bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–06–07
eighteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Is an emerging pharmacotherapeutic era for rare mitochondrial diseases here?
  2. Emerging therapeutic strategies for mitochondrial DNA-related diseases.
  3. A perinatal approach for unravelling mitochondrial function in preeclampsia and fetal growth restriction: a role for mitochondrial targeted therapies.
  4. MRPS22 variants alter mitochondrial ribosome assembly in patients with leukodystrophy, movement disorder and intellectual impairment.
  5. COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
  6. Compound Heterozygote Friedreich Ataxia Patients With Covert Proximal FXN Gene Deletions.
  7. Two Siblings with LRPPRC Mutation: Mitochondrial Complex IV Deficiency: Case Report.
  8. Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation.
  9. Intercellular mitochondrial transfer in disease: Therapeutic opportunity or driver of tumor progression?
  10. Asymmetric mitochondrial trafficking balances perinuclear biogenesis to maintain network morphology.
  11. Intestinal mitochondrial complex I inhibition essential for clinical benefits of metformin.
  12. Mitochondrial OXPHOS restricts SARS-CoV-2 replication.
  13. Autophagy activation by urolithin-a derivative UA-36 mitigates Friedreich's ataxia pathologies induced by frataxin deficiency.
  14. Cancer as a window into mitochondrial biology.
  15. TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.
  16. Oxidative Stress and Diminished Mitochondrial Proteostatic Reserve Are Linked to Enhanced mtUPR Initiation in Aged Mouse Muscle.
  17. In Utero Gene Therapy for Sickle Cell Disease: Current Evidence, Ethical Considerations, and Future Directions-A Scoping Review.
  18. POLG-related disorders: Clinical and molecular Spectrum in the Saudi population.
  1. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00152-X. [Epub ahead of print]38(6): 1079-1080
    Is an emerging pharmacotherapeutic era for rare mitochondrial diseases here?
    Jirair K Bedoyan, Jerry Vockley.
      After decades without approved pharmacotherapies, mitochondrial disease care is shifting. Two FDA approvals emerged in 1 year, elamipretide (Forzinity) for Barth syndrome and deoxynucleoside therapy (Kygevvi) for TK2 deficiency, with another under review. Zink et al.1 suggest sildenafil (Viagra) could treat Leigh syndrome, highlighting drug repurposing for severe pediatric mitochondrial disease.
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.014
  2. Cell Rep Med. 2026 Jun 02. pii: S2666-3791(26)00258-2. [Epub ahead of print] 102841
    Emerging therapeutic strategies for mitochondrial DNA-related diseases.
    Rubing Shi, Micol Falabella, Jana Aref, Michael G Hanna, Michal Minczuk, Carlo Viscomi, Robert D S Pitceathly.
      Primary mitochondrial diseases (PMDs) are among the most common inherited metabolic disorders, affecting approximately 1 in 4,300 individuals. They result from pathogenic variants in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that disrupt oxidative phosphorylation and lead to multisystem disease. Although advances in genomic testing have significantly improved diagnostic rates in PMDs, effective disease-modifying therapies remain limited. Therapeutic development increasingly focuses on mtDNA-targeted approaches because mtDNA variants are a major cause of disease and may offer opportunities for targeted intervention. Current strategies include allotopic expression, mitochondria-targeted nucleases, and next-generation base editors, which reduce or correct pathogenic mtDNA variants. Other emerging approaches include pharmacological modulation of heteroplasmy, reproductive techniques such as mitochondrial donation, and therapeutic strategies based on mitochondrial transplantation. This review summarizes advances in gene editing, pharmacological approaches, and reproductive and mitochondrial transplantation strategies for mtDNA-related PMDs, highlighting progress toward more targeted interventions.
    Keywords:  gene therapy; mitochondrial DNA; mitochondrial replacement therapy; primary mitochondrial diseases
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102841
  3. Am J Physiol Heart Circ Physiol. 2026 Jun 01.
    A perinatal approach for unravelling mitochondrial function in preeclampsia and fetal growth restriction: a role for mitochondrial targeted therapies.
    Myrthe J Brink, Fieke Terstappen, A Titia Lely, Kirsten T Nijholt.
