bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–06–07
72 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Is an emerging pharmacotherapeutic era for rare mitochondrial diseases here?
  2. MRPS22 variants alter mitochondrial ribosome assembly in patients with leukodystrophy, movement disorder and intellectual impairment.
  3. Emerging therapeutic strategies for mitochondrial DNA-related diseases.
  4. Regulation of mitochondrial protein translocases.
  5. Consequences of defective mitochondrial protein import: From targeting signals to pathology.
  6. COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
  7. Targeting the Mitochondrial Phenotype in Cockayne Syndrome Patient Cells: From Bioenergetic Fragility to Pharmacologic Rescue.
  8. Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.
  9. An Atypical Neurosensory-Predominant Presentation Associated with a Homozygous NDUFS3 Variant: A Diagnostic Challenge Involving Retinal and Hearing Phenotypes.
  10. A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.
  11. Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.
  12. Intestinal mitochondrial complex I inhibition essential for clinical benefits of metformin.
  13. Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.
  14. Functional specialization within the mitochondrial network: Are all mitochondria created equal?
  15. Asymmetric mitochondrial trafficking balances perinuclear biogenesis to maintain network morphology.
  16. Mutations Causative of CPEO Differentially Engage Innate Immunity Sensors.
  17. TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.
  18. AMC-F1 regulates mitochondria-autophagy crosstalk independent of nutrient stress.
  19. High level dynein impairs mitochondrial distribution and differentiation of rhabdomyosarcoma cells.
  20. Redox signals and oxidative stress in the control of mitochondrial protein import.
  21. Mitochondria across the globe: Diverse voices, shared energy.
  22. Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.
  23. Fmp30p is a mitochondrial phosphatidylinositol hydrolase that modulates CoQ biosynthesis.
  24. Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation.
  25. Activity-regulated circSamm50 modulates mitochondrial dynamics and spine structural plasticity.
  26. Measuring Calcium Efflux in Isolated Primary Mitochondria.
  27. Mitochondria across the globe: Diverse voices, shared energy.
  28. In Vivo 4D Oxy-Wavelet MRI as a Non-Invasive Biomarker of Brain Mitochondrial Function across the Lifespan.
  29. Two Siblings with LRPPRC Mutation: Mitochondrial Complex IV Deficiency: Case Report.
  30. Considerations and best practices for respirometry.
  31. Ago1 is required for the regulation of mitochondrial translation under heat stress in S. pombe.
  32. PKM2-driven glycolysis mediates rotenone neurotoxicity via MG-Hs in Parkinson's disease.
  33. Gastrointestinal Pseudo-Obstruction Is Not an Uncommon Phenotypic Manifestation of POLG1 Variants.
  34. The m.14484T>C MT-ND6 Mutation Presenting with a Hereditary Spastic-Paraparesis Phenotype.
  35. Intercellular mitochondrial transfer in disease: Therapeutic opportunity or driver of tumor progression?
  36. Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.
  37. Combining Fret and Super-Resolution Microscopy Reveals Kinase Activation and Mitochondrial Activity at the Nanoscale.
  38. Altered mitochondrial functionality in metabolic disorders: insights from Drosophila studies.
  39. From mitochondrial zonation to immune dysregulation: a mechanistic axis in diabetic cardiomyopathy.
  40. Skeletal muscle carnitine-acylcarnitine translocase deletion reveals vulnerability of oxidative muscle to fatty acid oxidation deficiency.
  41. POLG-related disorders: Clinical and molecular Spectrum in the Saudi population.
  42. Brieflow: an integrated computational pipeline for high-throughput analysis of optical pooled screening data.
  43. Iron Deficiency Impairs Mitochondrial Energetics and Early Axonal Growth and Branching in Developing Hippocampal Neurons.
  44. Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity.
  45. From autophagy-lysosomal deficits to neurodegeneration in Niemann-Pick type C1 disease: implications for age-related neurodegenerative disorders.
  46. Cells Engage Endogenous Malonate Synthesis to Drive Mitochondrial Metabolism.
  47. A comprehensive review of mitochondrial fluorescent probes: Design principles, fluorophore engineering, and functional parameter sensing.
  48. Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.
  49. A Slc5a6-Deficient Mouse Model Reveals Metabolically Driven Cardiomyopathy with Therapeutic Potential for Vitamin-Based Intervention.
  50. First Revision of the Guidelines for the Diagnosis and Management of Remethylation Disorders.
  51. Modeling the human retina in a dish: Advances and future directions.
  52. Mitochondrial protein COXFA4L3 (C15ORF48) confers resistance to DNA-damaging anticancer agents by repressing mitochondrial DNA damage responses.
  53. Mitochondrial-Endothelial Crosstalk in Cardiometabolic Disease: Mechanisms and Translational Opportunities in the Multi-omics Era.
  54. Evolving insights into mitochondrial presence in RBC in sickle cell disease: Red blood cell and reticulocyte pathophysiology, therapeutic strategies, and future directions.
  55. Cancer as a window into mitochondrial biology.
  56. Adjunctive transcranial DC stimulation in the management of refractory drug-resistant focal epilepsy in POLG mitochondrial disease: A case series.
  57. "Alternative" or integrated role of mitochondrial glycerol-3-phosphate dehydrogenase.
  58. Oxidative Stress and Diminished Mitochondrial Proteostatic Reserve Are Linked to Enhanced mtUPR Initiation in Aged Mouse Muscle.
  59. KRAS4A promotes oligomerization of hexokinase 1 on mitochondria.
  60. A Small-Molecule Mitochondrial Complex I Modulator Improves Behavioral and Mitochondrial Dysfunction in Schizophrenia.
  61. MitoNEET in cardiac mitochondria: Linking mitochondrial function and cardiac disease.
  62. Selective vulnerability of dopaminergic neurons in Parkinson's disease connects PRKN and differential expression of CHCHD2 and GPNMB.
  63. Exercise based Intervention For Metabolic Inflexibility Linked With Lipid Storage Myopathy Using Innovative CRISPR Etf-QO Mutant Knock-in Models.
  64. Compound Heterozygote Friedreich Ataxia Patients With Covert Proximal FXN Gene Deletions.
  65. Identifying and targeting abnormal mitochondrial localization associated with psychosis.
  66. Confident Identification and Quantification of Mouse Brain Tissues Reveals Sirtuin 5-Dependent Regulation.
  67. Skeletal Muscle Mitochondrial Function and Muscle Oxygenation Measured by Near-Infrared Spectroscopy During Brachial Artery Occlusion.
  68. COQ7-Related Neuropathy: Two New Cases and Review of the Literature.
  69. Gene Editing Technologies for Hereditary Hearing Loss: Prospects and Challenges.
  70. DL-3-n-Butylphthalide Protects Against PrP106 -126-Induced Neurotoxicity Through NRF2 Signaling and OPA1/DRP1-Mediated Mitochondrial Dynamics.
  71. The irony of Parkinson's disease: Converging mechanisms of redox imbalance and ferroptosis.
  72. HAX1 drives assembly and activation of the mitochondrial intermembrane space chaperone CLPB.
  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. 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
  3. 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
  4. Protein Sci. 2026 Jul;35(7): e70662
    Regulation of mitochondrial protein translocases.
    Lea Bertgen, Agnieszka Chacinska.
      Mitochondria are essential for cellular health, and their function is underlain by the plasticity of the mitochondrial proteome. Most mitochondrial proteins are nuclear encoded, synthesized in the cytosol, and require precise import into mitochondrial subcompartments to fulfill their proper functions. Multimeric mitochondrial translocases ensure accurate protein localization and membrane integration. Recent work has begun to reveal how translocase activity and composition are dynamically regulated within mammalian cells. This review discusses regulatory mechanisms, including phosphorylation and protein degradation, that emerge as important players in adjusting the capacity and/or selectivity of the mitochondrial translocase to metabolic demands. Particular emphasis will be placed on the TIM23 complex as an emerging regulator of the inner membrane and matrix proteome composition.
    Keywords:  TIM23 complex; TOM complex; mitochondria; mitochondrial biogenesis; proteases; protein translocases; protein turnover
    DOI:  https://doi.org/10.1002/pro.70662
  5. Biochim Biophys Acta Biomembr. 2026 Jun 03. pii: S0005-2736(26)00049-0. [Epub ahead of print] 184546
    Consequences of defective mitochondrial protein import: From targeting signals to pathology.
    Maya Cielo Cornejo, Sandy Che-Eun S Lee, Shaya Smith, Carla M Koehler.
      Cellular organelles are uniquely specialized membrane-bound structures that enable cells to organize and coordinate biochemical processes. Specifically, mitochondria are essential organelles for cellular metabolism, coordinating energy production, and connecting signaling networks for cellular homeostasis. 99% of mitochondrial proteins are encoded by nuclear genes that require precise and efficient translation and import into mitochondria for biological processes. This process is mediated by coordinated pathways involving the mitochondrial specific translocation complexes, chaperones, and specialized targeting routes. Tight regulation of these import mechanisms allows for proper protein localization, folding, and assembly. Disruptions in the mitochondrial protein import pathway compromise organelle homeostasis and activate proteostatic stress and quality control pathways. Such defects have been observed in a wide range of pathophysiological conditions, including cardiovascular disease, neurodegeneration, and cancer. The import defects destabilizing mitochondrial proteins can impair oxidative phosphorylation and metabolic signaling. In sum, defects to mitochondrial function can highlight a central role of mitochondrial protein import beyond maintaining cellular function and how defects at distinct stages of import contribute to disease, underscoring opportunities for therapeutic intervention targeting mitochondrial proteostasis.
    Keywords:  Mitochondria; Mitochondrial disorders; Mitochondrial protein import; Mitochondrial protein processing; Mitochondrial targeting sequence; Proteostasis; TIM23 complex; TOM complex
    DOI:  https://doi.org/10.1016/j.bbamem.2026.184546
  6. 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
  7. bioRxiv. 2026 May 26. pii: 2026.05.25.727505. [Epub ahead of print]
    Targeting the Mitochondrial Phenotype in Cockayne Syndrome Patient Cells: From Bioenergetic Fragility to Pharmacologic Rescue.
    Melis Kose, Elizabeth M McCormick, Kelsey Keith, Cristina Remes, Suraiya Haroon, Eiko Nakamaru-Ogiso, Marni J Falk.
       Background: Cockayne syndrome (CS), primarily caused by autosomal recessive pathogenic variants in ERCC6 (CSB) or ERCC8 (CSA), is a transcription-coupled nucleotide excision repair disorder. CS frequently presents with features similar to primary mitochondrial disease (PMD), including leukodystrophy, lactic acidemia, and skeletal muscle mitochondrial DNA (mtDNA) depletion. How this mitochondrial phenotype arises at the cellular level, and whether it can be pharmacologically targeted, is not yet clear.
    Methods: We characterized mtDNA content, respiratory chain (RC) protein abundance, mitochondrial biogenesis signaling pathways, and oxidative phosphorylation capacity in primary fibroblasts from two siblings with identical compound heterozygous ERCC6 pathogenic variants (c.1526+1G>T; c.2800C>A, p.Pro934Thr) despite marked intrafamilial phenotypic divergence. A combined metabolic stress exposure (galactose, reduced glutamine, and buthionine sulfoximine, (BSO)) which reduced CS cell survival was used to screen for therapeutic leads among twenty-three candidate mitochondrial disease therapeutic compounds. Lead compounds were mechanistically validated at the level of mitochondrial superoxide, total cellular oxidative stress, glutathione, and autophagic flux.
    Results: Patient fibroblasts exhibited several hallmarks of PMD, including reduced mtDNA content, decreased expression of complex I subunit NDUFB8, elevated expression of TOM20 with paradoxically decreased PGC1α suggestive of impaired mitophagic clearance, and decreased mitochondrial respiratory capacity. Under combined metabolic stress, ATP-levels indicative of survival in CS patient fibroblasts selectively collapsed to ∼20% of controls. Five dual-rescue compounds, defined as agents that reproducibly restored ATP-based cell survival in both patient fibroblast lines under stress, were identified, including N -acetylcysteine (NAC), coenzyme Q10 (CoQ10), rapamycin, taurine, and (-)-epicatechin. Mechanistic profiling resolved three functional classes of therapeutic effects in CS cells: (1) upstream mitochondrial reactive oxygen species reduction (NAC, CoQ10); (2) mTORC1 inhibition bypassing defective stress-induced autophagic induction (rapamycin); and (3) extra-mitochondrial improvement in cellular stress resilience ((-)- epicatechin, taurine).
    Conclusions: ERCC6 -based CSB deficiency produced a stress-sensitive and physiologically complex mitochondrial phenotype in patient fibroblasts that was pharmacologically treatable by targeting three mechanistically distinct pathways. Oxidative and broader stress buffering, autophagy modulation via mTORC1 inhibition, and enhanced cellular resilience highlight novel therapeutic opportunities to be advanced to clinical trials in CSB patients.
    DOI:  https://doi.org/10.64898/2026.05.25.727505
  8. bioRxiv. 2026 May 23. pii: 2026.05.22.727209. [Epub ahead of print]
    Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.
    Pieter R Norden, Riley J Wedan, Abigail E Ellis, Madeleine L Hart, Megan R Gendjar, Ryan D Sheldon, Sara M Nowinski.
