcriptomic profiling (n = 6) revealed modest upregulation of fatty acid-metabolism pathways. Although findings from this Phase 1b trial supported progression to later-phase evaluation, the subsequent Phase 2b trial did not demonstrate clinical efficacy for mavodelpar. The results reported here should be interpreted as exploratory and not indicative of therapeutic benefit. Nevertheless, this Phase 1b trial provides important methodological insights to inform future PMM clinical trial design and outcome measure development.
    Keywords:  Mitochondrial disease; Mitochondrial myopathy; Outcome measures; Peroxisome proliferator-activated receptor delta (PPARδ) agonist; Phase 1 trial; Rare disease
    DOI:  https://doi.org/10.1038/s41598-026-43287-0
  7. Acta Med Port. 2026 May 18.
    A Novel Combination of Biallelic Variants in the VARS2 Gene: A Severe Phenotype.
    Joana Capela, Mariana Reis, Inês Almeida, Marta Novo, Ana Ramalho, Patrícia Lipari, Márcia Rodrigues.
      To our knowledge, only 29 individuals have been described in the literature with biallelic pathogenic variants in the valyl-tRNA synthetase 2 (VARS2) gene, responsible for changes in the mitochondrial respiratory chain complex. We report two siblings with a novel combination of biallelic variants in the VARS2 gene (c.1079C>T p.Ala360Val, likely pathogenic, and c.1258G>A p.Ala420Thr, likely pathogenic). Both presented early hypertrophic cardiomyopathy and lactic acidosis, with fatal outcomes within the first year of life. The first also presented severe fetal growth restriction and a ventricular septal defect; the second developed epilepsy, respiratory failure, and psychomotor delay. This genotype may be linked to a particularly severe cardiac phenotype. Our report broadens the clinical and genetic spectrum of VARS2-related mitochondrial disease, highlights the variability of phenotypic expression, and reinforces the importance of early molecular diagnosis in neonatal-onset cardiomyopathy. Genetic confirmation enables accurate genetic counselling and consideration of prenatal or preimplantation diagnosis in future pregnancies.
    Keywords:  Cardiomyopathy; Epilepsy; Hypertrophic; Mitochondrial Diseases; Valine-tRNA Ligase/genetics
    DOI:  https://doi.org/10.20344/amp.23831
  8. Cell Chem Biol. 2026 May 21. pii: S2451-9456(26)00147-9. [Epub ahead of print]33(5): 591-593
    "SelO"ective NAD+ hydrolysis regulates mitochondrial NAD+ and homeostasis.
    Qing Zhang, Trina Chia Min Tan, Vincenzo Sorrentino.
      Nicotinamide adenine dinucleotide (NAD+) is a metabolic redox cofactor whose compartmentalization in mitochondria is crucial for cellular function; however, its regulation mechanisms are largely unknown. In a recent Cell publication, Jia et al.1 uncover that the enzyme SelO catalyzes mitochondrial NAD+ hydrolysis to regulate β-oxidation and maintain mitochondrial and liver homeostasis.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.04.012
  9. Protein Sci. 2026 Jun;35(6): e70622
    The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
    Kira Ritzenhofen, Stefano Rossi, Axel Mogk, Fabian den Brave.
      Mitochondria are essential organelles of eukaryotic cells, with vital roles in energy production, biosynthesis of macromolecules, and intracellular signaling. Their function depends on a complex proteome with proteins targeted to different mitochondrial sub-compartments. Synthesis of precursors of mitochondrial proteins (mitoPREs) mostly occurs in the cytosol followed by post-translational import. Delay or block of mitochondrial import leads to mitoPRE accumulation in the cytosol, where they interact with cytosolic protein quality control (PQC) factors and might get re-routed to other cellular organelles, including the nucleus. Recent research implies the nucleus as a central hub in cellular PQC. Here, not only nuclear but also proteins from other organelles, including mitochondria or the cytosol, are handled by intra-nuclear PQC factors. In addition, the nucleus controls the expression of mitochondrial proteins and PQC components involved in handling mitoPREs and surveilling the integrity of mitochondrial import channels. In this review, we discuss recent insights from yeast on the dual function of the nucleus in controlling the biogenesis of mitoPREs and as a compartment for quality control of non-imported mitoPREs. We additionally describe how mitochondrial dysfunction and defects in mitochondrial import trigger compensatory stress responses inside the nucleus. Here, nuclear targeting of non-imported mitoPREs may serve as a direct signal to adjust stress response pathways to the status of mitochondrial import.