      Preeclampsia (PE) is a complex hypertensive disorder resulting from placental insufficiency during pregnancy. PE contributes to maternal and fetal morbidity and mortality and often co-occurs with fetal growth restriction (FGR), these two are both considered placental insufficiency syndromes. Alterations in mitochondrial function levels due to placental insufficiency play an important role in the pathophysiology of PE and FGR. Changes in these processes can lead to maternal and fetal organ damage with subsequent risk to develop cardiovascular disease. This review therefore investigates the effects of placental insufficiency syndromes including PE and FGR on mitochondrial function and its underlying mechanisms, using a perinatal approach including: maternal heart and kidney, placenta and fetal heart and kidney. This review also explores the potential of mitochondrial targeted therapies in mitigating these effects. We provide an overview of the literature at hand and demonstrate the critical role of mitochondrial function in different organ systems. Subsequently we also discuss the need for mitochondrial targeted therapies, in particular focused on oxidative stress, metabolic pathways, mitochondrial quality control and mitochondrial calcium handling. This knowledge provides guidance for future studies and potential therapies to improve PE and FGR and their consequences for maternal and fetal outcomes during pregnancy and cardiovascular health later in life.
    Keywords:  Placental insufficiency; fetal growth restriction (FGR); mitochondrial function; mitochondrial targeted therapies; preeclampsia (PE)
    DOI:  https://doi.org/10.1152/ajpheart.00957.2025
  4. Hum Mol Genet. 2026 Jun 01. pii: ddag042. [Epub ahead of print]35(10):
    MRPS22 variants alter mitochondrial ribosome assembly in patients with leukodystrophy, movement disorder and intellectual impairment.
    Ruth I C Glasgow, Finn Lennartsson, Snjolaug Arnardottir, Dmitrii Igorevich Shiriaev, Sandrina P Correia, Marco Moedas, Lucía Peña-Pérez, Martin Paucar, Karin Naess, Helene Bruhn, Nicole Lesko, Rolf Wibom, Joanna Rorbach, Christoph Freyer, Anna Wedell, Sofia Ygberg, Erik A Eklund, Anna Wredenberg.
      Mitochondrial diseases are clinically and genetically heterogeneous, often complicating diagnosis. Here, we describe four unrelated individuals with suspected mitochondrial disease who shared similar neuroimaging features, including bilateral symmetrical supra- and infratentorial white-matter abnormalities, together with variable movement disorders and intellectual impairment. Whole-genome sequencing identified the same homozygous MRPS22 variant (c.798_799delinsTA) in all four patients. MRPS22 encodes a component of the mitochondrial small ribosomal subunit (mtSSU). Functional studies in patient-derived fibroblasts showed impaired mitoribosome assembly and reduced de novo mitochondrial translation. Despite largely preserved steady-state levels of OXPHOS proteins, respiratory chain analysis identified a mild, isolated complex I deficiency. Proteomic profiling revealed reduced levels of mitochondrial ribosomal proteins and dysregulation of mitochondrial translation pathways. In line with the proteomic findings, RNA sequencing of fibroblasts from three patients revealed a distinct transcriptional signature compared with controls, with mitochondrial translation emerging as the most affected pathway. Mitochondrial-encoded transcripts were decreased, whereas nuclear-encoded mitochondrial genes were generally increased. Structural modelling suggested that the variant disrupts key interactions important for mitoribosome stability. While previously reported MRPS22 variants have been associated with severe, often prenatal-onset disease, the individuals described here exhibited a milder phenotype, thereby expanding the clinical spectrum of MRPS22-related disorders. Together, these findings support the pathogenicity of this variant and highlight the value of integrated genomic and functional analyses in diagnosing mitochondrial disease.
    Keywords:  MRPS22; adult-onset; mS22; mitochondrial ribosome; translation
    DOI:  https://doi.org/10.1093/hmg/ddag042
  5. Nat Commun. 2026 May 30.
    COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    Micol Falabella, Sandra Lopez Calcerrada, Jana Aref, Jiaze Gao, William L Macken, Chiara Pizzamiglio, Renata Kabiljo, Anna Lucia Francavilla, Pauline Gaignard, Antoine Pouzet, Jonathan Levy, Giulia Barcia, Jamie K Leighton, Efstathia Chronopoulou, Germaine Pierre, Riza Köksal Özgül, Ali Dursun, Rebecca Halligan, Helen Mundy, Javeria Raza Alvi, Tipu Sultan, William James Craigen, Lisa Emrick, Jill A Rosenfeld, Gehad Elmakkawy, JiHye Kim, Joseph J Gleeson, Aboulfazl Rad, Gabriela Oprea, Maqbool Hussain, Khalil Ur Rehman, Sadia Riaz, Robert W Taylor, Vincent Procaccio, Maha S Zaki, Erika Fernandez-Vizarra, Ciro Leonardo Pierri, Michael G Hanna, Henry Houlden, Reza Maroofian, Cristina Ugalde, Jan-Willem Taanman, Robert D S Pitceathly.