      α-Lipoic acid (LA) is widely included in "mitochondrial cocktails" recommended to patients with primary mitochondrial disorders, yet its mechanism of action remains unclear. Here, we define the intracellular availability and functional utilization of LA in mammalian cells. We show that LA exists in two functionally distinct cellular pools: a low-abundance free pool and a protein-bound pool generated through mitochondrial fatty acid synthesis (mtFAS). Disruption of the mtFAS pathway abolishes protein lipoylation and impairs oxidative phosphorylation without altering free LA levels. Conversely, supplementation with exogenous LA markedly increases free intracellular LA without restoring protein lipoylation, mitochondrial respiration, or cell proliferation. Instead, the cellular effects of LA supplementation resemble those of the antioxidant N-acetylcysteine. These findings clarify the mechanism of action of a widely used mitochondrial supplement and identify a fundamental disconnect between cellular LA abundance and mitochondrial utilization, challenging the rationale for using LA supplementation to restore mitochondrial function.
    DOI:  https://doi.org/10.64898/2026.05.22.727209
  9. Mol Syndromol. 2026 Mar 11.
    An Atypical Neurosensory-Predominant Presentation Associated with a Homozygous NDUFS3 Variant: A Diagnostic Challenge Involving Retinal and Hearing Phenotypes.
    Hacer Basan, Emin Emre Kurt, Çiğdem Seher Kasapkara.
       Introduction: Mitochondrial complex I deficiency represents a major cause of pediatric mitochondrial disease and is associated with a broad phenotypic spectrum, classically including Leigh syndrome and severe neurodegenerative presentations. Variants in NDUFS3, encoding a core structural subunit of complex I, are rare and most often linked to severe multisystem involvement. However, emerging reports suggest that NDUFS3 variants may be associated with more heterogeneous and atypical clinical manifestations. Here, we describe a child with a neurosensory-predominant phenotype presenting a diagnostic challenge involving retinal and auditory findings in the context of a homozygous NDUFS3 variant.
    Case Presentation: A girl born to consanguineous parents presented with global developmental delay, bilateral digital contractures, impaired visual responses, and progressive hearing difficulties. Ophthalmologic evaluation revealed Stargardt-like maculopathy, while audiologic assessment confirmed bilateral sensorineural hearing loss. Neurological examination showed mild motor delay without neuroregression. Brain magnetic resonance imaging and spectroscopy were unremarkable, and no cardiomyopathy or metabolic crises were observed. Whole-exome sequencing identified a homozygous NDUFS3 c.721G>A (p.Ala241Thr; rs776795187) variant, classified as a variant of uncertain significance and predicted to be deleterious by multiple in silico tools (SIFT, PolyPhen-2, MutationTaster, and CADD). Heterozygous variants were also detected in ABCA4 and HMCN1. Parental segregation analysis was not available at the time of evaluation. Supportive mitochondrial therapy was initiated, and the patient remained clinically stable during long-term follow-up, with nonprogressive neurosensory findings.
    Conclusion: This case highlights the diagnostic complexity of interpreting atypical neurosensory-predominant phenotypes in mitochondrial disease. While the homozygous NDUFS3 variant may contribute to systemic mitochondrial vulnerability, the coexistence of heterozygous retinal gene variants suggests a possible modifying or oligogenic effect. Rather than defining a distinct monogenic entity, this report underscores the importance of cautious genotype-phenotype correlation and comprehensive genetic evaluation in children presenting with combined retinal and auditory involvement.
    Keywords:  Atypical phenotype; Mitochondrial complex I deficiency; NDUFS3; Retinopathy; Sensorineural hearing loss
    DOI:  https://doi.org/10.1159/000551507
  10. J Cell Biol. 2026 Aug 03. pii: e202511088. [Epub ahead of print]225(8):
    A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.
    Erqing Gao, Liwei Guan, Kehang Zhang, Shuze Qi, Jingxiu Xu, Jie Zhang, Tianyi Zhu, Bing Yang, Chonglin Yang, Eric Miska, Mao Zhang, Suhong Xu.
      Maintenance of mitochondrial integrity is fundamental for cellular survival, yet how cells recognize catastrophic mitochondrial membrane damage remains unknown. Here, we identify MAI-1 as the first genetically encoded reporter of severe mitochondrial membrane damage. MAI-1 is a Caenorhabditis elegans homolog of the ATP synthase inhibitor IF1 that lacks a mitochondrial targeting sequence, resides in the cytosol under basal conditions, but rapidly and irreversibly translocates to severely damaged mitochondria within milliseconds. We validate MAI-1 across diverse injury paradigms and demonstrate that cytosolic IF1 variants from other species exhibit conserved damage-induced recruitment. Mechanistically, MAI-1 recruitment requires the presence of an intact ATP synthase complex. Using MAI-1 as a sensor, we uncover that these severely damaged mitochondria are cleared through the LGG-1-mediated, PINK1/PARKIN-independent lysosomal pathway. Together, our findings establish a powerful tool for visualizing severe mitochondrial membrane damage and reveal a surveillance mechanism dedicated to structural integrity control.
    DOI:  https://doi.org/10.1083/jcb.202511088
  11. J Cancer Immunol (Wilmington). 2026 ;8(1): 17-22
    Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.
    Prakash Jeysankar, Sonal Srikanth, Beibei Wu, Yousang Gwack.
      Effector T cells rely on tightly coordinated metabolic and epigenetic programs to sustain immune function. Emerging evidence highlights a central role for mitochondria in integrating these programs through nutrient utilization and regulation of metabolite flux. The electron transport chain (ETC), localized to the inner mitochondrial membrane, directs cellular metabolism toward oxidative phosphorylation. The efficiency of ETC activity is governed by the highly folded architecture of the inner mitochondrial membrane into cristae. Although mitochondrial metabolism is well recognized as a key determinant of cellular metabolic states, the regulatory roles of cristae-organizing structural proteins, particularly in T cells, remain poorly defined. Our recent study identifies the inner mitochondrial membrane protein TMEM11 as a critical structural determinant of cristae organization and demonstrates how cristae integrity governs effector T cell function by controlling oxidative phosphorylation and metabolite flux. TMEM11 deficiency disrupts cristae architecture in T cells without affecting mitochondrial biogenesis or cell viability. Mechanistically, loss of TMEM11 impairs ETC function, leading to elevated mitochondrial reactive oxygen species (mtROS), which diverts acetyl-CoA away from histone acetylation toward fatty acid synthesis, thereby suppressing cytokine production. Collectively, these findings reveal a structural-metabolic-epigenetic axis that is essential for effector T cell immunity and suggest potential relevance for T cell-mediated cancer therapy.
    Keywords:  Cristae; Effector T cells; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.33696/cancerimmunol.8.120
  12. 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
  13. bioRxiv. 2026 May 22. pii: 2026.05.20.726656. [Epub ahead of print]
    Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.
    Santanu Ghosh, Andrew F Jarvis, Jordi C J Hintzen, Nate R McKnight, Pedro Costa-Pinheiro, Noelle H Noughton, Yumi Kim, Alison Jaccard, Scot C Leary, Paul A Cobine, Caroline R Bartman, Gina M DeNicola, Nathaniel W Snyder, Kathryn E Wellen, George M Burslem, Donita C Brady.
      Copper (Cu) is an essential cofactor for mitochondrial cytochrome c oxidase, yet whether it directly regulates mitochondrial metabolism beyond respiration remains unclear. Here we show that mitochondrial Cu, delivered by SLC25A3, is required to maintain the stability of lipoylated TCA cycle proteins. Loss of Slc25a3 or pharmacological Cu depletion selectively destabilized the lipoylated E2 subunits of mitochondrial dehydrogenases and the lipoylation enzymes LIPT1 and LIPT2, an effect not reproduced by acute electron transport chain inhibition. Mechanistically, we find that Cu directly engages the reduced lipoyl moiety using chemical probes and synthetic peptide approaches. Cu depletion impaired PDH and OGDH activity, rewired TCA cycle metabolism, and imposed a dependence on pyruvate carboxylase for anaplerosis. This metabolic defect depleted aspartate, suppressed mTORC1 signaling, and limited proliferation. Conversely, selective delivery of Cu to the mitochondria restored lipoylation, TCA cycle function, and cell growth. Together, these findings identify mitochondrial Cu as a structural regulator of the lipoylation machinery and reveal a direct link between Cu homeostasis and central carbon metabolism.
    DOI:  https://doi.org/10.64898/2026.05.20.726656
  14. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00184-1. [Epub ahead of print]38(6): 1089-1092
    Functional specialization within the mitochondrial network: Are all mitochondria created equal?
    Jessica B Spinelli.
      Mitochondria are classically viewed as a uniform ATP-producing network; however, a growing body of evidence suggests distinct subpopulations exist within tissues and even single cells. Here, I highlight evidence supporting the presence of functionally distinct mitochondria and propose mechanisms by which these subpopulations are formed and regulated.
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.019
  15. 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
  16. bioRxiv. 2026 May 25. pii: 2026.05.24.727547. [Epub ahead of print]
    Mutations Causative of CPEO Differentially Engage Innate Immunity Sensors.
    Joshua Okletey, Megan Muench, Chenxiao Yu, Alessandra Maresca, Valerio Carelli, Marco Tigano.
      Chronic Progressive External Ophthalmoplegia (CPEO) is a primary mitochondrial disorder (PMD) caused by mutations in nuclear genes encoding mitochondrial DNA (mtDNA) maintenance proteins. CPEO is characterized by mtDNA depletion and deletions, and patients primarily present with ocular and muscular features (isolated CPEO). However, additional encephalomyopathy, neurological complications, and Parkinsonism can drive a more severe disease form, CPEO-plus. The evolution from isolated CPEO to CPEO-plus remains poorly understood. Inflammatory and innate immune processes are emerging as strong disease modifiers and may underlie this heterogeneity. Instability of mitochondrial DNA is a major driver of organellar stress and release of mitochondrial contents into the cytosol. Mutations in several genes involved in mtDNA replication and maintenance have been implicated in triggering the escape of mitochondrial nucleic acids from the mitochondrial matrix. Once exposed to cytosolic innate immune sensors, mtDNA and mitochondrial double-stranded RNA (mt-dsRNA) act as potent immunogens, with more than 10 innate immune sensors capable of recognizing them. Therefore, mtDNA and mt-dsRNA release are likely pathological mechanisms in CPEO, yet the list of CPEO-related genes that can trigger inflammatory processes is far from complete. Here, we use patient-derived fibroblasts from individuals with CPEO carrying mutations in RNASEH1 and Twinkle, and provide - for the first time - evidence that their mutations drive innate immune activation through the release of different mitochondrial nucleic acids. RNASEH1 mutations lead to the accumulation and subsequent release of mt-dsRNA, while mtDNA remains protected. On the other hand, mutations in Twinkle cause the release of mtDNA without triggering mt-dsRNA production, or leakage. Supporting this notion, the POLRMT inhibitor IMT-1, and the STING inhibitor H-151, reduced interferon stimulated genes expression downstream of RNASEH1 and Twinkle mutations, respectively. Further, when we analyzed a unique compound patient line carrying mutations in both genes simultaneously, we detect both species of nucleic acids in its cytosol, indicating that both pathways can be engaged simultaneously in the same cell. Lastly, we show that cytosolic sensing triggers paracrine signaling to activate bystander microglia - the resident macrophages of the retina and brain - with potential implications to the neurological progression of CPEO. Overall, our findings reveal a new role for RNASEH1 and Twinkle in driving aberrant innate immunity and paracrine inflammation in CPEO. Our data support a model in which innate immunity is a universal feature of mutations causing mtDNA instability; yet different mutations engage distinct sensing pathways, and in complex scenarios multiple pathways can be triggered at the same time. Given the clinical heterogeneity observed in patients with PMDs, our findings that different signaling pathways are triggered in patient-specific manners might have direct implications for precision medicine approaches aimed at targeting specific innate immunity.
    DOI:  https://doi.org/10.64898/2026.05.24.727547
  17. 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
  18. Nat Commun. 2026 Jun 05.
    AMC-F1 regulates mitochondria-autophagy crosstalk independent of nutrient stress.
    Yuqin Wang, Raksha K Rao, Trung Vu, Ayano Sekine, Zhengmei Mao, Nami McCarty.
      Mitochondria and autophagy are fundamental yet distinct regulators of cellular homeostasis. Here, we identify AMC-F1 (Autophagy-Mitochondria Coupling Factor 1; formerly TRIM44) as a central integrator of mitochondrial bioenergetics and autophagy. Using Amcf1 knockout and knock-in mouse models, we demonstrate that AMC-F1 bidirectionally regulates these pathways: its loss reduces mitochondrial respiration and autophagic flux, whereas its overexpression promotes mitochondrial elongation and increases autophagy independently of nutrient stress. Transcriptomic analyses reveal AMC-F1-dependent regulation of mitochondrial biogenesis programs that engage autophagy, involving mitochondrial respiratory chain complex genes under basal conditions and mitochondrial organization factors under starvation-induced autophagy. Although dispensable under homeostasis, this coupling becomes essential during stress adaptation. In an acute liver-injury model, Amcf1 knock-in mice were fully protected, exhibiting elevated OPA1, reduced caspase-3 and PARP activation, and preserved Beclin 1. This functional duality reflects AMC-F1's ability to modulate the mitochondrial integrated stress response (mtISR), enabling adaptive ATF4 signaling while preventing maladaptive responses when stress exceeds a threshold. Autophagy upregulation by AMC-F1 is critical for fine-tuning the ISR and preserving cellular resilience. Together, our findings position AMC-F1 as a stress-responsive gatekeeper and a novel coordinator of mitochondrial-autophagy crosstalk, defining a cellular state primed for stress adaptation.