    Keywords:  chaperones; mitochondria; nucleus; protein quality control; protein sorting; stress response; ubiquitin‐proteasome system
    DOI:  https://doi.org/10.1002/pro.70622
  10. Pharmacol Res. 2026 May 18. pii: S1043-6618(26)00142-8. [Epub ahead of print] 108227
    Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.
    Julia Brechtel, Christine Lietz, Selin Akpinar Adscheid, Kristina Friedland.
      Mitochondrial dysfunction is considered one of the key drivers of neurodegeneration and pathological aging, characterized by impaired energy production, oxidative stress, disrupted mitophagy, and biogenesis. Because mitochondria regulate bioenergetics, redox balance, and neuronal survival, therapeutic strategies that restore mitochondrial integrity are of growing interest. This review outlines mechanisms of mitochondrial function and failure, links them to Alzheimer's and Parkinson's disease, and summarizes evidence on phytochemicals and mitochondria-targeted small molecules, which enhance biogenesis, mitophagy, respiratory efficiency, and antioxidant defence in preclinical models together with life-style interventions. Although many compounds demonstrate preventive rather than restorative benefit and clinical evidence remains limited, next-generation approaches, including nanoparticles for mitochondrial delivery, mtDNA editing, and mitochondrial transfer, suggest increasing therapeutic potential. We underline that future success will rely on improved delivery, synergistic combinations, and rigorous clinical trials. Mitochondria-directed therapies may ultimately provide disease-modifying or preventive strategies for neurodegenerative disorders.
    Keywords:  Alzheimer’s Disease; Mitochondria-Targeted Therapies; Mitochondrial Dynamics; Mitochondrial Dysfunction; Parkinson’s Disease; Phytochemicals; Small Molecule
    DOI:  https://doi.org/10.1016/j.phrs.2026.108227
  11. Free Radic Biol Med. 2026 May 20. pii: S0891-5849(26)00771-9. [Epub ahead of print]
    Mitochondrial Dynamics and Transfer in Mesenchymal Stromal Cells: Redox Regulation, Therapeutic Mechanisms, and Engineering Strategies.
    XueXia Liu, XiaoXin Wang, FuJun Liu.
      Mesenchymal stromal cells (MSCs) are metabolically active and redox-sensitive therapeutic cells, with their therapeutic potency tightly linked to mitochondrial integrity and function. Beyond paracrine and immunomodulatory actions, MSCs can transfer functional mitochondria to damaged cells, restoring bioenergetics, maintaining redox homeostasis via ROS regulation, and facilitating tissue repair and regeneration. This review summarizes recent progress in MSC mitochondrial biology, highlighting how metabolic reprogramming, mitochondrial biogenesis, fusion-fission dynamics and mitophagy coordinately regulate MSC stemness, differentiation, senescence and therapeutic capacity. It outlines core redox regulatory networks covering mitochondrial ROS production (ETC Complexes I/III and reverse electron transport), non-mitochondrial oxidases (NADPH oxidases), and canonical antioxidant signaling (Nrf2/Keap1, thioredoxin/peroxiredoxin and glutathione/glutaredoxin). Redox-dependent post-translational modifications governing mitochondrial transfer machinery are emphasized, including cysteine oxidation of connexin 43, redox-regulated Drp1 phosphorylation, and oxidative modulation of Miro1-mediated mitochondrial trafficking. Major intercellular mitochondrial transfer routes, such as tunneling nanotubes, connexin 43-based intercellular communication and extracellular vesicles, are discussed under inflammatory, hypoxic and metabolic stress conditions. Preclinical studies across pulmonary, cardiovascular, neurological, renal, hepatic and immune-mediated diseases validate that MSC-derived mitochondrial transfer preserves ATP production, mitigates oxidative injury and remodels recipient cell immunometabolic phenotypes. Emerging engineering strategies to improve mitochondrial delivery and therapeutic outcomes are also reviewed, alongside translational bottlenecks including cell source heterogeneity, mitochondrial quality control, in vivo tracking, dosage optimization and long-term biosafety. Overall, MSC mitochondrial dynamics and intercellular transfer bridge redox biology, metabolism and regenerative medicine, offering mechanistic insights for next-generation precision regenerative therapies.