      Primary mitochondrial diseases (PMDs) affect approximately 1 in 4300 individuals and cause early-onset neuromuscular and multisystem dysfunction with reduced lifespan. They result from pathogenic variants in mitochondrial or nuclear DNA that impair oxidative phosphorylation. Cytochrome c oxidase (COX; complex IV) deficiency is a well-established cause of PMD, leading to a broad spectrum of phenotypes. COXFA4 (cytochrome c oxidase subunit FA4), formerly NDUFA4, is a nuclear-encoded COX subunit, but its role in disease remains poorly defined. We report the largest genetically confirmed cohort of COXFA4-related PMD to date, comprising 13 individuals from 12 families with biallelic pathogenic COXFA4 variants. All present with Leigh-like encephalopathy and complete loss of COXFA4 protein; however, patient-derived fibroblasts retain residual COX activity, with upregulation of COXFA4L2 (cytochrome c oxidase subunit FA4-like 2), a poorly characterised paralog. Here, we show that COXFA4 is a late-stage COX assembly subunit and identify a paralog-mediated compensatory mechanism with translational potential.
    DOI:  https://doi.org/10.1038/s41467-026-73455-9
  6. Ann Clin Transl Neurol. 2026 Jun 02.
    Compound Heterozygote Friedreich Ataxia Patients With Covert Proximal FXN Gene Deletions.
    Michael P Lazaropoulos, Morgan C Devore, Christina Lam, Courtney Park, Sanjay Bidichandani, David R Lynch.
      We present Friedreich ataxia patients with frataxin gene deletions. Data and records were collected at the Children's Hospital of Philadelphia from patients enrolled in the FACOMS natural history study. Patients with proximal deletions initially diagnosed with only one GAA expanded allele had more severe disease than their homozygous expansion counterparts, including increased frequency of cardiomyopathy, diabetes, and optic neuropathy. Their phenotypes were like those of individuals with distal deletions and null pathogenic variants in the frataxin gene. Covert proximal frataxin gene deletions should be suspected when genetic testing fails to demonstrate two distinct expanded alleles in patients with severe phenotypes.
    Keywords:  FXN gene; Friedreich ataxia; gene deletions; genetic testing; repeat expansions
    DOI:  https://doi.org/10.1002/acn3.70408
  7. Mol Syndromol. 2026 Jun;17(3): 288-295
    Two Siblings with LRPPRC Mutation: Mitochondrial Complex IV Deficiency: Case Report.
    Merve Setenay Akyüzlüer Güneş, Duygu Duman, Emine Kübra Şen, Miraç Yıldırım, Elif Özsu, Ömer Erdeve, Seda Kaynak Şahap, Fatma Tuba Eminoğlu, Engin Köse.
       Introduction: Mitochondrial diseases caused by mutations in the LRPPRC gene are rare and lead to multisystemic dysfunction. We report two siblings from consanguineous Iraqi parents, both harboring a rare homozygous deletion in LRPPRC (c.2726_2728del; p.Lys909del), previously reported in one other patient. These cases contribute to the expanding phenotypic and geographic spectrum of LRPPRC-related mitochondrial disease.
    Case Presentation: The younger sibling, a 9-year-old girl, presented with severe growth retardation, global developmental delay, hypotonia, spastic ataxic gait, and lactic acidosis. Magnetic resonance imaging showed symmetrical hyperintensities in the mesencephalon and thalami, cerebellar atrophy, and an inverted lactate peak on spectroscopy. Hypertrophic cardiomyopathy was also detected. The older sibling, aged 13, exhibited milder manifestations, including axial hypotonia, tremor, ataxia, and persistent hyperlactatemia. Both siblings had elevated lactate levels but otherwise normal metabolic panels. Whole exome sequencing revealed a homozygous mutation in the LRPPRC gene (c.2726_2728del; p.Lys909del) in both patients.