    DOI:  https://doi.org/10.1038/s41467-026-73841-3
  19. iScience. 2026 Jun 19. 29(6): 116057
    High level dynein impairs mitochondrial distribution and differentiation of rhabdomyosarcoma cells.
    Ting-Ling Ke, Linyi Chen.
      Rare disease rhabdomyosarcoma-derived RD cells and RH30 cells are defective in myogenesis. In this study, we demonstrate that mitochondria in these cells are enlarged and display a perinuclear distribution. Given that impaired mitochondrial morphology, trafficking, and activity are implicated in many human diseases, characterizing the link between these phenotypes and their physiological outcomes is essential. We found that RD cells had reduced levels of the myosin motor MYO19 and elevated levels of the dynein motor and MIRO1/2 adaptors. Our findings indicate that impaired local actin-based anterograde transport, together with enhanced microtubule-based retrograde transport, drives this perinuclear mitochondrial clustering. Overexpression of MYO19 in RD cells partially rescued this phenotype, while dynein inhibition altered mitochondrial distribution and restored myogenic differentiation in both RD and RH30 cells. Collectively, these findings reveal an intricate interplay among mitochondrial morphology, distribution, and myoblast fusion that underlies both normal physiology and disease.
    Keywords:  Cell biology; Molecular biology; Specialized functions of cells
    DOI:  https://doi.org/10.1016/j.isci.2026.116057
  20. Protein Sci. 2026 Jul;35(7): e70665
    Redox signals and oxidative stress in the control of mitochondrial protein import.
    Lidwina Hasberg, Viktoria Katharina Lauterbach, Torsten Ochsenreiter, Jan Riemer.
      Mitochondrial protein import is essential for organelle biogenesis and cellular homeostasis. It operates in an environment that is intrinsically shaped by redox chemistry. Mitochondria are major sources of reactive oxygen species (ROS), which arise as by-products of oxidative phosphorylation. Cells therefore maintain sophisticated ROS-handling systems, including compartmentalized antioxidant networks, to balance redox signaling with protection from oxidative stress. Increasing evidence indicates that these redox conditions directly influence mitochondrial protein import at multiple levels. In this review, we provide an overview of ROS production, ROS signaling, and oxidative stress in relation to mitochondrial protein import. We outline the major mitochondrial protein import pathways, and discuss how their activity is modulated by redox-dependent mechanisms. A particular focus is placed on the mitochondrial disulfide relay system of the intermembrane space, which directly couples protein import to redox chemistry through oxidative folding, and how it is influenced by the local redox environment. Collectively, we propose that mitochondrial protein import is partially governed by redox-dependent mechanisms, enabling integration of metabolic state, stress responses, and signaling pathways.
    Keywords:  disulfide relay; mitochondrial protein import; oxidative stress; reactive oxygen species (ROS); redox signaling
    DOI:  https://doi.org/10.1002/pro.70665
  21. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00153-1. [Epub ahead of print]38(6): 1075-1078
    Mitochondria across the globe: Diverse voices, shared energy.
    Ichitaro Abe, Alejandro Failde Fiestras, Maia Hjerting Ekstrand, Nahid A Khan, Kenneth Bowitz Larsen, Jason Maynes, Agata M Rudolf, Francois Singh.
      Like mitochondria themselves, research on the organelle can take many shapes and sizes. This month, to coincide with the Cell Press Symposia: Multifaceted mitochondria, we are highlighting the diversity of the global mitochondria community with contributions from researchers at all career stages published across Cell Metabolism, Molecular Cell, Cell Reports, and Trends in Endocrinology & Metabolism. Together, these voices showcase the central role of mitochondrial research in metabolism, inflammation, cell biology, and much more.
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.015
  22. NPJ Aging. 2026 Jun 03.
    Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.
    Jiahui Yang, Jianfeng Li, Xintong Hou, Yifei Zheng, Zeyu Zhao, Ting Zhou, Tongwei Jing, Jiming Kong, Guohui Zhang, Ying Guo.
      Mitochondria are essential for neuronal energy production, cellular homeostasis, and overall neuronal function. Due to their high metabolic demands and limited regenerative capacity, neurons are particularly vulnerable to mitochondrial dysfunction, which leads to ATP depletion, excessive reactive oxygen species (ROS) production, and calcium imbalance-ultimately causing oxidative stress, metabolic disruption, and neuronal death. Mitophagy is a selective process that removes damaged mitochondria through the autophagy-lysosome pathway. As a key mechanism of mitochondrial quality control, mitophagy preserves energy production, limits oxidative damage, and maintains mitochondrial network integrity. This process is regulated by pathways such as PINK1-Parkin and receptor-mediated mechanisms involving BNIP3 and FUNDC1, all of which help sustain cellular health by preventing mitochondrial dysfunction. Impaired mitophagy is a common feature of several neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease, exacerbating mitochondrial damage and neuronal stress. Emerging therapeutic strategies that target mitophagy-ranging from pharmacological agents and gene therapies to dietary interventions-show promise in restoring mitochondrial quality and protecting neurons from degeneration. Nevertheless, challenges remain in translating these findings into effective clinical treatments. Mitophagy represents a critical mechanism for preserving neuronal integrity and offers a compelling target for innovative therapies against neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41514-026-00424-3
  23. Nat Commun. 2026 May 30.
    Fmp30p is a mitochondrial phosphatidylinositol hydrolase that modulates CoQ biosynthesis.
    Zakery N Baker, Rachel M Guerra, Sean W Rogers, David J Pagliarini.
      Organellar membranes feature bespoke lipid compositions; however, the enzymes that craft these compositions and the functional implications these lipids exert on membrane protein organization and activity are insufficiently understood. Here, we discover that the inner mitochondrial membrane protein Fmp30p, a member of the metallo-β-lactamase superfamily, displays phospholipase type D activity toward phosphatidylinositol (PI)-a notable mitochondrial membrane component with unclear functional roles. FMP30 deletion caused substantial and specific elevation of PI species in purified mitochondria. Augmenting mitochondrial PI levels in this way, or by targeting established PI-modifying enzymes to the organelle, increased coenzyme Q (CoQ) biosynthesis concomitant with elevated expression of CoQ-related enzymes and enhanced CoQ metabolon formation. Collectively, our work establishes Fmp30p as a mitochondrial PI phospholipase related to CoQ biology and reveals the broader importance of inner membrane PI in regulating mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-026-73766-x
  24. 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
  25. Cell Rep. 2026 Jun 01. pii: S2211-1247(26)00456-0. [Epub ahead of print]45(6): 117378
    Activity-regulated circSamm50 modulates mitochondrial dynamics and spine structural plasticity.
    Kaushik Chanda, Ojasee Bapat, Jenna Lynne Wingfield, Yosef Avchalumov, Melissa Kazantzis, Jackson P Carter, Neelam Sharma, Ronald Davis, Jason X-J Yuan, Vidhya Rangaraju, Sathyanarayanan V Puthanveettil.
      Circular RNAs (circRNAs) are highly enriched in the brain, yet their functional contributions to synaptic plasticity remain unclear. Here, we uncover a plasticity-induced circRNA that links mitochondrial regulation to activity-dependent spine remodeling. Chemical long-term potentiation in primary hippocampal neurons identified circSamm50, derived from Samm50, which encodes a mitochondrial outer membrane protein, as robustly upregulated. circSamm50 sequesters miR-186-5p to sustain Samm50 mRNA levels, thereby coupling circRNA signaling to mitochondrial gene regulation. Acute CRISPR-Cas13-mediated depletion of circSamm50 disrupted mitochondrial morphology, transport, and bioenergetics across neuronal compartments. Functionally, circSamm50 loss impaired excitatory synaptic transmission, reduced spine density, and compromised two-photon glutamate uncaging-induced structural plasticity. Together, our findings uncover circSamm50 as a plasticity-modulated circRNA that coordinates mitochondrial function with activity-dependent spine remodeling, revealing a mechanism by which circRNAs couple metabolic control to synapse function and structural plasticity.
    Keywords:  CP: molecular biology; CP: neuroscience; LTP; circular RNA; gene networks; hippocampal neurons; mitochondria; structural plasticity; synaptic transmission
    DOI:  https://doi.org/10.1016/j.celrep.2026.117378
  26. Curr Protoc. 2026 Jun;6(6): e70393
    Measuring Calcium Efflux in Isolated Primary Mitochondria.
    Ta'Aliyah M Jones, Stephen Hurst, Michael J Bround.
      Mitochondrial calcium (mCa2+) homeostasis promotes oxidative metabolism within the physiological range; however, dysregulation can trigger necrotic cell death in diseases such as cardiac ischemia-reperfusion injury, muscular dystrophy, and neurodegenerative disorders, including Alzheimer's disease. It is widely understood that mitochondria exhibit rapid Ca2+ uptake primarily mediated by the mitochondrial calcium uniporter (MCU) complex, and that Ca2+ is exported via a combination of Na+/Ca2+ and H+/Ca2+ exchange processes. However, the proteins which mediate mCa2+ transport have only been partially identified. A particular challenge in determining which proteins mediate mCa2+ efflux and their relative contributions to mCa2+ homeostasis is the lack of a clear, reproducible assay for mCa2+ efflux applicable across genotypes. Here, we provide instructions for an optimized fluorometric method to measure mCa2+ efflux in isolated mitochondria that establishes robust Ca2+ efflux signals, differentiates between total and Na+-independent Ca2+ efflux modalities, and generates highly reproducible data, allowing comparisons across tissues and genotypes. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Total Calcium Efflux Assay in Isolated Mitochondria Alternate Protocol 1: Na+-Independent Calcium Efflux Assay in Isolated Mitochondria Support Protocol 1: Isolation of Cardiac Mitochondria Support Protocol 2: Isolation of Skeletal Muscle Mitochondria Support Protocol 3: Isolation of Liver Mitochondria Support Protocol 4: Isolation of Cell Line Mitochondria Basic Protocol 2: Analysis of Calcium Efflux.
    Keywords:  calcium signaling; fluorimetry; mitochondria; mitochondrial calcium
    DOI:  https://doi.org/10.1002/cpz1.70393
  27. Mol Cell. 2026 Jun 04. pii: S1097-2765(26)00287-X. [Epub ahead of print]86(11): 2038-2040
    Mitochondria across the globe: Diverse voices, shared energy.
    Tim Pflästerer, Andrea Dlasková, Stuart Caldwell, Marijana Croon, Staffan Strömblad, Jae Bum Kim.
      Like mitochondria themselves, research on this organelle can take many shapes and sizes. This month, to coincide with the Cell Press Symposia: Multifaceted Mitochondria, we are highlighting the diversity of the global mitochondria community with contributions from researchers at all career stages published across Cell Metabolism, Molecular Cell, Cell Reports, and Trends in Endocrinology and Metabolism. Together, these voices showcase the central role of mitochondrial research in metabolism, inflammation, cell biology, and much more.
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.033
  28. bioRxiv. 2026 May 23. pii: 2026.05.21.726892. [Epub ahead of print]
    In Vivo 4D Oxy-Wavelet MRI as a Non-Invasive Biomarker of Brain Mitochondrial Function across the Lifespan.
    Devin Raine Everaldo Cortes, Sean Hartwick, Thomas Becker-Szurszewski, Kristina Elsa Schwab, Cody Ruck, Shanim Manzoor, Noah William Coulson, Dalton West, Margaret Caroline Stapleton, Samuel Wyman, Cecilia Wen-Ya Lo, Sivakama Bharathi, Eric S Goetzman, Anthony G Christodoulou, Yijen Lin Wu.
      Mitochondria are essential for cellular energy production and are particularly critical for brain development and function. Neurons rely predominantly on oxidative phosphorylation for energy production, rendering the brain highly vulnerable to mitochondrial dysfunction. Consequently, impaired mitochondrial function contributes to a broad spectrum of neurological and systemic disorders, making mitochondria attractive therapeutic targets. Despite this importance, there is currently no non-invasive, spatially resolved method to assess mitochondrial function in the intact living brain. Here, we establish a non-invasive functional MRI approach-4D Oxy-wavelet MRI-to probe in vivo mitochondrial electron transport chain (ETC) function in a spatially specific manner across the lifespan, from fetal to adult brains. This method employs a low-rank k -t sub-Nyquist acquisition strategy to achieve simultaneous structural and functional imaging with high spatial (78 μm) and temporal (∼14 ms) resolution, enabling motion-robust imaging in multi-fetal mouse pregnancies. Mitochondrial ETC function is interrogated by measuring oxygen homeostasis responses to brief hypoxic challenges, analyzed using computational time-frequency wavelet profiling. We validate this approach in mouse models of mitochondrial respiratory chain disease and late-onset Alzheimer's disease, from in utero fetuses to adults, and demonstrate reproducibility and specificity using pharmacological hyperemia and ETC complex I inhibition. We further show parallel wavelet responses in placenta and fetal brain, enabling multi-organ interrogation of the placenta-brain axis. Finally, we present first-in-human feasibility data, supporting translational potential for non-invasive assessment of mitochondrial function in living brains across the lifespan.