    Keywords:  Extracellular vesicles; Mesenchymal stromal cells; Mitochondrial transfer; Redox homeostasis; Regenerative medicine
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.291
  12. Kidney Int. 2026 May 21. pii: S0085-2538(26)00394-7. [Epub ahead of print]
    Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.
    Matthew D Campbell, Monica Sanchez-Contreras, Britta D Sibley, Phoebe Keiser, Carla Ruiz-Sanchez, Carolyn N Mann, Anna A Bakhtina, James E Bruce, David J Marcinek, Behzad Najafian, Mariya T Sweetwyne.
       INTRODUCTION: Whether and how podocytes depend on mitochondria across their long post-mitotic lifespan is unclear. With limited cell numbers and broad kidney distribution, isolation of podocyte mitochondria typically requires first isolating podocytes themselves. Disassociation of podocytes from their basement membrane, however, recapitulates an injured state and stresses mitochondria. Here, we devise a new strategy to examine mitochondria in podocytes.
    METHODS: To address this, we crossed floxed hemagglutinin (HA)-mitochondria tagged (MITO-Tag) mice with those expressing Cre in either podocytes (NPHS2) or mixed tubules (CDH16), thus allowing for rapid, kidney cell-specific, isolation of mitochondria via immunoprecipitation.
    RESULTS: Mitochondrial respiration in fresh isolates from young (4-7 months) and aged (22-26 months) mice of both sexes demonstrated several previously unreported significant differences between podocyte and tubule mitochondria. First, although podocytes contain fewer mitochondria than tubule cells, mitochondria isolated from podocytes averaged twice the respiratory capacity of tubule mitochondria when normalized to mitochondrial content by citrate synthase levels. Second, age-related decline in respiration was detected only in podocyte mitochondria and only in aged male mice. Third, disassociating podocytes for cell culture initiates functional decline in mitochondria as those from cultured primary podocytes have half the respiratory capacity, but twice the hydrogen peroxide production, of podocyte mitochondria isolated directly from fresh kidneys. Finally, conformation of electron transport chain proteins differed between podocyte and tubule mitochondria, suggesting that cell-specific mitochondrial protein conformations dictate cell-specific mitochondrial function.
    CONCLUSIONS: Previous studies suggesting a limited role for mitochondrial regulation of podocytes relied on cell culture. This resulted in artifactual suppression of mitochondrial function and masks the roles of mitochondria in maintenance of podocyte health. Our approach shows that per organelle, podocytes maintain sexually dimorphic mitochondria with greater oxidative phosphorylation capacity than the mitochondria-dependent tubules.
    Keywords:  animal model; distal tubule; mitochondria; podocyte
    DOI:  https://doi.org/10.1016/j.kint.2026.04.016
  13. Nat Aging. 2026 May;6(5): 987-1006
    Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.
    Arpit Sharma, Aditi Prabhakar, Miriam Valera-Alberni, Jamie D Kraft, Abigail E Ellis, Ryan D Sheldon, Meeta Mistry, Pallas Yao, Yanshan Liang, Sheng Hui, William B Mair.