    Conclusions: These cases highlight the clinical variability of LRPPRC-related disorders. Our report underscores the importance of considering LRPPRC mutations in the differential diagnosis of early-onset neurodevelopmental delay and multisystemic dysfunction with lactic acidosis, especially in populations with high rates of consanguinity. Early genetic diagnosis via whole exome sequencing is essential for accurate diagnosis, genetic counseling, and family planning.
    Keywords:  Ataxia; French-Canadian Leigh syndrome; LRPPRC; Mitochondrial complex IV deficiency
    DOI:  https://doi.org/10.1159/000548731
  8. Cell Death Dis. 2026 Jun 05.
    Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation.
    Daniel Lagos, Pamela R de Santiago, Nicolás Pérez-Bravo, Benjamín Cartes-Saavedra, Josefa Vial-Brizzi, Diego Troncoso-Chandía, Oliver Podmanicky, Rita Horvath, Verónica Eisner.
      Mitochondria undergo fusion and fission. While DRP1 regulates fission, fusion is controlled by OPA1, MFN1, and MFN2. The balance between these processes and the crosstalk between machineries remains poorly understood. MFN2 mutations cause Charcot-Marie-Tooth disease type 2 A (CMT2A), affecting mitochondrial fusion and morphology. However, their role in fission is unclear. Using skin fibroblasts from CMT2A patients (L248H and M376V MFN2 mutations) and wild-type mouse embryonic fibroblasts expressing these variants, we studied how MFN2 mutations impact mitochondrial dynamics beyond fusion. We analyzed mitochondrial morphology and dynamics by live-cell confocal microscopy and tested fusion/fission protein levels, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and oxidative phosphorylation complex subunits. MFN2 mutations impaired mitochondrial fusion and displayed distinct effects on fission and cellular metabolism. L248H-expressing cells showed hyper-elongated mitochondria, impaired fission, and increased OCR, while M376V cells exhibited fragmentation, enhanced fission, and elevated ECAR. These effects correlated with differential Drp1 phosphorylation. Our findings demonstrate that MFN2 mutants differentially influence fission and metabolism, highlighting the need to consider these effects in therapies aimed at modulating mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41419-026-08838-3
  9. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00155-5. [Epub ahead of print]38(6): 1081-1084
    Intercellular mitochondrial transfer in disease: Therapeutic opportunity or driver of tumor progression?
    Gwang-Bum Im, Juan M Melero-Martin.
      Intercellular mitochondrial transfer has emerged as a key mode of metabolic communication across tissues. Its outcomes are context dependent, spanning from therapeutic benefits to pathological risks.
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.017
  10. J Cell Biol. 2026 Aug 03. pii: e202409118. [Epub ahead of print]225(8):
    Asymmetric mitochondrial trafficking balances perinuclear biogenesis to maintain network morphology.
    Julius Winter, Juan C Landoni, Keaton B Holt, Sheda Ben Nejma, Emine Berna Durmus, Tatjana Kleele, Elena F Koslover, Suliana Manley.
      In functionally polarized cells, mitochondria can form distinct subpopulations, positioned at sites of varying metabolic and energetic demands. Thus far, the potential presence of such subpopulations and implications of their intracellular trafficking in immobile and proliferative cells remain largely undescribed, despite such cells serving as key models. Here, we use substrate micropatterning to create reproducible morphologies of cultured immortalized cells, enabling us to define mitochondrial subpopulations and follow their trafficking by photoactivation. We discovered that mitochondrial material is dispersed asymmetrically throughout the cell via biased anterograde transport from the perinuclear area. Combining quantitative analysis and in silico modeling, we characterize the causes and consequences of unbalanced mitochondrial trafficking. Our findings indicate that this bias is required to distribute new material resulting from perinuclear mitochondrial biosynthesis to sustain mitochondrial mass distribution across the cell and to maintain normal network connectivity.
    DOI:  https://doi.org/10.1083/jcb.202409118
  11. Nat Rev Endocrinol. 2026 Jun 03.
    Intestinal mitochondrial complex I inhibition essential for clinical benefits of metformin.
    Olivia Tysoe.
      
    DOI:  https://doi.org/10.1038/s41574-026-01269-2
  12. Sci Adv. 2026 Jun 05. 12(23): eadz3081
    Mitochondrial OXPHOS restricts SARS-CoV-2 replication.