    DOI:  https://doi.org/10.64898/2026.05.21.726892
  29. 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
  30. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00186-5. [Epub ahead of print]38(6): 1093-1096
    Considerations and best practices for respirometry.
    Andréa B Ball, Linsey Stiles, Ajit S Divakaruni.
      Oxygen consumption rate (OCR) measurements are now widely used to assess mitochondrial function and cellular metabolism. Here, we review the strengths and limitations of plate-based respirometry, propose unified reporting standards, and discuss how OCR measurements can be integrated with complementary assays to evaluate cellular energy demands and mitochondrial function.
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.001
  31. J Biol Chem. 2026 Jun 04. pii: S0021-9258(26)02107-1. [Epub ahead of print] 113235
    Ago1 is required for the regulation of mitochondrial translation under heat stress in S. pombe.
    Mengling Yu, Yuanqi Xu, Yijing Lu, Minjie Li, Yucheng Yao, Gang Feng, Ying Huang, Jinjie Shang.
      Mitochondrial protein synthesis is a critical component of OXPHOS complexes, vital for both mammals and Schizosaccharomyces pombe. In our study, we investigated the effect of heat stress on mitochondria, analyzed the mitochondrial proteome and found that during heat stress, the translation of all mtDNA-encoded transcripts was impaired, leading to a reduction in the steady-state levels of mtDNA-encoded proteins, suggesting that heat stress plays a general role in mitochondrial protein synthesis. We also found that heat stress affects the association of mitochondrial translation initiation factors to mitoribosomal small subunits. Interestingly, ago1 deletion compensates for the heat-induced disruption of the interaction between mitochondrial translation initiation factor and mitoribosomes, leading to partial recovery of both translation and steady-state levels of mtDNA-encoded proteins in S. pombe. Under heat stress, Ago1 accumulates in the mitochondrial matrix. C-terminal truncation ablates this localization and abolishes rescue of translational suppression, confirming mitochondrial targeting is essential for regulatory function. Furthermore, our data demonstrate that Ago1's small RNA-loading related N-terminal domain is required for heat-induced translational suppression and that Ago1 physically engages with mitochondrial RNAs, collectively indicating potential RNA interference (RNAi) activity within mitochondria. These findings provide insight into the regulation of mitochondrial protein synthesis in heat stress.
    Keywords:  Heat stress; Mitochondria; Mitochondrial protein synthesis; Mitochondrial translation; Schizosaccharomyces pombe
    DOI:  https://doi.org/10.1016/j.jbc.2026.113235
  32. Sci Rep. 2026 May 30.
    PKM2-driven glycolysis mediates rotenone neurotoxicity via MG-Hs in Parkinson's disease.
    Rong Li, Jia Wen Ma, Hui Chen, Dan Mu, Lang Qu, Dan Wang, Ya Zhao.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder lacking disease-modifying therapies. Rotenone (Rot) is widely used to model PD, but its neurotoxicity is not fully understood beyond mitochondrial complex I inhibition. Here, we identify a glycolytic mechanism that contributes to Rot-induced neuronal damage downstream of complex I inhibition. Our in vitro data demonstrate that Rot enhances glycolytic flux, leading to accumulation of methylglyoxal-derived hydroimidazolones (MG-Hs), which drive irreversible cellular damage. Shikonin effectively attenuates Rot-induced apoptosis by inhibiting PKM2, thereby suppressing glycolysis and reducing MG-Hs formation. In a rat model, shikonin robustly improves motor function and preserves nigrostriatal dopaminergic neurons. Collectively, our findings reveal a previously unrecognized glycolytic-mediated pathway involving PKM2-driven glycolysis and MG-Hs accumulation that contributes to rotenone neurotoxicity alongside mitochondrial dysfunction, and highlight shikonin as a promising neuroprotective agent for Parkinson's disease intervention.
    Keywords:  Glycolytic activation; MG-Hs; PKM2; Parkinson’s disease; Shikonin
    DOI:  https://doi.org/10.1038/s41598-026-54865-7
  33. Eur J Neurol. 2026 Jun;33(6): e70655
    Gastrointestinal Pseudo-Obstruction Is Not an Uncommon Phenotypic Manifestation of POLG1 Variants.
    Josef Finsterer.
      
    Keywords:  POLG1; gastro‐intestinal pseudoobstruction; mitochondrial disorder; myopathy; neuropathy
    DOI:  https://doi.org/10.1111/ene.70655
  34. Mov Disord Clin Pract. 2026 Jun 03.
    The m.14484T>C MT-ND6 Mutation Presenting with a Hereditary Spastic-Paraparesis Phenotype.
    Gabriel Amorelli, Christelle Nilles, Gerald Pfeffer, Matthew Joel, Davide Martino.
      
    Keywords:  LHON plus; ataxia; degenerative; hereditary spastic paraparesis; mitochondrial
    DOI:  https://doi.org/10.1002/mdc3.70703
  35. 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
  36. Ann Med. 2026 Dec;58(1): 2677288
    Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.
    Iman Aolymat, Diala Walid Abu-Hassan, Aya Khleaf Oleimat, Wasan Sameer, Ban Wreikat, Tala Iqilan, Hafez Al-Momani, Heba Ali, Lubna Tahtamouni, Mahmoud Iqsairi, Mohammed Albeik, Omar Debas.
       BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) is a kinase with multi-signalling function that regulates various processes essential for neuronal and systemic physiology. It is involved in autophagy, vesicular trafficking, mitochondrial dynamics, and immune response. Pathogenic mutations of LRRK2 can significantly interfere with these physiological pathways essential for neuronal homeostasis, inducing degeneration of dopaminergic neurons-a characteristic feature of Parkinson's disease (PD).
    OBJECTIVE: This review comprehensively summarizes the normal cellular functions of LRRK2 and the potential impact of its dysregulation on various physiological pathways, predisposing individuals to familial and sporadic PD. The mechanistic connections between LRRK2's kinase hyperactivity, disturbances in vesicular trafficking and redox status, systemic and neuronal inflammation, and metabolic disorders will be thoroughly discussed.
    RESULTS: Dysregulation of vesicular trafficking, mitochondrial redox balance, inflammatory pathways, and metabolism promotes α-synuclein accumulation and contributes to the degeneration of nigrostriatal dopaminergic neurons, a central pathological feature of PD. Understanding the physiological role of LRRK2 across neuronal and peripheral tissues uncovers its connection with multiple pathways to maintain homeostasis. Its dysfunction disseminates local stresses into broader neurodegenerative changes.
    CONCLUSION: LRRK2 is implicated in multiple pathways that control neuronal integrity and neurodegeneration. Therefore, therapeutic targeting of LRRK2 could potentially help in restoring physiological function and management of PD.
    Keywords:  Neurodegeneration; diagnostic innovations; molecular mechanisms; oxidative stress; therapeutic development
    DOI:  https://doi.org/10.1080/07853890.2026.2677288
  37. Adv Sci (Weinh). 2026 Jun 02. e22243
    Combining Fret and Super-Resolution Microscopy Reveals Kinase Activation and Mitochondrial Activity at the Nanoscale.
    Nicolas Y Jolivet, Pierre-Jean Desmaison, Xavier Pinson, Arthur Masson, Olivier Delalande, Giulia Bertolin.
      Protein kinases are key regulators of intracellular signaling in specific subcellular compartments and in micro- or nano-domains. Genetically encoded biosensors based on Förster's resonance energy transfer (FRET) are powerful tools to track kinase dynamics. Yet, they are typically limited by spatial resolution. Aurora kinase A (AURKA), a multifunctional serine/threonine kinase, has recently emerged as a critical regulator of mitochondrial physiology. However, visualising AURKA activation and activity with sub-diffraction precision remains a challenge. Here, we introduce BioSenSRRF, a versatile approach combining conventional FRET biosensors with super-resolution radial fluctuations (SRRF) microscopy. BioSenSRRF requires no modification of existing probes, can be implemented using standard microscopy setups, and is supported by publicly available image analysis tools . With BioSenSRRF, we uncover that mitochondrial AURKA activation and activity are compartmentalized into distinct mitochondrial domains containing the ATP synthase. These subdomains depend on AURKA catalytic activity, and they can be altered using validated AURKA inhibitors. Finally, we demonstrate that the cancer-associated polymorphism F31I enhances AURKA activation and ATP production on ATP synthase-enriched subdomains. Altogether, BioSenSRRF provides a broadly accessible framework to enhance the spatial resolution of genetically encoded biosensors. This strategy opens new avenues for dissecting the subcellular organization of kinases and their contribution to physiology and disease.
    Keywords:  AURKA; FRET biosensors; SRRF super‐resolution microscopy; metabolism; mitochondria
    DOI:  https://doi.org/10.1002/advs.202522243
  38. Front Endocrinol (Lausanne). 2026 ;17 1817121
    Altered mitochondrial functionality in metabolic disorders: insights from Drosophila studies.
    Yunlin Zeng, Yang Yang, Yuao Zhu, Peixin Xu, Chakin Cheong, Yong Juan Zhao, Gyeong Hun Baeg.
      The pathophysiological association between obesity and type 2 diabetes (T2D) increasingly highlights the central role of mitochondrial dysfunction. As critical signaling hubs orchestrating metabolism, mitochondria are pivotal in maintaining metabolic homeostasis. Imbalances in mitochondrial quality control mechanisms lead to an accumulation of damaged mitochondria with abnormal dynamics and functions, exacerbating the progression of obesity, insulin resistance, and T2D. Although therapeutic interventions for obesity and T2D have shown promise, they remain insufficient for achieving sustained remission from obesity and T2D on a global scale. Furthermore, existing rodent models often struggle to fully recapitulate human metabolic disorders due to species-specific metabolic differences and technical limitations. Drosophila melanogaster has emerged as a powerful model organism for deciphering mitochondrial-metabolism interactions due to numerous advantages, including easy genetic manipulation, low gene redundancy, rapid phenotype verification, and the unique opportunity to image live tissues in vivo. Drosophila models effectively recapitulate high-sugar- and high-fat-diet-induced mitochondrial fragmentation, adipose tissue expansion, and insulin resistance-like phenotypes. Furthermore, studies leveraging the genetic tractability of Drosophila have provided critical insights into how mitochondrial impairment contributes to systemic metabolic dysfunction. Here, we introduce recent advances in mitochondrial research regarding metabolic disorders and demonstrate how Drosophila serves as a useful in vivo model to dissect mitochondrial function. Future research should integrate multi-omics approaches and precision medicine strategies targeting mitochondrial metabolic remodeling to break the vicious cycle of obesity and T2D, while developing non-invasive intervention methods to advance translational medicine.
    Keywords:  Drosophila melanogaster; mitochondrial dysfunction; mitochondrial quality control; mitophagy; obesity and type 2 diabetes
    DOI:  https://doi.org/10.3389/fendo.2026.1817121
  39. Front Cardiovasc Med. 2026 ;13 1775592
    From mitochondrial zonation to immune dysregulation: a mechanistic axis in diabetic cardiomyopathy.
    Jiahui Chen, Linghua Fu, Jing Zhang, Rui Ding, Hanbin Zhang, Gaosi Xu, Jinzhu Hu, Pingping Yang.
      Diabetic cardiomyopathy (DbCM) is characterized by early diastolic dysfunction, myocardial fibrosis, and progressive energetic failure, in which mitochondria dysfunction have a central role. Although mitochondrial dysfunction is well established in DbCM, emerging spatially resolved data indicate that cardiomyocytes contain functionally distinct mitochondrial subpopulations with differential susceptibility to metabolic stress. In this Review, we synthesize mechanistic and translational evidence and propose a unifying, testable hypothesis. Selective remodeling of membrane lipids and cristae destabilization may render specific mitochondrial subsets "early-damaged." These mitochondria produce sustained mitochondrial reactive oxygen species (mtROS), release oxidized mtDNA or mitochondrial-derived vesicles (MDVs), and subsequently activate innate immune pathways. We particularly emphasize distinct mitochondrial subpopulations, including subsarcolemmal (SSM), interfibrillar (IFM), and perinuclear mitochondria (PNM). Finally, we posit a proof-of-concept translational roadmap involving biomarker-guided, spatially informed preclinical endpoints and targeted interventions. Conceptualizing DbCM as a disease of mitochondrial heterogeneity and maladaptive mtROS-mtDNA-innate immune coupling reorients therapeutic strategy from global antioxidant suppression toward precision, organelle- and location-specific modulation.
    Keywords:  diabetic cardiomyopathy; innate immunity; mitochondrial heterogeneity; mitochondrial reactive oxygen species; mitophagy; myocardial fibrosis
    DOI:  https://doi.org/10.3389/fcvm.2026.1775592
  40. Am J Physiol Endocrinol Metab. 2026 Jun 01.
    Skeletal muscle carnitine-acylcarnitine translocase deletion reveals vulnerability of oxidative muscle to fatty acid oxidation deficiency.
    Filip Jevtovic, Nicholas C Williamson, Andrea S Pereyra, Molly Alexander, Espen E Spangenburg, Jessica M Ellis.