      Aging impairs coordinated organelle dynamics essential for lipid metabolism, causing a decline in intracellular metabolic flexibility. However, the drivers of organelle collapse and their temporal order remain unclear. Here we identify peroxisomal function as a critical regulator of metabolic flexibility during youth and low-energy states. Using Caenorhabditis elegans, we show that fasting robustly induces peroxisomal function in youth, whereas this response is blunted during aging. Loss of peroxisomal import via PRX-5 declines over age, causing pathological lipid droplet expansion, dysfunctional mitochondrial bioenergetics and metabolic inflexibility. Although targeted PRX-5 degradation recapitulates metabolic aging, its overexpression preserves lipid dynamics and mitochondrial integrity. Notably, dietary restriction maintains peroxisomal pathways and organelle coordination into late life and peroxisomal function causally underpins dietary restriction-mediated longevity. Our findings highlight peroxisomes as central upstream regulators of a dynamic interorganelle cascade driving metabolic plasticity and highlight peroxisomal maintenance as a key determinant of metabolic flexibility during aging.
    DOI:  https://doi.org/10.1038/s43587-026-01122-1
  14. Methods Mol Biol. 2026 ;3010 175-188
    Metabolic Plasticity in Embryogenesis Throughout the Lens of NAD.
    Quetzalcoatl Escalante-Covarrubias, Paul Delgado-Olguín.
      Changes in cell fate during early mammalian development are supported by the dynamic regulation of energy metabolic pathways. These transitions fulfill energetic demands and influence transcriptional reprogramming and cell differentiation. Variations in NAD+/NADH ratios during early developmental transitions correlate with metabolic remodeling. Indeed, NAD+ bioavailability acts as an early signal for a change in the metabolic landscape by controlling the redox state and activity of multiple NAD+ dependent enzymes. Here, we summarize recent studies on NAD+ bioavailability and its function as the master organizer of energy metabolism during early mouse development. Additionally, we examine the function of NAD+ dependent chromatin remodelers in synchronizing transcriptional programs with pathways that fulfil the metabolic demands of developmental stage transitions.
    Keywords:  2-; 4-cell stage; Blastocyst; Energy metabolism; NAD+/NADH radio; Redox state; Zygote
    DOI:  https://doi.org/10.1007/978-1-0716-5126-1_17
  15. Mol Ther Adv. 2026 Mar 12. 34(1): 201661
    Development of a secretable frataxin for enhanced efficacy in treating Friedreich's Ataxia.
    Daniel M DuBreuil, Michael Fleming, Yashvi Parikh, Mikaela Woo, Jie Bu, Swathi Ayloo, Ingeborg M Langohr, Dinesh S Bangari, Christian Mueller, Shyam Ramachandran.
      Friedreich's Ataxia (FA) exemplifies a critical challenge for gene therapies targeting multi-system disorders: achieving widespread therapeutic protein repletion while minimizing vector dose and systemic exposure. No disease-modifying therapies are approved for FA, and current gene therapy approaches fail to address the full disease, forcing patients to choose between cardiac protection and neurological benefit. Here, we present "Engineered Cross-Correction," in which the therapeutic protein is bioengineered for secretion, expanding the therapeutic footprint. We apply this approach to FA by engineering a secretable frataxin and delivering it via a single intra-cerebrospinal fluid (CSF) injection of an adeno-associated viral (AAV) vector equipped with a novel capsid and tissue-selective promoter. We achieved broad protein repletion across key target tissues-heart, dorsal root ganglia, and cerebellum-in mouse and non-human primate. In FA mouse models, we observed rescue of cardiac and neurological phenotypes, marking the first demonstration of dual correction with a single, minimally invasive administration. These benefits were achieved without widespread transduction, reducing vector burden and associated toxicity. Our findings establish a scalable platform that contrasts with intravenous blood-brain barrier (BBB)-penetrant gene delivery and offers a generalizable strategy for multi-system disorders. Beyond FA, this positions Engineered Cross-Correction as a new frontier for the next generation of gene therapies.