    Yentli E Soto Albrecht, Ryan M Morrow, Devin Kenney, Arnold Z Olali, Alan Wacquiez, Nader Chehadeh, Zimu Cen, Jeffrey A Haltom, Ian Chen, Sujata S Ranshing, Gabrielle A Widjaja, Alessia Angelin, Jesus A Tintos-Hernandez, Wanqing Xie, Prasanth Potluri, Marie T Lott, Shiping Zhang, Mohsan Saeed, Deborah G Murdock, Susan R Weiss, Florian Douam, Douglas C Wallace.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rewires host metabolism to optimize virus production. Although glycolysis is necessary for virus production, the importance of mitochondrial oxidative phosphorylation (OXPHOS) is unknown. The mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS polypeptides plus the 22 transfer RNAs (tRNAs) and 2 ribosomal RNAs (rRNAs) for mitochondrial protein synthesis. We found an ∼5- to 100-fold greater SARS-CoV-2 virus production in infected human ACE2-expressing A549 lung cells when OXPHOS was inhibited by mtDNA depletion (ρ0 cells), inhibition of mitochondrial translation with chloramphenicol (CAP), or chemical inhibition of OXPHOS complexes. OXPHOS inhibition led to a marked increase in the size and distribution of viral replication centers and accelerated the production and release of infectious particles, occurring ∼2 hours earlier than in parental A549-ACE2 (wild type) cells. Subsequently, we found that increased glycolytic capacity was required for enhanced viral replication whereas differences in innate immune pathway activation were not. Reintroduction of mtDNA from a well-defined maternal lineage into the ρ0 cells reinstated OXPHOS, impaired SARS-CoV-2 replication, and reversed associated viral and glycolytic correlates. Thus, metabolic balance regulates SARS-CoV-2 replication, with OXPHOS exerting an antiviral effect.
    DOI:  https://doi.org/10.1126/sciadv.adz3081
  13. Mol Biomed. 2026 Jun 04. pii: 82. [Epub ahead of print]7(1):
    Autophagy activation by urolithin-a derivative UA-36 mitigates Friedreich's ataxia pathologies induced by frataxin deficiency.
    Qichao Gong, Tiansu Liu, Xiao Han, Ruiming Zhang, Xinlei Liu, Bocheng Xiong, Tahir Ali, Jianxiang Huang, Yongmei Xie, Shupeng Li, Xifei Yang.
      Friedreich's ataxia (FA) is a progressive autosomal recessive neurodegenerative disorder caused by frataxin (FXN) deficiency, resulting in mitochondrial dysfunction, oxidative stress, defective autophagy, and progressive motor impairment. Despite extensive efforts, effective disease-modifying therapies for FA remain lacking. Here, we investigate the therapeutic efficacy and underlying mechanisms of UA-36, a novel water-soluble and bioavailable derivative of urolithin A, in cellular and animal models of FA. In Fxn-knockdown N2a cells, UA-36 significantly restored FXN protein levels, enhanced autophagic flux, improved mitochondrial function, and attenuated oxidative stress-induced damage. In vivo, oral administration of UA-36 for eight weeks in YG8R transgenic mice, a well-established FA model, markedly improved motor coordination, gait performance, and skeletal muscle strength. Histological and ultrastructural analyses revealed substantial protection against cerebellar Purkinje cell loss and iron deposition, cardiac hypertrophy, and the degree of skeletal muscle atrophy and fibrosis. Proteomic analysis of cerebellar tissue demonstrated that UA-36 robustly reprograms the FA-associated molecular landscape by upregulating pathways related to autophagy, mitochondrial biogenesis, oxidative phosphorylation, and redox homeostasis, while suppressing apoptosis and neuroinflammatory signaling. Together, these findings identify UA-36 as a promising lead compound and provide compelling evidence that therapeutic enhancement of autophagy and mitochondrial quality control represents a viable, mechanism-based strategy for the treatment of FA.
    Keywords:  Autophagy; Frataxin; Friedreich’s ataxia; Mitochondrial dysfunction; UA-36
    DOI:  https://doi.org/10.1186/s43556-026-00457-w
  14. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00188-9. [Epub ahead of print]38(6): 1085-1088
    Cancer as a window into mitochondrial biology.
    Thomas MacVicar, Laura C Greaves, Payam A Gammage, Stephen W G Tait, Kelsey H Fisher-Wellman, Gordon Freedman.