      Fatty acid oxidation (FAO) is a critical bioenergetic source for skeletal muscle with FAO impairments being linked to metabolic and contractile dysfunction. FAO is regulated by the carnitine shuttle in which FAO eligible fatty acids, in the form of acylcarnitines, are transported into the mitochondrial matrix by carnitine‑acylcarnitine translocase (CACT), yet the role of CACT in muscle in vivo has remained unexplored. To determine the requirement of CACT in muscle FAO and its influence on muscle mitochondrial bioenergetics, lipid profile, and muscle contractility, a novel conditional skeletal muscle-specific CACT knockout mouse (CactSk-/-) was generated. The requirement of CACT for long-chain FAO was confirmed by the complete abrogation of FAO flux in CactSk-/- muscle mitochondria. CACT was also required for the oxidative flux of medium-chain octanoyl-carnitine and acetyl-carnitine. CACT loss disrupted the lipid profile of skeletal muscle with long-chain acylcarnitine accumulation and shifted saturation profile of phospholipids away from saturated and highly unsaturated and towards di- and tri-saturated phospholipids. Elevated mitochondrial content was demonstrated by increased phospholipid content and mitochondrial staining in CactSk-/- muscles, occurring to a greater extent in oxidative muscles. Loss of CACT reduced muscle specific force production by ~70% in oxidative soleus muscle despite increased fiber size, and compensatory mitochondrial accumulation that preserved muscle metabolic capacity. These findings demonstrate the crucial role of CACT in muscle FAO and that oxidative muscles, in particular, undergo extensive lipid compositional, metabolic, and structural remodeling that coincides with impaired contractile function.
    Keywords:  Skeletal muscle; carnitine-acylcarnitine translocase; fatty acid metabolism; muscle contraction
    DOI:  https://doi.org/10.1152/ajpendo.00117.2026
  41. 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
  42. Nat Commun. 2026 May 30.
    Brieflow: an integrated computational pipeline for high-throughput analysis of optical pooled screening data.
    Matteo Di Bernardo, Roshan S Kern, Ana Karla Cepeda Diaz, Alexa Mallar, Samuel J Choi, Andrew Nutter-Upham, Sebastian Lourido, Paul C Blainey, Iain Cheeseman.
      Optical pooled screening (OPS) has emerged as a powerful technique for functional genomics, enabling researchers to link genetic perturbations with complex cellular morphological phenotypes at scale. However, OPS data analysis presents challenges due to massive datasets, complex multi-modal integration requirements, and the absence of standardized frameworks. Here, we present Brieflow, a computational pipeline for end-to-end analysis of fixed-cell optical pooled screening data. We demonstrate Brieflow's capabilities through reanalysis of a CRISPR-Cas9 screen encompassing 5072 fitness-conferring genes, processing more than 70 million cells with multiple phenotypic markers. To accelerate biological interpretation, we additionally present MozzareLLM, a framework leveraging large language models to identify biological processes within phenotypic clusters and prioritize gene candidates for experimental validation. Our combined analysis recovers coherent biological modules missed by existing analytical approaches, including five core mitochondrial sub-programs absent from the original study. The modular design and open-source implementation of Brieflow facilitates the integration of new analytical components while ensuring computational reproducibility and improved performance for the use of high-content phenotypic screening in biological discovery.
    DOI:  https://doi.org/10.1038/s41467-026-73643-7
  43. J Nutr. 2026 Jun 03. pii: S0022-3166(26)00279-8. [Epub ahead of print] 101630
    Iron Deficiency Impairs Mitochondrial Energetics and Early Axonal Growth and Branching in Developing Hippocampal Neurons.
    List Daniel C Mendez, Karishma Devgun, Luke H Carlson, Daniel J Mickelson, Timothy R Monko, Livia Reeves, Lorene M Lanier, Michael K Georgieff, Thomas W Bastian.
       BACKGROUND: Energy deficits underlie many neurodevelopmental, neuropsychiatric and neurodegenerative diseases implicating mitochondria as a potential therapeutic target. Iron is necessary for neuronal energy output through its direct role in mitochondrial oxidative phosphorylation. Iron deficiency (ID) reduces mitochondrial energetic capacity in developing hippocampal neurons and causes simplified dendritic arbors and impaired learning and memory.
    OBJECTIVE: To determine the effect of ID on axonogenesis, which has not been previously explored.
    METHODS: We used an embryonic mouse mixed-sex primary hippocampal neuron culture model of developmental ID, using iron chelation with low micromolar deferoxamine (DFO) from 3 days in vitro (DIV) to 7DIV compared to untreated control cultures. Mitochondrial respiration and dynamics, cytoskeletal and metabolic gene expression, and axonal and synaptic morphology were quantified and compared using t-test, ANOVA, and multivariate statistical analyses.
    RESULTS: 7DIV DFO-treated neuron cultures (n=4-17) demonstrated moderate ID with significantly decreased mRNA levels for genes involved in axon cytoskeletal development (Gda, Pfn2, and Nuak1; ∼20-40% lower) and metabolic homeostasis (Ndufs1, Ddit4, and Slc2a3; ∼20-25% lower). DFO significantly reduced total ATP production rate and measures of mitochondrial oxidative phosphorylation by ∼25-50% compared to control cultures (n=11-14). DFO significantly reduced the length of the primary axon and axonal branches by ∼20%, without affecting branch number (n=100 neurons). Axonal mitochondrial motility was not altered by ID (n=11-12 neurons), suggesting that impaired mitochondrial energetics, and not trafficking, is the predominate mitochondrial contribution to axon morphological deficits. Ultimately, at 18DIV, DFO significantly reduced the density of post-synaptic density puncta, a measure of neuronal capacity for synapse formation, by 30% (n=26-32 neurons).
    CONCLUSIONS: These findings provide the first link between iron-dependent neuronal energy production and early axon structural development and highlight the importance of maintaining sufficient iron during the embryonic period of rapid axonal growth to prevent the persistent negative consequences of ID on neuronal structure.
    Keywords:  axon; axonogenesis; energy metabolism; gene expression; iron deficiency; mitochondria; mitochondrial motility; mitochondrial trafficking; neuron development
    DOI:  https://doi.org/10.1016/j.tjnut.2026.101630
  44. J Clin Invest. 2026 Jun 01. pii: e199716. [Epub ahead of print]136(11):
    Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity.
    Yuheng Liao, Hanze Wang, Hengxin Liu, Xi Chen, Renqiang Sun, Xie Li, Zhen Yang, Chenying Liu, Wei Wu, Ziqian He, Yuzheng Zhao, Ying Mao, Dan Ye, Hui Yang.
      Metabolic signals critically shape innate immune responses. Through pharmacological screening of metabolic pathways, we identified aspartate metabolism as a key regulator of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. Genetically or aminooxyacetic acid-mediated (AOA-mediated) pharmacologically reducing aspartate levels markedly potentiated the cGAS-STING pathway, leading to stronger upregulation of type I interferons and interferon-stimulated genes. Mechanistically, disruption of de novo pyrimidine synthesis, a major downstream pathway of aspartate, induced mtDNA replication stress and increased mtDNA double-strand breaks, promoting mtDNA release into the cytosol. Cytosolic mtDNA synergized with cGAS-STING agonists to upregulate Z-DNA binding protein 1 (ZBP1), which recruits RIPK1/3 to sustain IRF3 phosphorylation, forming a positive feedback loop that amplifies innate immune signaling. In immunocompetent mouse models, AOA enhanced the antitumor efficacy of STING agonists, chemotherapy, or radiotherapy, whereas aspartate supplementation abrogated these effects. Consistently, aspartate levels negatively correlated with antitumor immunity in colorectal cancer patient samples. Together, our study identifies aspartate-pyrimidine metabolism as a critical metabolic checkpoint that licenses STING signaling by enabling mtDNA stress to cooperate with agonist stimulation, driving type I interferon-dependent ZBP1 induction and feed-forward amplification of STING signaling, thus offering a promising strategy to enhance antitumor immunity.
    Keywords:  Cellular immune response; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI199716
  45. Front Neurosci. 2026 ;20 1857866
    From autophagy-lysosomal deficits to neurodegeneration in Niemann-Pick type C1 disease: implications for age-related neurodegenerative disorders.
    Yuki Kawachi, Gamze Kocak, Viktor I Korolchuk, Tetsushi Kataura, Sovan Sarkar.
      Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by loss-of-function mutations in the NPC1 gene. NPC1 deficit primarily disrupts lipid homeostasis and subsequently drives cellular degeneration through mechanisms involving impaired autophagy and mitophagy, mitochondrial dysfunction, and, recently demonstrated NAD depletion that links autophagy impairment to neuronal death. Emerging evidence also highlights the activation of innate immune signaling leading to neuroinflammation. In this review, we synthesize current mechanistic insights and describe how these molecular deficits are interconnected to drive neuronal death in NPC1 disease. We also discuss how these pathological processes parallel those observed in major age-related neurodegenerative pathologies such as Alzheimer's and Parkinson's disease. Finally, we highlight emerging therapeutic strategies that can potentially ameliorate these cellular deficits, offering avenues for mitigating neurodegeneration in NPC1 disease and other related neurodegenerative disorders.
    Keywords:  NAD; NPC1; autophagy; cell death; lysosome; mitochondria; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3389/fnins.2026.1857866
  46. bioRxiv. 2026 May 29. pii: 2026.05.22.727248. [Epub ahead of print]
    Cells Engage Endogenous Malonate Synthesis to Drive Mitochondrial Metabolism.
    Riley J Wedan, Pieter R Norden, Morgan T Canfield, Abigail E Ellis, Sanskriti Saxena, Jacob Z Longenecker, Michelle Dykstra, Ryan D Sheldon, Sara M Nowinski.
      Malonate is often described as an endogenous inhibitor of complex II of the electron transport chain. However, the cellular source of malonate is unclear, and current knowledge concerning its metabolism is limited to the action of a single enzyme, Acyl-CoA Synthetase Family Member 3 (ACSF3), which converts malonate to malonyl-CoA in the mitochondrial matrix. One potential route of malonate metabolism downstream of ACSF3 is its consumption by the mitochondrial fatty acid synthesis (mtFAS) pathway. However, studies examining the link between ACSF3 and mtFAS have yielded conflicting results. We developed a novel mass spectrometry approach to perform stable isotope tracing into products of mtFAS, and found that while malonate is in fact a carbon source for mtFAS, ACSF3 is not required for malonate incorporation into mtFAS products. Using this method to trace other nutrients into mtFAS, we also found evidence of acetyl-CoA carboxylase 1 (ACC1)-dependent malonate synthesis from glucose. We further show that ACC1 is required for optimal mtFAS activity, with downstream effects on oxidative phosphorylation. Together these findings establish the malonate as a regulated endogenous intermediate that supports mtFAS activity and mitochondrial oxidative function.
    DOI:  https://doi.org/10.64898/2026.05.22.727248
  47. Mater Today Bio. 2026 Jun;38 103255
    A comprehensive review of mitochondrial fluorescent probes: Design principles, fluorophore engineering, and functional parameter sensing.
    Fei Peng, Bo Wang, Ran Chai, Mingming Xue, Aibing Wu, Yan Lv, Huijuan Tian, Jianyuan Yu, Guigui Pang, Bin Hao, Baoxiang Gao.
      Mitochondria are essential organelles that play pivotal roles in cellular energy metabolism, signaling, and homeostasis, and their dysfunction is closely associated with various human diseases. In recent years, the rapid development of mitochondria-targeted fluorescent probes has greatly expanded our ability to visualize mitochondrial structure and monitor diverse physicochemical and biochemical parameters in situ. While existing reviews have primarily categorized these probes by specific physiological readouts, a unified perspective that integrates probe design strategies, fluorophore engineering, and target physiological parameters is stilling lacking. To address this gap, we provide a systematic overview of mitochondrial fluorescent probes, focusing on molecular design principles, fluorophore selection, targeting strategies, and the sensing of key mitochondrial physiological indices. In addition, we critically discuss current limitations and emerging challenges, and outline future directions in this field. This review aims to offer theoretical insights and practical guidance for the rational design of mitochondrial fluorescent probes, promoting their broader applications in life science and biomedical research.
    Keywords:  Design strategies; Fluorescent probes; Mitochondria; Physiological parameters
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103255
  48. Nat Commun. 2026 May 30.
    Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.
    Geethu Emily Thomas, Veronique Voisin, Kazem Nouri, Rose Hurren, Karen Kai-Lin Fang, Ali Chegini, Marcela Gronda, Yongran Yan, Neil MacLean, Yulia Jitkova, Dakai Ling, Mary Ma, Xiao Ming Wang, Andrea Arruda, Vito Spadavecchio, Mark D Minden, Li Zhang, Jong Bok Lee, Aaron D Schimmer.
      Eukaryotic cells have separate genomes in the nucleus and mitochondria. Mitochondrial DNA is transcribed bi-directionally to generate mitochondrial RNA (mtRNA) and dsRNA as a by-product of this transcription. We demonstrate that mtRNA transcription and degradation are increased in AML (Acute Myeloid Leukemia) cells and stem cells resulting in higher rates of mtRNA turnover. We discover that the mitochondrial degradosome, SUV3 and PNPase, is upregulated in AML cells and stem cells and functionally important for degradation of mtRNA and mitochondrial dsRNA (double stranded RNA) in AML. Depleting SUV3 or PNPase impairs mtRNA degradation and promotes the accumulation of dsRNA. dsRNA that accumulates after depleting SUV3 or PNPase, stimulates IFN-I signaling that induces AML differentiation, decreases stemness and increases sensitivity to immune-mediating cytotoxicity. Thus, this work highlights mitochondrial RNA regulation in AML and identifies a mechanism by which mtRNA turnover influences AML differentiation, stem cell function, and immune sensitization.