    Keywords:  AAV; Friedreich’s Ataxia; cross-correction; gene therapy; protein engineering
    DOI:  https://doi.org/10.1016/j.omta.2025.201661
  16. Ecotoxicol Environ Saf. 2026 May 20. pii: S0147-6513(26)00536-1. [Epub ahead of print]319 120207
    Early-life mitochondrial impact of prenatal DL-PCB exposure: A signal from cord blood mtDNA.
    Chen Yang, Xiang Li, Xiaohui Zhang, Hua Chang, Hui Li, Lulu Liu, Bingnan Liu, Zaili Zhang.
      Mitochondrial DNA (mtDNA) copy number in umbilical cord blood is increasingly recognized as a sensitive indicator of mitochondrial health and vulnerability to environmental exposures during early development. Although persistent organic pollutants (POPs), such as dioxin-like polychlorinated biphenyls (DL-PCBs), have been associated with mitochondrial disturbances, the relationship between prenatal exposure to DL-PCBs and neonatal mtDNA levels remains insufficiently characterized. This study set out to assess the relationship between maternal DL-PCB concentrations during gestation and mtDNA content in cord blood at birth. We recruited 1620 pregnant women from China between 2022 and 2023. Cord blood levels of 12 WHO-identified DL-PCB congeners were quantified using validated Gas Chromatography-Mass Spectrometry methods. Umbilical cord blood samples were collected at birth, and relative mtDNA copy number was measured by quantitative real-time PCR. Associations between individual and mixture DL-PCB exposures and mtDNA copy number were evaluated using multivariable linear regression, quantile g-computation (g-comp), generalized weighted quantile sum (gWQS) regression, and Bayesian kernel machine regression (BKMR). After adjusting for potential confounders, a significant inverse relationship was observed between mtDNA copy number and several specific DL-PCB congeners, notably PCB77, PCB81, PCB126, and PCB169. The g-comp models supported a robust negative association between cumulative DL-PCB exposure and mtDNA levels (β = -0.264, 95% CI: -0.415 to -0.113; p < 0.001). Additionally, the BKMR analysis revealed a non-linear dose-response relationship, with more pronounced changes in mtDNA copy number occurring at low-to-moderate DL-PCB exposure levels. Our findings suggest that prenatal exposure to DL-PCBs is associated with reduced mtDNA copy number in cord blood, which may reflect potential mitochondrial disturbances in the developing fetus. These results underscore the need for further mechanistic studies to clarify the role of mitochondrial pathways in the developmental effects of DL-PCBs.
    Keywords:  Environmental Exposure; Mitochondrial DNA; Polychlorinated Biphenyls (PCBs); Pregnancy; Umbilical Cord Blood
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.120207
  17. Mitochondrion. 2026 May 19. pii: S1567-7249(26)00061-9. [Epub ahead of print] 102171
    Role of oxidative stress in the susceptibility to mitophagy of the skin fibroblasts and iPSC-derived neurons of patients with MERRF syndrome.
    Yu-Ting Wu, Hui-Yi Tay, Hsiao-Hui Liao, Jung-Tse Yang, Yau-Huei Wei.
      Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is mainly caused by the m.8344A > G mutation and mitochondrial dysfunction, but the pathogenesis remains unclear. In this study, we demonstrated that carbonyl cyanide m-chlorophenyl hydrazine (CCCP) induced PINK1-mediated mitophagy and accelerated mitochondrial turnover in the skin fibroblasts of MERRF patients. We found that CCCP led to more pronounced increase of PINK1 accumulation, activation of LC3B II and degradation of Mfn1, Mfn2, OSCP and OPA1 cleavage in MERRF skin fibroblasts as compared with normal skin fibroblasts. Moreover, N-acetylcysteine suppressed PINK1 accumulation and ubiquitin phosphorylation and thus impaired clearance of damaged mitochondria. This inhibitory effect was validated in MERRF patient iPSC-derived neurons harboring the m.8344A > G mutation, which displayed mitochondrial dysfunction, ROS overproduction and impaired electrophysiological function of mature neurons. These findings suggest that oxidative stress plays a crucial role in the susceptibility to mitophagy of skin fibroblasts and iPSC-derived neurons of MERRF patients and that restoring proper mitophagic flux is a potential therapeutic approach.
    Keywords:  MERRF syndrome; Mitophagy; N-acetylcysteine; PINK1; iPSC-derived neural stem cells (iNSCs); iPSC-derived neurons; mtDNA mutation
    DOI:  https://doi.org/10.1016/j.mito.2026.102171
  18. Adv Sci (Weinh). 2026 May 22. e75806
    Xenogeneic Mitochondrial Transplantation Improves Selected Age-Associated Phenotypes in Mice.
    Wenpeng Li, Xijia Wang, Yaning Hu, Zhen Yang, Tian Niu, Xingbo Zhao.
      Xenogeneic mitochondrial transplantation (xeno-MT) improves selected age-associated phenotypes and mitochondrial functional readouts in mice while engaging host mitochondrial quality-control-related pathways. Donor mitochondrial preparations with impaired membrane potential retained measurable activity, but both respiratory competence and in vivo efficacy declined progressively with more extensive room-temperature damage and were largely lost after complete disruption. Although beneficial effects were observed in additional donor contexts, the present study provides the most detailed in vivo evidence for yak-derived xeno-MT, and broader donor equivalence remains to be established. These findings support xeno-MT as proof-of-concept evidence of biological activity and short-term tolerability under the conditions tested, while long-term safety, germline relevance, and pathway-specific dependence remain to be defined.
    Keywords:  ageing; age‐related features; mitochondrial heteroplasmy; mitochondrial quality control; xenogeneic mitochondrial transplantation
    DOI:  https://doi.org/10.1002/advs.75806
  19. Nat Biotechnol. 2026 May 20.
    Directed evolution of small RNA-stabilizing motifs that improve prime-editing efficiency.
    Holt A Sakai, Sarah E Pierce, Allen Y Jiang, Ana Cristian, Meirui An, Chae Rin Kim, Nouraiz Ahmed, Colin F Hemez, Y Allen Tao, Emily Zhang, Sophia J Wu, David R Liu.
      The performance of prime-editing (PE) systems has been improved by systematic engineering of their protein and small RNA components but the structured RNA motifs appended to the 3' end of PE guide RNAs (pegRNAs)-a key determinant of pegRNA stability and editing efficiency-have not been extensively studied. We introduce PE-PRISM, a high-throughput pooled screen to identify and optimize these 3' RNA motifs in human cells. Here, using PE-PRISM, we evaluated 2,858 RNA motifs across four iterative libraries, including natural and engineered pseudoknots, G-quadruplexes and reverse transcriptase recruitment elements. We applied structure-guided mutagenesis and combinatorial variant screening to refine hits, culminating in the engineered and evolved pseudoknot variants tevo2.0, eHAV and eSBRMV1-A. In a screen correcting 847 pathogenic ClinVar variants, the top-performing motifs improved PE efficiency over the widely used tevopreQ1 motif for >90% of edits. They also increased PE efficiencies for correcting disease-associated mutations in primary human cells and in vivo in mouse brain and liver.
    DOI:  https://doi.org/10.1038/s41587-026-03123-2
  20. Mol Genet Metab. 2026 May 17. pii: S1096-7192(26)00443-9. [Epub ahead of print]148(3): 110160
    Progressive short stature in Pearson syndrome and the impact of organ failure.