      Cancer has revealed that the mitochondrion is not a static organelle but a system of extraordinary plasticity. Here, we introduce fundamental mitochondrial behaviors that have been illuminated by cancer research and propose that further investigation in mitochondrial biology holds promise for oncology and beyond.
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.003
  15. Nat Commun. 2026 Jun 05.
    TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.
    Hannah E Ball, Abby C Woods, Yvette C Wong.
      Inter-organelle contact sites are key hubs for organelle bidirectional crosstalk. However, how mitochondria and RNA granules interact at contact sites and its regulation by mitochondrial oxidative phosphorylation (OXPHOS) remain unclear. Here, using Super-Resolution live microscopy, we identify RNA granule-mitochondria contact site formation in OXPHOS conditions. Reactive oxygen species (ROS) generated by mitochondrial OXPHOS promotes TDP-43 localization to cytoplasmic RNA granules via TDP-43 cysteine oxidation at Cys173/Cys175. Mechanistically, RNA granule-mitochondria contact tethering is mediated by TDP-43 on RNA granules binding to GADD34 on mitochondria, while contact untethering is regulated by TDP-43 oxidation. Functionally, this allows for GADD34 and its binding partner PP1 to regulate TDP-43 RNA granule dynamics, and conversely, for TDP-43 oxidation to regulate the ability of the phosphatase PP1 to form granules. Finally, disease-associated mutant TDP-43 misregulates this pathway, ultimately leading to PP1 granules lacking TDP-43. This dynamic crosstalk between TDP-43 oxidation and PP1 has significant consequences for TDP-43-associated diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
    DOI:  https://doi.org/10.1038/s41467-026-74009-9
  16. Aging Cell. 2026 Jun;25(6): e70573
    Oxidative Stress and Diminished Mitochondrial Proteostatic Reserve Are Linked to Enhanced mtUPR Initiation in Aged Mouse Muscle.
    Grant R Laskin, Baylah R Mazonson, LaDora V Thompson.
      Mitochondrial dysfunction, impaired proteostasis, and reduced stress resistance and resilience are aging hallmarks. At the core of these hallmarks, the mitochondrial unfolded protein response (mtUPR) is a transcriptional pathway that restores mitochondrial proteostasis in response to proteotoxicity. Although the mtUPR is well studied in invertebrates and cell culture models, how the mtUPR is engaged in aged mammalian tissue is poorly defined. Here, we defined the extent to which repeated physical stress initiates mtUPR transcription in aged mouse skeletal muscle and assessed candidate regulatory mechanisms in vivo. Aged muscle exhibited reduced mitoprotective chaperone and protease availability and greater carbonylation of intermyofibrillar mitochondria relative to young muscle, suggesting diminished proteostatic reserve and increased oxidative burden. Short-term physical stress induced a greater initiation of mtUPR genes in aged muscle than young muscle, coinciding with reduced physiological reserve. Physical stress shifted ATF5 localization from the mitochondria to the nucleus in the muscle of both ages, whereas CHOP mRNA and nuclear localization were selectively elevated in aged muscle. Mechanistically, we show mitochondrial reactive oxygen species (mtROS) contribute to mtUPR initiation in aged skeletal muscle. Using in vivo ChIP-qPCR and in vitro knockdown/inhibition experiments, we provide support for CHOP as a redox-sensitive factor contributing in part to the enhanced mtUPR initiation in aged mouse muscle, potentially linked to JNK signaling. Collectively, these data suggest reduced mitochondrial proteostatic reserve and mtROS signaling in aged muscle contribute to an amplified mtUPR transcriptional response following repetitive physical stress, providing the foundation to explore the mtUPR in mammalian aging.
    DOI:  https://doi.org/10.1111/acel.70573
  17. Clin Ther. 2026 Jun 01. pii: S0149-2918(26)00145-1. [Epub ahead of print]
    In Utero Gene Therapy for Sickle Cell Disease: Current Evidence, Ethical Considerations, and Future Directions-A Scoping Review.
    Efe Cudjoe, Margaret Thorsen, Nneka Molokwu, Melissa Russo.