    DOI:  https://doi.org/10.1038/s41467-026-73558-3
  49. JCI Insight. 2026 Jun 02. pii: e200381. [Epub ahead of print]
    A Slc5a6-Deficient Mouse Model Reveals Metabolically Driven Cardiomyopathy with Therapeutic Potential for Vitamin-Based Intervention.
    Millie O Fullerton, Lauren C Phillips, Rachael E Redgrave, Luke Spray, Vincent Haufroid, George Merces, Scott T Kerridge, Gavin D Richardson, Nathalie Mercier, Dominique Roland, Rebecca Crossley, Andrew Dh Morgan, Joseph P Dewulf, John Burn, Simon D Bamforth, Helen M Phillips.
      The sodium-dependent multivitamin transporter, encoded by SLC5A6, mediates cellular uptake of biotin and pantothenic acid, essential cofactors for energy metabolism. We identified two families with SLC5A6 mutations presenting with early-onset dilated cardiomyopathy (DCM). To investigate the link between vitamin deficiency and cardiomyopathy, we generated a cardiac-specific SLC5A6 knockout (Slc5a6cKO) mouse model and evaluated the impact of vitamin supplementation. Slc5a6cKO mice developed progressive cardiac dysfunction, culminating in cardiac pathology and premature death at 26 weeks; earlier stages exhibited cardiomyocyte hypertrophy, fibrosis, impaired Coenzyme A synthesis, and metabolic imbalance, indicating progression toward cardiomyopathy. Cardiac magnetic resonance imaging and ECG confirmed progressive functional decline. Proteomic analysis revealed early mitochondrial metabolic disruption and extracellular matrix protein upregulation at 8 weeks, preceding overt cardiac dysfunction. Strikingly, vitamin supplementation from preconception onwards prevented the cardiac phenotype, preserving cardiac structure, function, morphology and survival. This paralleled the clinical outcome in one patient who received early vitamin treatment, compared to another who required a heart transplant without vitamin treatment. This study establishes a direct link between SLC5A6-mediated vitamin transport, mitochondrial function, and cardiac health. It highlights how vitamin deficiency contributes to cardiomyopathy pathogenesis and supports early vitamin supplementation as a potential therapeutic strategy for metabolic cardiomyopathies.
    Keywords:  Cardiology; Cardiovascular disease; Metabolism; Mouse models
    DOI:  https://doi.org/10.1172/jci.insight.200381
  50. J Inherit Metab Dis. 2026 Jul;49(4): e70177
    First Revision of the Guidelines for the Diagnosis and Management of Remethylation Disorders.
    Giorgia Olivieri, Andrea Bordugo, Birute Burnyte, Alessandro Costetti, Maria-Luz Couce, Luisa Diogo, Francois Feillet, D Sean Froese, Benedetta Greco, Jean-Louis Gueant, Luciana Hannibal, Friederike Hörster, Viktor Kožich, Giancarlo La Marca, Irini Manoli, Fanny Mochel, Lorenzo Orazi, Belén Pérez, Manuel Schiff, Bernd C Schwahn, Ida Schwartz, Karolina M Stepien, Jolanta Sykut-Cegielska, Trine Tangeraas, Rolf H Zetterström, Carlo Dionisi-Vici, Martina Huemer.
      This guideline summarizes diagnostic and therapeutic approaches based on a systematic literature review and evidence evaluation using the GRADE methodology. Given the limited high-quality data, expert consensus was additionally obtained through a modified Delphi process. Remethylation disorders are rare inherited conditions that disrupt the methionine-homocysteine cycle and consecutively impair essential methylation dependent metabolic pathways. Remethylation disorders are caused by defects in the cobalamin or folate metabolism. The disorders typically result in elevated homocysteine and often low methionine; combined cobalamin-related defects also affect mitochondrial methylmalonic acid clearance. The cblC-MMACHC defect is the most common cobalamin-related remethylation disorder. Early-onset patients usually present with severe neurological and eye symptoms. Late-onset cases show variable symptoms (e.g., psychiatric, renal, thromboembolic events). Plasma total homocysteine, methionine, methylmalonic acid, serum vitamin B12 (and folates) should be assessed in suspected cases. Early detection through newborn screening is associated with improved clinical outcomes. Betaine as first-line therapy for methylenetetrahydrofolate reductase deficiency and parenteral hydroxocobalamin for cobalamin-related defects have reduced mortality and morbidity. Total homocysteine, methionine (and methylmalonic acid) should be kept as close to normal values as achievable. Emerging evidence suggests that early use of high-dose hydroxocobalamin (> 0.35 mg/kg/day) may improve neurocognitive impairment and may ameliorate eye disease in severe cobalamin-related defects. A major limitation in current practice is the lack of availability of high concentration hydroxocobalamin formulations for parenteral administration.
    Keywords:  cblC; cblD; cblE; cblF; cblG; cblJ; homocysteinemia; methylmalonic acidemia; severe MTHFR deficiency
    DOI:  https://doi.org/10.1002/jimd.70177
  51. Handb Clin Neurol. 2026 ;pii: B978-0-443-22212-2.00019-7. [Epub ahead of print]218 447-468
    Modeling the human retina in a dish: Advances and future directions.
    Xue DU, Holly Y Chen.
      Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, can be directed to self-organize into three-dimensional retinal organoids that recapitulate the development, cellular architecture, and key functional features of the human retina. These organoids provide a powerful in vitro platform that models key stages of human retinogenesis and offers unique opportunities to study mechanisms of retinal development and disease in a human context that is not easily accessible in vivo. Recent advances in genome editing, single-cell and multiomics technologies, and bioengineering strategies have further expanded the potential of retinal organoids by enabling precise genetic manipulation, high-resolution profiling, and improved culture systems that more closely approximate native tissue environments. In this chapter, we first highlight how foundational insights from animal models of retinal development have guided the differentiation of human pluripotent stem cells into retinal organoids. We then discuss how these organoids have been applied to advance our understanding of human retinal biology and to model the pathogenesis of inherited and acquired retinal disorders. Finally, we examine emerging technologies, including organ-on-a-chip systems, biomaterial scaffolds, and 3D printing, that promise to refine the fidelity and translational potential of retinal organoids, setting the stage for their future role in regenerative medicine and therapeutic discovery.
    Keywords:  3D bioprinting; Bioengineering platform; Disease modeling; Genome editing; Human pluripotent stem cells; Multiomics; Organoids-on-a-chip; Regenerative medicine; Retinal organoids; Retinogenesis
    DOI:  https://doi.org/10.1016/B978-0-443-22212-2.00019-7
  52. Sci Rep. 2026 Jun 04.
    Mitochondrial protein COXFA4L3 (C15ORF48) confers resistance to DNA-damaging anticancer agents by repressing mitochondrial DNA damage responses.
    Yuki Takakura, Seika Kawamura, Yui Hashiguchi, Manami Yamanaka, Yasuyuki Kurihara, Taishin Akiyama, Hiroyuki Takano, Noritaka Yamaguchi.
      DNA-damaging anticancer agents selectively kill highly proliferative cancer cells by inducing DNA damage, such as DNA double- or single-strand breaks, and by inhibiting DNA replication and transcription. These agents have been used for cancer chemotherapy for a long time; however, acquired resistance remains a serious problem that limits their effectiveness. Although mitochondria have their own DNA, which is distinct from nuclear DNA, the involvement of mitochondria and mitochondrial DNA (mtDNA) in resistance to DNA-damaging anticancer agents remains largely unknown. In this study, we found that the mitochondrial small protein cytochrome c oxidase-associated subunit FA4-like 3 (COXFA4L3), formerly known as C15ORF48, confers resistance to DNA-damaging anticancer agents. Mechanistically, DNA-damaging anticancer agents damage mtDNA and induce the cytosolic release of TFAM-unbound mtDNA via the mitochondrial permeability transition pore (mPTP), thereby promoting cell death via activation of the innate immune signalling cGAS-STING pathway. COXFA4L3 inhibits the cytosolic release of mtDNA by repressing mtDNA damage and mPTP opening. These results suggest that mitochondria affect sensitivity to DNA-damaging anticancer agents through COXFA4L3-mediated repression of mtDNA damage responses.
    DOI:  https://doi.org/10.1038/s41598-026-54548-3
  53. Rev Cardiovasc Med. 2026 May;27(5): 47549
    Mitochondrial-Endothelial Crosstalk in Cardiometabolic Disease: Mechanisms and Translational Opportunities in the Multi-omics Era.
    Di Liu, Jiaxi Sun, Yuwei He, Yuhang Sun, Mengjie Yin, Jie Zhang, Xin Zhao.
      Mitochondria and endothelial cells engage in bidirectional crosstalk to maintain vascular tone, barrier integrity, and inflammatory quiescence. In cardiometabolic diseases (CMDs), metabolic overload and chronic inflammatory cues disrupt endothelial mitochondrial bioenergetics, dynamics, and quality-control mechanisms. As protective systems weaken, redox imbalance and impaired nitric oxide signaling-further exacerbated by barrier dysfunction-trigger endothelial activation and loss of homeostasis. Clinical translation has lagged largely because endothelial responses vary across vascular beds and microenvironments, and most clinical trials fail to align patient selection or endpoints with mitochondrial mechanisms. This review addresses a major translational gap: how mitochondrial stress programs map onto context-specific endothelial phenotypes in human CMDs, and how this mapping can inform the selection of actionable therapeutic strategies. Indeed, this review integrates single-cell and spatial multi-omics data to link mitochondrial stress and metabolic remodeling to specific anatomical niches, transforming the broad notion of "endothelial dysfunction" into defined biological programs for biomarker selection and target discovery. Moreover, this review categorizes translational opportunities by the strength of human evidence. Near-term priorities include repurposed cardiometabolic drugs (e.g., sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1(GLP-1) receptor agonists) and circulating biomarkers for patient stratification or pharmacodynamic monitoring (e.g., growth differentiation factor 15 (GDF15), cell-free mitochondrial DNA (cf-mtDNA), endothelium-derived extracellular vesicles). In contrast, gene and cell therapies, as well as advanced delivery and regenerative platforms, remain at the preclinical stage and require stronger mechanistic validation, improved safety profiles, and scalable delivery systems before clinical evaluation. Thus, a key unmet need is for multicenter, mechanism-informed trials that integrate endothelial functional endpoints (e.g., flow-mediated dilation (FMD)/peripheral arterial tonometry (PAT) with mitochondrial-associated molecular readouts under harmonized protocols and standardized reference criteria to enhance reproducibility and cross-study comparability. Collectively, these insights establish mitochondrial-endothelial biology as an evidence-based entry point for precision vascular medicine in CMDs.
    Keywords:  cardiometabolic diseases; endothelial dysfunction; mitochondria; multi-omics; translational therapy
    DOI:  https://doi.org/10.31083/RCM47549
  54. Semin Hematol. 2026 May 09. pii: S0037-1963(26)00041-7. [Epub ahead of print]
    Evolving insights into mitochondrial presence in RBC in sickle cell disease: Red blood cell and reticulocyte pathophysiology, therapeutic strategies, and future directions.
    Yaw Ansong-Ansongton, Daisy Zapet Bamac, Angela Rivers.
      Recent advances in understanding sickle cell disease (SCD) pathophysiology have revealed the critical role of abnormal mitochondrial retention in mature erythrocytes. This comprehensive review examines how disrupted mitochondrial clearance contributes to disease progression through multiple mechanisms, including oxidative stress, metabolic dysfunction, and immune activation. We will review evidence from both human studies and animal models demonstrating that retained mitochondria remain functionally active and contribute to cellular damage. Furthermore, we will highlight emerging findings that active mitochondria in reticulocytes are also detrimental in SCD, exacerbating oxidative stress, and promoting premature cellular damage. This review examines therapeutic approaches targeting mitochondrial dysfunction, including pyruvate kinase activation and mitophagy enhancement strategies. Understanding these mechanisms provides new opportunities for therapeutic intervention in SCD and related disorders.
    Keywords:  Erythrocyte mitochondrial retention; Mitochondria; Mitophagy; Reactive oxygen species; Sickle cell disease
    DOI:  https://doi.org/10.1053/j.seminhematol.2026.05.003
  55. 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
  56. Seizure. 2026 May 09. pii: S1059-1311(26)00139-1. [Epub ahead of print]
    Adjunctive transcranial DC stimulation in the management of refractory drug-resistant focal epilepsy in POLG mitochondrial disease: A case series.
    Katrin A Bangel, Yi Ng, Albert Lim, Naomi J P Thomas, Stephan R Jaiser, H Ming Lai, Gráinne S Gorman, Rhys R Thomas, Douglass M Turnbull, Venkateswaran Ramesh, Andrew M Schaefer, Robert McFarland, Mark R Baker.