    Ayami Yoshimi, Holger Cario, Kirsten Timmermann, Udo Kontny, Stephan Lobitz, Helen S Odenthal, Irene Schmid, Barbara Seitz, Tanja Höll, Thomas Lücke, Arndt Borkhardt, Gabriele Strauß, Alexander Hohnecker, Markus Metzler, Daniela Karall, Peter Noellke, Charlotte M Niemeyer, Sarah C Grünert.
       BACKGROUND: Pearson syndrome (PS) is a rare, unique primary mitochondrial disorder characterized by single large-scale mitochondrial DNA deletions, bone marrow failure, lactic acidosis, and progressive multi-organ complications.
    METHODS: We retrospectively evaluated anthropometric data from 25 patients with PS.
    RESULTS: The median height, weight, and body mass index (BMI) standard deviation scores (SDS) at the last measurement were - 1.95 (range: -7.32 to 1.09), -1.70 (range: -12.26 to 0.11), and - 1.52 (range: -5.01 to 2.19), respectively; 50%, 40%, and 37.5% of patients, respectively, had values below -2 SDS. Longitudinal data from 18 patients showed that height and weight SDS declined progressively with age in most patients, whereas BMI SDS fluctuated without a clear age-related trend. Initiation of tube feeding improved weight and BMI SDS in some patients, while height SDS continued to decline without catch-up growth. Patients with organ failure exhibited an earlier decline in height SDS than those without organ failure.
    CONCLUSIONS: Patients with PS are generally short and underweight, and their short stature worsens over time. The presence of organ failure further exacerbates growth impairment.
    Keywords:  Pearson syndrome; Short stature; Single large-scale mitochondrial DNA deletions
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110160
  21. Int J Biol Sci. 2026 ;22(9): 4938-4955
    Mitochondria and polycystic ovary syndrome: The role of ferroptosis, inflammasomes, and endoplasmic reticulum stress.
    Xinyi Zhang, Tong Sun, Xinxin Wang, Yujiu Ma, Liu Cao, Jichun Tan.
      Polycystic ovary syndrome (PCOS) poses a major threat to women of reproductive age and is strongly associated with metabolic and inflammatory abnormalities. Over the past decade, tremendous progress has been made in our understanding of signaling events regulated by mitochondria. Emerging evidence underscores mitochondrial dysfunction as a central pathophysiological hub in PCOS. The intricate crosstalk among mitochondrial dysfunction, ferroptosis, inflammasomes, and endoplasmic reticulum (ER) stress creates a pathological network that underpins ovarian dysfunction, metabolic abnormalities, and chronic inflammation in PCOS, highlighting promising novel targets for diagnosis and therapeutic intervention in this complex disorder.
    Keywords:  endoplasmic reticulum stress; ferroptosis; inflammasome; mitochondria; polycystic ovary syndrome
    DOI:  https://doi.org/10.7150/ijbs.128537
  22. EMBO Rep. 2026 May 18.
    SIRT2 mediates integrated stress response by deacetylating and stabilizing 4E-BP1 to suppress translation.
    Yanlin Zi, Jiaqi Zhao, Miao Wang, Dan Hou, Richard A Cerione, Hening Lin.
      The ability to adapt to nutrient stress, such as amino acid limitation, is crucial for cell survival. The mTORC1 complex and integrated stress response (ISR) are two mechanisms that sense the availability of amino acids and regulate protein synthesis. Here, we reveal a new SIRT2-mediated pathway, downstream of the ISR, that is activated under amino acids limitation to suppress global translation. Under amino acid deprivation, SIRT2 protein level is upregulated translationally by its upstream open reading frame (uORF). SIRT2 in turn suppresses translation, which helps cells to survive amino acid limitation. We identify eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), which binds to eIF4E and inhibits translation, as a substrate of SIRT2. SIRT2 deacetylates 4E-BP1 at lysine 69 and stabilizes 4E-BP1 by protecting it from proteasomal degradation, leading to suppression of global translation. Our study uncovers a role for SIRT2 in regulating translation and identifies a new regulatory mechanism of 4E-BP1 in cells.