       PURPOSE: Sickle Cell Disease (SCD) is a monogenic, autosomal recessive disorder caused by mutations in the β-globin gene, resulting in the production of abnormal hemoglobin S (HbS). When deoxygenated HbS polymerizes, it causes red blood cells to become sickle-shaped, and prone to hemolysis. These abnormal and sickled cells obstruct small blood vessels, leading to vaso-occlusion and tissue ischemia, contributing to multiple complications. SCD impacts nearly 8 million people worldwide, and is estimated to affect 500,000 newborns annually. Historically, potentially curative therapies have been limited, but advances in fetal diagnosis and gene-editing technologies have highlighted the potential use of in utero gene therapy as a strategy to correct the β-globin mutation before clinical disease onset. This scoping review summarizes the current evidence on in utero and fetal gene-editing strategies for SCD.
    METHODS: A systematic search of PubMed, Embase, and Scopus was conducted from database inception through September 2025 following PRISMA-ScR guidelines. Eligible studies included preclinical and translational investigations, early clinical reports, and expert policy or consensus statements focusing on in utero gene therapy or fetal gene editing for SCD. 25 studies met inclusion criteria and were categorized into 4 domains: ex vivo or in vivo gene editing, in utero gene editing, transplantation and tolerance, and reviews/policy/framework.
    FINDINGS: Preclinical studies demonstrated that targeted in utero gene editing can achieve postnatal correction of disease-relevant alleles in animal models using CRISPR-Cas9 and base-editing technologies. Lipid nanoparticle (LNP) and viral vector delivery platforms enabled efficient editing of fetal hematopoietic stem cells, supporting long-term persistence of edited genes. Transplantation studies showed that fetal immune tolerance can persist as well. Review and consensus statements emphasized ethical, regulatory, and procedural considerations, including maternal autonomy, risk assessment, and long-term monitoring. Collectively, the evidence supports the feasibility of prenatal intervention as an acceptable and potentially curative approach for SCD.
    IMPLICATIONS: In utero gene therapy represents a promising strategy for early correction of the β-globin mutation, with the potential to prevent disease onset and reduce long-term morbidity. However, translation to clinical practice will require additional studies and nuanced ethical oversight. Future research should prioritize the optimal timing of intervention, maternal-fetal immune compatibility, and equitable access to ensure accessible clinical implementation.
    Keywords:  Fetal therapy; Genome editing; In utero gene therapy; Sickle cell disease (SCD)
    DOI:  https://doi.org/10.1016/j.clinthera.2026.04.026
  18. Mol Genet Metab Rep. 2026 Jun;47 101322
    POLG-related disorders: Clinical and molecular Spectrum in the Saudi population.
    Fuad Al Mutairi, Faisal Joueidi, Ziyad A Al Mutairi, Maha Alshalan, Wafaa Eyaid, Aziza M Mushiba, Malak AlGhamdi, Brahim Tabarki, Abdulaziz AlGhamdi, Ruqaiah AlTassan, Hamad Alzaidan, Abubakar Sharif, Hesham Aldhalaan, Muhammad Umair, Majid Alfadhel.
       Background: POLG-related disorders are a group of mitochondrial diseases caused by variants in the POLG gene, which is essential for mitochondrial DNA replication and repair. These disorders encompass a wide spectrum of clinical manifestations, ranging from severe, early-onset conditions to milder, adult-onset syndromes.
    Methods: We conducted a retrospective study of 19 molecularly confirmed cases with POLG-related disorders from 16 unrelated families in six different referral centers. Clinical, radiological, and molecular analysis were performed following standard methods.
    Results: Most of the patients in this study presented with variable neurological symptoms before the age of 12 years (80%); commonly, these symptoms included developmental delay and encephalopathy (63%), seizures (58%), ataxia and dysphagia (42% each). Molecular analysis revealed eight different disease-causing variants in the POLG gene. The most frequently observed variant was c.3286C > T; p.(Arg1096Cys). Notably, the POLG c.1957G > A; p.(Glu653Lys) variant has not been reported in the literature previously, and might impact protein folding and stability.
    Conclusion: Despite the management of these conditions remaining largely supportive, advances in understanding the molecular mechanisms of POLG-related disorders offer promise for future therapeutic strategies targeting mitochondrial function and stability. This study highlights the complexity of POLG-related disorders and underscores the need for continued research into their pathophysiology and treatment.
    Keywords:  Developmental delay; Mitochondrial depletion; Mitochondrial replication; Myopathy; POLG; Seizures
    DOI:  https://doi.org/10.1016/j.ymgmr.2026.101322
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