       BACKGROUND: Pathogenic POLG variants produce an age-related progressive multi-system mitochondrial disorder, with neurologic manifestations that include focal onset seizures, stroke-like episodes, cerebellar ataxia, sensory neuronopathy, complex ophthalmoplegia and myopathy. Focal onset status epilepticus or epilepsia partialis continua (EPC) frequently occurs in patients with paediatric and early adulthood onset disease.
    METHODS: Between 2014 and 2020, we treated 15 episodes of drug-refractory focal epileptic status (epilepsia partialis continua) in 5 patients with POLG-related mitochondrial disease with cathodal transcranial direct current stimulation (tDCS). Here we describe the management of each episode of EPC, including the application of tDCS.
    RESULTS: Transcranial DCS, delivered for 20 min at 2 mA, once daily (minimum 3 days; maximum 14 days), as an adjunct to optimal standard medical care, was associated with a significant reduction (93% of episodes after 4.3 sessions) or a cessation of seizures (63% of episodes after 8.4 sessions). No major side effects of tDCS were noted.
    CONCLUSION: Our findings support further exploration of tDCS as a potential adjunctive therapy for complex neurological challenges in mitochondrial disorders.
    Keywords:  Cathodal transcranial direct current stimulation (tDCS); Drug-refractory epilepsy; Epilepsia partialis continua (EPC); Focal onset status epilepticus; Mitochondrial disorder; POLG
    DOI:  https://doi.org/10.1016/j.seizure.2026.05.009
  57. Proc Natl Acad Sci U S A. 2026 Jun 09. 123(23): e2611388123
    "Alternative" or integrated role of mitochondrial glycerol-3-phosphate dehydrogenase.
    Hélène Lemieux, Clément Joël Lucien Chevret, Erich Gnaiger.
      
    DOI:  https://doi.org/10.1073/pnas.2611388123
  58. 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
  59. Cell Rep. 2026 Jun 04. pii: S2211-1247(26)00470-5. [Epub ahead of print]45(6): 117392
    KRAS4A promotes oligomerization of hexokinase 1 on mitochondria.
    Cristina Nuevo-Tapioles, Zhihua Qin, Andrew Bazley, Cristina Branco, George Hamilton, Xiang-Peng Kong, Eli Rothenberg, Mark R Philips.
      Among the ways by which oncogenic KRAS upregulates glycolysis in cancer is direct interaction of KRAS4A with hexokinase 1 (HK1), but the mechanism is unknown. HK1 associates with the outer mitochondrial membrane (OMM) where its allosteric regulation depends on homodimerization. Using affinity capture, FRET, and blue native gels, we show that KRAS4A enhances oligomerization of HK1 on the OMM. Modeling the HK1/KRAS4A complex with AlphaFold3 predicts that the membrane association sequences of both HK1 and KRAS4A are oriented toward the OMM. Super-resolution microscopy showed colocalization of HK1 and KRAS4A on the OMM with HK1 enriched at discrete locations. Single-molecule tracking reveals HK1 diffusing freely along the OMM and dwelling at discrete regions where two molecules can be seen to colocalize transiently. KRAS4A expression decreased the diffusion coefficient of HK1 on the organelle. Thus, KRAS4A alters the dynamics of HK1 on the OMM and promotes oligomerization.
    Keywords:  CP: cell biology; KRAS4A; alternative splicing; hexokinase; mitochondria; oncogene; single-molecule tracking; super-resolution microscopy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117392
  60. bioRxiv. 2026 May 21. pii: 2026.05.19.726440. [Epub ahead of print]
    A Small-Molecule Mitochondrial Complex I Modulator Improves Behavioral and Mitochondrial Dysfunction in Schizophrenia.
    Maltesh Kambali, Sergey Trushin, Muxiao Wang, Rajasekar Nagarajan, Jinrui Lyu, Eugenia Trushina, Uwe Rudolph.
      Weak inhibition of mitochondrial complex I (mtCI) has been shown to have neuroprotective effects in cellular and animal models of Alzheimer's and Huntington's diseases, at least in part by enhancing mitochondrial biogenesis and function. Mitochondrial dysfunction has also been demonstrated in schizophrenia patients and mouse models of schizophrenia. We tested whether weak inhibition of mtCI would ameliorate mitochondrial and behavioral phenotypes in a mouse model of schizophrenia. In mice with four copies of the Gldc gene, 8 weeks of treatment with the weak mtCI inhibitor, the small-molecule tricyclic pyrone compound CP2, reversed spontaneous alternation deficits in the Y maze, startle habituation deficits, and social novelty deficits in the three-chamber social interaction test. Consistent with the mechanism of action, Western blots revealed that CP2 reverses the reduced expression of PGC-1α, a master regulator of mitochondrial biogenesis, and of the VDAC1, a primary gatekeeper for the exchange of metabolites, ions, and ATP between mitochondria and the cytosol. These findings suggest that the improvement of mitochondrial function may represent a novel strategy to reverse pathophysiological and behavioral deficits in schizophrenia.
    DOI:  https://doi.org/10.64898/2026.05.19.726440
  61. Metabolism. 2026 Jun 04. pii: S0026-0495(26)00179-4. [Epub ahead of print] 156669
    MitoNEET in cardiac mitochondria: Linking mitochondrial function and cardiac disease.
    Lechen Su, Yinru Huang, Hangfei Zhou, Zhangping Liao.
      MitoNEET is a protein localized to the mitochondrial outer membrane and is recognized as an important regulator of mitochondrial activity, participating in redox signaling, iron-sulfur cluster trafficking, and trace element homeostasis. The heart is an organ with exceptionally high energy demands and relies critically on tightly coordinated mitochondrial processes to sustain continuous contractile activity. Accumulating evidence indicates that mitoNEET influences multiple aspects of cardiac mitochondrial biology, including mitochondrial dynamics, energy production, redox balance, ion homeostasis, and metabolic regulation of fatty acid and glucose utilization, all of which are essential for normal cardiac contraction and relaxation. Alterations in mitoNEET expression or activity are closely associated with mitochondrial dysfunction in cardiovascular diseases, including ischemic heart disease and heart failure, in which it regulates mitochondrial oxidative stress, ion homeostasis, and metabolic flexibility. In this review, we outline the molecular mechanisms through which mitoNEET affects cardiac mitochondrial function, providing a perspective on its therapeutic potential for the prevention and treatment of cardiovascular disease through modulation of mitochondrial function.
    Keywords:  Cardiovascular disease; Iron-sulfur clusters; MitoNEET; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.metabol.2026.156669
  62. Cell Death Dis. 2026 Jun 05. pii: 544. [Epub ahead of print]17(1):
    Selective vulnerability of dopaminergic neurons in Parkinson's disease connects PRKN and differential expression of CHCHD2 and GPNMB.
    Franca Vulinovic, Arian Hach, Zied Landoulsi, Kerstin Tanzer, Daniel Alvarez-Fischer, Philip Seibler, Christine Klein, Patrick May, Aleksandar Rakovic.
      The mechanism(s) causing selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) remain largely elusive. To improve our understanding of mitochondrial involvement and related pathways suggested to play a role in this selective vulnerability, we used tyrosine hydroxylase (TH)-mCherry reporter-induced pluripotent stem cells generated by CRISPR/Cas9. We sorted neurons into pure TH-positive and TH-negative neurons upon differentiation into a dopaminergic neuron-containing cell culture. We characterized mitochondrial function in both dopaminergic and non-dopaminergic neurons from PD patients and controls and identified differentially expressed genes between patients and controls in both cell populations. Dopaminergic neurons had a lower mitochondrial membrane potential than non-dopaminergic neurons. Furthermore, ATP levels were lower in PRKN mutation carriers than controls, and mitochondrial mass was reduced in PRKN mutation carriers only in the TH-positive but not in TH-negative neurons. Importantly, in PRKN mutation carriers, we demonstrated elevated levels of dopamine, which can serve as a significant source of toxic, oxidized dopamine. Using unbiased RNA sequencing, we detected increased levels of CHCHD2 and decreased expression of GPNMB in TH-positive neurons from Parkin mutation carriers compared to healthy controls. This suggests a possible interaction of these three PD genes in response to a dopaminergic neuron-specific increase in oxidative stress, which further leads to the selective vulnerability of dopaminergic neurons.
    DOI:  https://doi.org/10.1038/s41419-026-08926-4
  63. bioRxiv. 2026 May 20. pii: 2026.05.18.726022. [Epub ahead of print]
    Exercise based Intervention For Metabolic Inflexibility Linked With Lipid Storage Myopathy Using Innovative CRISPR Etf-QO Mutant Knock-in Models.
    Sachin Budhathoki, Yiming Guo, Mary Doamekpor, Girish Melkani.
      Multiple acyl-CoA dehydrogenase deficiency (MADD) is a mitochondrial lipid storage myopathy characterized by impaired fatty acid β-oxidation, mitochondrial dysfunction, and progressive neuromuscular and cardiac disease. MADD is most commonly caused by pathogenic variants in electron transfer flavoprotein dehydrogenase (ETFDH), which encodes electron transfer flavoprotein-ubiquinone oxidoreductase (Etf-QO), a critical redox enzyme that transfers electrons from acyl-CoA dehydrogenases to the mitochondrial electron transport chain. Defective Etf-QO activity disrupts electron flow, promotes reactive oxygen species (ROS) production, and impairs cellular energy metabolism, linking abnormal lipid oxidation to oxidative stress-mediated tissue damage. To investigate the role of redox imbalance in MADD pathogenesis, we generated CRISPR/Cas9 knock-in Drosophila melanogaster models carrying patient-relevant Etf-QO missense mutations (L127R, S296C, and L399F; corresponding to human L138R, S307C, and L409F) within conserved FAD- and ubiquinone-binding domains. Mutant flies developed progressive locomotor impairment, reduced muscle performance, and marked lipid droplet accumulation in skeletal muscle, cardiac tissue, and fat bodies, indicating systemic defects in mitochondrial lipid utilization. Cardiac analyses demonstrated reduced fractional shortening, prolonged heart period, and increased arrhythmia index, consistent with metabolic cardiomyopathy associated with mitochondrial oxidative stress. In vivo respirometry revealed significantly decreased oxygen consumption, reflecting impaired oxidative phosphorylation. At the molecular level, mutant flies exhibited elevated ROS levels and ATP depletion, accompanied by increased expression of AMPK, PGC-1α, and Tfam, suggesting activation of energy stress signaling and compensatory mitochondrial biogenesis. Importantly, endurance exercise significantly improved locomotor and cardiac function while reducing lipid accumulation and oxidative stress. Together, these findings establish a redox-centered in vivo model of MADD and identify oxidative stress as a major driver of disease pathology and a potential therapeutic target.
    DOI:  https://doi.org/10.64898/2026.05.18.726022
  64. 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
  65. bioRxiv. 2026 May 29. pii: 2025.10.08.676630. [Epub ahead of print]
    Identifying and targeting abnormal mitochondrial localization associated with psychosis.
    Marzieh Haghighi, Donna McPhie, Mohammad Rohban, Erin Weisbart, David J Logan, Kyle W Karhohs, Suzann M Babb, Jessica D Ewald, Johan Fredin Haslum, Caitlin Ravichandran, Beth A Cimini, Shantanu Singh, Bruce M Cohen, Anne E Carpenter.
      Therapeutics working by novel mechanisms are needed for patients with psychiatric conditions. Cell-based assays to identify candidates that reverse observed abnormalities could accelerate the process. Here, we imaged peripheral cells (skin fibroblasts) of 168 patients, stained for DNA, actin, and mitochondria. We found mitochondria tend to be farther from the cell border for patients who experience psychosis (including subsets of individuals with bipolar disorder, schizophrenia, and schizoaffective disorder). We observed a reverse trend, albeit not statistically significant, for patients diagnosed with major depression. Because the phenotype could be identified by a single metric, we could query existing databases of cells stained for their mitochondria and treated with various chemical or genetic perturbations. We identified compounds and genes both negatively and positively affecting the psychosis-associated phenotype, including some known to impact psychiatric conditions. Developing therapeutics with novel mechanisms is a complex multi-step challenge. This cell-based assay holds promise for virtual and physical screening to identify candidates for treating psychiatric conditions.
    DOI:  https://doi.org/10.1101/2025.10.08.676630
  66. bioRxiv. 2026 May 28. pii: 2026.05.26.726073. [Epub ahead of print]
    Confident Identification and Quantification of Mouse Brain Tissues Reveals Sirtuin 5-Dependent Regulation.
    Landgrave-Gomez Jorge, Bons Joanna, Vega-Hormazabal Genesis, Riley Rebeccah, Schilling Birgit, Verdin Eric.