    DOI:  https://doi.org/10.1038/s44319-026-00803-7
  23. J Hazard Mater. 2026 May 15. pii: S0304-3894(26)01378-6. [Epub ahead of print]512 142400
    Environmental cadmium drives placental senescence and fetal growth restriction via activating CLPP-dependent mitochondrial stress.
    Rui Pan, Jin Zhang, Lan-Lan Wu, Cheng-Fang Sun, Xin-Xin Zhang, Yu-Xi Wu, Xu-Ai Yin, Ye-Xin Luo, Si-Ting Liu, Zi-Jian Bao, Wei Chang, Ling-Li Zhao, De-Xiang Xu, Ya-Ling Feng, Hua Wang, Hua-Long Zhu.
      The role of placental cellular senescence in environmental cadmium (Cd)-evoked fetal growth restriction (FGR) and its underlying mechanisms require further clarification. Here, we generated a murine FGR model by simulating internal exposure doses of Cd in humans. Human and mouse studies revealed that placental senescence linked environmental Cd exposure to FGR. Furthermore, environmental Cd degraded mitochondrial anti-aging protein SIRT3 to evoke placental cellular senescence and FGR, as demonstrated by SIRT3 overexpression and its activator resveratrol treatment. Interestingly, CLPP was identified as a mitochondrial protease targeting placental SIRT3 degradation under environmental Cd. In vitro CLPP knockdown and in vivo CLPP inhibitor tamarixetin treatment reversed environmental Cd-induced SIRT3 degradation and placental cellular senescence. Additionally, environmental Cd elevated the level of METTL3 protein to promote m6A modification of ClpP mRNA in placentae. In vitro METTL3 knockdown and in vivo its inhibitor S-Adenosylhomocysteine treatment blocked the activation of CLPP-dependent mitochondrial protease stress, attenuating placental cellular senescence and FGR upon environmental Cd. Based on a human case-control study, m6A-driven CLPP-dependent mitochondrial protease stress was positively correlated with placental cellular senescence and all-cause FGR. Taken together, environmental Cd enhances m6A modification to activate CLPP-dependent mitochondrial protease stress, thereby causing placental cellular senescence and FGR.
    Keywords:  CLPP; Environmental cadmium; M6A; Mitochondrial protease stress; Placental cellular senescence
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.142400
  24. Nucleic Acids Res. 2026 May 20. pii: gkag500. [Epub ahead of print]54(10):
    Optimized lentivirus-derived virus-like particles for efficient delivery of Cas9-based genome editors.
    Boya Liu, Denise Klatt, Chad Harris, Meaghan McGuinness, Christian Brendel, David A Williams.
      Implementation of therapeutic genome editing requires a potent, versatile, and transient delivery system to enable safe and effective in vivo applications. Here, we report on an optimized virus-like particle (VLP) platform for protein-based delivery of Cas9 ribonucleoproteins and Cas9-derived base editors and prime editors, termed LV-VLP-MA, that enables flexible editor deployment. By systematically engineering a panel of truncated Gag-Cas9 fusion variants, we identify a minimal MA-Cas9 configuration that maximizes editor packaging while effectively preserving efficient particle production and functional delivery. Systematic refinement of VLP production parameters enhances particle yield, supporting robust editing activity across diverse genomic targets. Importantly, systemic administration of LV-VLP-MA mediates efficient in vivo editing of the Pcsk9 locus with functional target suppression, establishing proof-of-concept for therapeutic application. Together, these results define a programmable, modular VLP-based platform that combines potency, flexibility, and transient delivery to expand the scope of in vivo genome engineering for therapeutic development.
    DOI:  https://doi.org/10.1093/nar/gkag500
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒24 at 7:09.