      Methylmalonylation is a non-enzymatic lysine post-translational modification derived from methylmalonyl-CoA, a reactive intermediate that accumulates during mitochondrial dysfunction and branched-chain amino acid catabolism. Although reported in models of methylmalonic acidemia, its broader distribution and functional relevance remain largely unexplored. Progress has been hindered by a key analytical challenge: methylmalonyl-and succinyl-lysine are isobaric (+100.0160 Da) and generate overlapping mass spectrometric fragmentation spectra, preventing confident identification in conventional proteomic workflows. Here, we establish a straightforward proteomic workflow that overcomes this barrier and enables confident identification and quantification of lysine methylmalonylation by combining antibody-based enrichment with data-independent acquisition mass spectrometry (DIA-MS). Anti-malonyl antibodies were used to enrich methylmalonylated peptides through cross-reactivity. Using synthetic peptide standards containing malonyl-, succinyl-, or methylmalonyl-lysine, we defined distinguishing analytical features including chromatographic retention time, ion mobility, and fragmentation patterns. Applying this approach to mouse brain tissues from Sirtuin-5 (SIRT5) knockout and wild-type mice, we identified 44 methylmalonylated peptides across 41 proteins, enriched in neuronal and myelin-associated proteins (NEFM, NEFL, MBP) and mitochondrial enzymes such as ADT1. Several sites were increased in SIRT5-deficient brains, consistent with regulation by this mitochondrial deacylase. Functional assays demonstrated that methylmalonylation of myelin basic protein (MBP) impairs lipid binding, linking this modification to myelin stability. Together, this workflow enables confident methylmalonylation identification and defines it as a widespread and regulated modification in the brain, providing a framework to study metabolically driven protein acylation in neurobiology and disease.
    Significance: Lysine methylmalonylation has remained largely unexplored due to its isobaric overlap with succinylation, which prevents confident identification using conventional proteomic workflows. Here, we establish an integrated strategy combining antibody-based enrichment, data-independent acquisition mass spectrometry, and orthogonal analytical features to resolve these modifications with high confidence. Applying this approach to mouse brain tissue reveals a SIRT5-regulated methylmalonylome enriched in mitochondrial and myelin-associated proteins, including myelin basic protein (MBP). Functional assays demonstrate that methylmalonylation impairs MBP lipid binding, linking this modification to myelin stability. Beyond this specific application, our workflow provides a generalizable framework to resolve isobaric post-translational modifications and expands the study of metabolically driven protein acylation in neurobiology and disease.
    DOI:  https://doi.org/10.64898/2026.05.26.726073
  67. Am J Physiol Heart Circ Physiol. 2026 Jun 02.
    Skeletal Muscle Mitochondrial Function and Muscle Oxygenation Measured by Near-Infrared Spectroscopy During Brachial Artery Occlusion.
    Tommi Jeskanen, Venla P Ylinen, Rasmus I P Valtonen, Ville Stenbäck, Kari A Mäkelä, Risto Kerkelä, Noora Pöllänen, Eija Pirinen, Karl-Heinz Herzig, Mikko P Tulppo.
      Background: Near-Infrared Spectroscopy (NIRS) is a widely used technique allowing the non-invasive measurement of skeletal muscle microvascular and mitochondrial function. However, the association between NIRS technology measurements and mitochondrial function analyzed from muscle biopsy by high-resolution respirometry is not clear. Methods: Healthy adults (n=20; 10 females; age 25.3±4.6 years) participated in the study. A NIRS device was used to measure muscle oxygenation during a 5-min brachial occlusion. Muscle oxygen consumption (mVO2) and the change in tissue saturation index (TSI) from baseline to the end of occlusion (ΔTSI Base-Min) were calculated. Muscle biopsy from the vastus lateralis was collected on a separate day to assess complex I mediated mitochondrial respiration. Results: mVO2 (from 0.021 to 0.070 mlO2/min/100g), ΔTSI Base-Min (from 25.2 to 50.2 %) and complex I mediated mitochondrial respiration (from 9.7 to 57.3 pmol·mg⁻¹·s⁻¹) showed wide interindividual variation. Complex I mediated mitochondrial respiration was correlated negatively with mVO2 (r=-0.64, p=0.002) and ΔTSI Base-Min (r=-0.80, p=0.0003). In multivariate linear regression analysis (Enter-method), complex I mediated respiration was the only variable significantly associated with mVO2 and ΔTSI Base-Min when sex, body fat percentage and peak oxygen uptake (VO2peak) during cycle ergometer test were included in the analysis as confounding factors (Standardized Coefficients ß=-0.431, p=0.017 and ß=-0.691, p=0.0006, respectively). Conclusions: Our findings suggest that during 5-min occlusion, higher mitochondrial respiratory capacity is associated with lower mVO2 utilization. Lower oxygen utilization during occlusion may indicate a more efficient use of oxygen by mitochondria and better preserved energy metabolism.
    Keywords:  Near-infrared spectroscopy; mitochondrial function; mitochondrial respiration ; skeletal muscle oxygenation
    DOI:  https://doi.org/10.1152/ajpheart.00383.2026
  68. J Peripher Nerv Syst. 2026 Jun;31(2): e70132
    COQ7-Related Neuropathy: Two New Cases and Review of the Literature.
    Julian Theuriet, Shams Ribault, Fanny Fontaine, Naïg Gueguen, Arnaud Jacquier, Isabelle Quadrio, Zoe Dmitrievsky, Marina Konyukh, Dominique Bonneau, Stéphane Allouche, Julien Cassereau, Christophe Verny, Virginie Guillet-Pichon, Antoine Pegat.
       BACKGROUND AND AIMS: Biallelic variants in COQ7 have been associated with inherited neuropathy. COQ7 encodes a mitochondrial protein directly involved in coenzyme Q10 (CoQ10) biosynthesis.
    METHODS: Two unreported and unrelated cases of COQ7-related neuropathy are presented, along with a review of all previously published cases to highlight the key clinical features. The frequency of COQ7 variants was assessed in our cohort of distal hereditary motor neuropathy (dHMN) patients with upper motor neuron (UMN) signs.
    RESULTS: The two patients were compound heterozygous for the COQ7 variants c.197T>A, p.(Ile66Asn) and c.478del, p.(Asp160Thrfs*11); the latter has not been reported. Symptoms began in childhood, and both were diagnosed with dHMN based on distal motor weakness predominantly affecting the lower limbs and a pure motor length-dependent axonal neuropathy on electrodiagnostic study. They had pes cavus and brisk reflexes. In the 28 patients identified in the literature, including the two reported herein, the median age at symptom onset was 10 years (IQR [5-11]). The predominant neuropathy subtype was dHMN (89%). Foot deformities were observed in 19/23 patients (83%). Signs of UMN involvement were present in 20/27 patients (74%). In fibroblasts, CoQ10 levels were low, and 6-demethoxy-CoQ10 (DMQ10) levels were elevated in all tested patients (8/8, 100%). No other case was identified in 71 patients with dHMN and UMN signs.
    INTERPRETATION: COQ7-related neuropathy is rare but should be considered in young patients presenting with distal hereditary motor neuropathy, especially when UMN signs are present. Elevated DMQ10 levels and low CoQ10 levels in fibroblasts represent valuable diagnostic biomarkers.
    Keywords:  CMT; COQ7; Charcot–Marie‐tooth; dHMN; distal hereditary motor neuropathy
    DOI:  https://doi.org/10.1111/jns.70132
  69. Neurosci Bull. 2026 Jun 04.
    Gene Editing Technologies for Hereditary Hearing Loss: Prospects and Challenges.
    Man Wang, Bei Wang, Minhao Yang, Fangzhi Tan, Jieyu Qi, Renjie Chai.
      Hereditary deafness represents a significant global health challenge with limited therapeutic interventions. Most cases are caused by monogenic mutations inherited in an autosomal dominant or recessive manner, making them suitable targets for gene editing therapies. Recent advances in gene editing technologies have expanded the toolkit for precise genomic modification, including engineered nucleases for gene disruption, base editors (BEs) for point mutations, prime editors (PEs) for substitutions, insertions, and deletions, and mitochondrial editors for modifying mitochondrial DNA (mtDNA). These tools have demonstrated significant efficacy in mouse models of hereditary deafness, highlighting their clinical potential. However, given the high degree of genetic heterogeneity, gene editing technologies in this field remain in an early exploratory stage. In this review, we provide a comprehensive overview of the latest breakthroughs in gene-editing platforms and critically evaluate the potential benefits and existing hurdles to their clinical application for treating congenital hearing impairment.
    Keywords:  Gene editing technology; Gene therapy; Hearing restoration; Hereditary hearing loss
    DOI:  https://doi.org/10.1007/s12264-026-01651-0
  70. CNS Neurosci Ther. 2026 Jun;32(6): e70948
    DL-3-n-Butylphthalide Protects Against PrP106 -126-Induced Neurotoxicity Through NRF2 Signaling and OPA1/DRP1-Mediated Mitochondrial Dynamics.
    Wei Wu, Xixi Zhang, Mingyue Jiang, Ning Ma.
       BACKGROUND: Prion diseases are fatal neurodegenerative diseases caused by misfolded prion protein. DL-3-n-butylphthalide (NBP), a synthetic agent derived from celery seeds, exhibits neuroprotective effects in multiple neurological disorders. However, its effects against prion peptide-induced neurotoxicity remain unclear.
    METHODS: A PrP106-126-induced neurotoxicity model was established in N2a cells to evaluate the effects of NBP. Apoptosis, oxidative stress, mitochondrial function, mitochondrial dynamics, and respiratory chain integrity were assessed following NBP pretreatment. Mechanistic causality was examined using OPA1 knockdown, DRP1 overexpression, NRF2 inhibition, and NRF2 overexpression. Key findings were further validated in human iPSC-derived neurons.
    RESULTS: NBP attenuated PrP106-126-induced neuronal apoptosis, decreasing cytochrome c release and caspase 3 cleavage. NBP also alleviated oxidative stress by lowering ROS and MDA levels, restoring T-AOC and SOD activity, and increasing NRF2/HO-1 signaling. In parallel, NBP preserved mitochondrial integrity and bioenergetics by maintaining MMP, ATP production, OCR, and mtDNA content, while sustaining respiratory chain complex expression and activity. NBP further normalized mitochondrial dynamics, restoring OPA1 levels and reducing DRP1 enrichment in mitochondrial fractions. Functionally, OPA1 knockdown, DRP1 overexpression, or NRF2 inhibition abolished NBP-mediated protection, whereas NRF2 overexpression recapitulated key protective effects and normalized OPA1/DRP1-related markers. Consistent protective trends were observed in human iPSC-derived neurons.
    CONCLUSION: NBP mitigates PrP106-126-induced neurotoxicity by engaging NRF2-dependent antioxidant signaling and preserving mitochondrial homeostasis, with associated normalization of OPA1/DRP1-related mitochondrial dynamics. These findings support further evaluation of NBP in prion disease-relevant models.
    Keywords:  DL‐3‐n‐butylphthalide; DRP1; NRF2; OPA1; mitochondrial dysfunction; oxidative stress; prion diseases
    DOI:  https://doi.org/10.1002/cns.70948
  71. Redox Biol. 2026 May 27. pii: S2213-2317(26)00237-5. [Epub ahead of print]95 104239
    The irony of Parkinson's disease: Converging mechanisms of redox imbalance and ferroptosis.
    Lauren E Cooke, Emily Rocha, Roberto DiMaio, Adam C Straub, Marco Fazzari.
      Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and its prevalence will increase with population aging. PD is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to severe motor and debilitating non-motor symptoms. Current therapies provide symptomatic relief without preventing the progressive nigrostriatal neurodegeneration. Unfortunately, clinical trials investigating single-target drugs and antioxidant supplementation have not provided robust clinical responses. Since PD is a multifactorial disease involving mitochondrial dysfunction, oxidative stress, α-synuclein aggregation, and neuroinflammation, the classical "one-drug-one-target" philosophy may be ineffective in preventing progression of the disease, while "one-drug-multiple-targets" approaches may offer greater neuroprotection. This review summarizes PD-related pathogenic events and potential disease-modifying strategies, with a particular focus on ferroptosis, a regulated iron-dependent cell death mechanism that has recently emerged as a key driver of dopaminergic degeneration. By synthesizing recent iron chelators- and antioxidant-based clinical trials, repurposed drugs and emerging preclinical pleiotropic strategies, we advocate for an integrated, multi-targeted approach to effectively halt the progression of PD.
    Keywords:  Ferroptosis; Neuropharmacology; Oxidative stress; Parkinson's disease; Selective vulnerability
    DOI:  https://doi.org/10.1016/j.redox.2026.104239
  72. bioRxiv. 2026 May 26. pii: 2026.05.24.727526. [Epub ahead of print]
    HAX1 drives assembly and activation of the mitochondrial intermembrane space chaperone CLPB.
    Monifa A V Fahie, Julia G Hoffman, Julia R Kardon.
      The multicellular metazoan lineage acquired a novel chaperone in the mitochondrial intermembrane space, the AAA+ disaggregase and refoldase CLPB. Although it is not known how they function together, CLPB and the intrinsically disordered IMS protein HAX1 interact and share disease and cellular phenotypes; loss of function in either gene causes severe congenital neutropenia as well as neuropathology and causes many proteins in the IMS and its bounding membranes to become insoluble. We sought to determine how HAX1 functions with CLPB. Through biochemical reconstitution, we find that HAX1 is a stimulatory cofactor of CLPB. HAX1 promotes oligomerization of CLPB into an active disaggregase and stimulates the ATPase and refoldase activities of the oligomeric complex. A short peptide within HAX1 is necessary for direct interaction with the ankyrin domain of CLPB, but stimulation of CLPB activity requires additional elements of HAX1. Characterization of CLPB and CLPB-HAX1 oligomers indicates that HAX1 shifts the predominant oligomeric state of CLPB from a dodecamer to a hexamer elaborated 1:1 with HAX1, suggesting that this smaller oligomer is important during the cycle of CLPB function with clients.
    DOI:  https://doi.org/10.64898/2026.05.24.727526
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