bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–10–25
fifty-five papers selected by
Catalina Vasilescu, Helmholz Munich
  1. BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
  2. Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
  3. Ketogenic diet in treating NADH accumulation caused by complex I dysfunction: the metabolic wisdom of "dredging, not repairing".
  4. A cell death ballet in two acts.
  5. Mitochondrial dysfunction in neurology: biomarkers and clinical implications.
  6. TargetMITO: a rule-based model for generating functional synthetic mitochondrial targeting sequences in yeast.
  7. Rethinking mitochondrial isolation for the next generation of mitochondrial therapies.
  8. Confocal microscopy-based radial profile analysis for submitochondrial protein localization.
  9. Apparent methylation of mitochondrial DNA in WGBS is dominated by technical artifacts.
  10. A Droplet Digital Polymerase Chain Reaction Assay for Detecting and Quantifying Pre-Existing Mutations and De Novo Editing Events in Mitochondrial DNA.
  11. Characterization of the Trimeric TOM Complex by HS-AFM Single-Molecule Analysis.
  12. Harnessing Yeast Mitochondria for the Sustainable Production of High-Value Chemicals.
  13. Drosophila dendrites are resilient to adult-onset deficits in mitochondrial dynamics.
  14. Imaging Characteristics in the Ataxia-Neuropathy Spectrum Related to POLG Mutation.
  15. HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
  16. Acute loss of PLIN5 in brown adipocytes reveals its indispensable role in maintaining mitochondrial function and cold tolerance.
  17. Human induced pluripotent stem cells and organoid models in space for investigating severe pediatric metabolic and congenital disorders.
  18. Extracellular Mitochondrial Components as Emerging Biomarkers and Therapeutic Targets in Human Diseases.
  19. Phasic metabolic remodeling coordinates cardiac myofibroblast differentiation and function.
  20. Should mitochondrial membrane potential be reconsidered as a criterion of cell death?
  21. Discussions with the gene editor.
  22. Lipid droplet-mitochondria crosstalk in osteoarthritis: linking lipid routing to metabolic mismatch.
  23. Mitochondrial DNA mediated Kupffer cell activation in the pathogenesis and progression of liver diseases.
  24. A Micropeptide Component of the OGDH Complex Modulates ATP Production in the TCA Cycle.
  25. PRKN dephosphorylation by PTEN-L couples mitophagy inhibition to GSDME pyroptosis suppression.
  26. A critical mechanistic synthesis of PINK1-mediated mitophagy signaling and its therapeutic targeting in Parkinson's disease neurodegeneration.
  27. Mitochondrial Neurogastrointestinal Encephalopathy: A Case Report from Northeast of Iran.
  28. Lipid-fuelled synaptic plasticity: integrating membrane turnover, β-oxidation, and protein lipidation.
  29. GRP75-dependent SIMPA mediates inter-organellar quality control.
  30. Spatial Control of Cleavage Site Accessibility via 12S rRNA Gating on Tetrahedral Nucleic Acid Scaffold Enables Mitochondrial APE1 Imaging for In Vivo Neuroblastoma Risk Stratification.
  31. 2-Aminoisobutylic Acid-Stabilized Helical Peptides for Selective Mitochondrial Gene Delivery.
  32. Pyrophosphatase 2 Deficiency: Clinical Presentation, Diagnosis and Management.
  33. Context-specific hypermetabolism in humans with mitochondrial defects.
  34. Human Induced Pluripotent Stem Cells in Rare Neurological Disorders: Opportunities and Challenges for Disease Modeling and Drug Discovery.
  35. AKAP1 Protects Retinal Ganglion Cells and Preserves Vision by Improving Mitochondrial and Synaptic Health in Glaucomatous Neurodegeneration.
  36. Mitophagy coordinates organelle crosstalk in health and diseases.
  37. Phosphorylation of the mitochondrial calcium uniporter beta subunit matrix domain locks a conformation that suppresses mitochondrial calcium flux.
  38. Structure bioinformatics of eight human ATP synthase F0 subunits and their AlphaFold3-predicted reduced-hydrophobicity QTY analogues.
  39. Mitochondrial genome homeodynamics across scales.
  40. Grouped but not unified: mechanistic diversity in mitochondrial skeletal disorders.
  41. Development of Organocatalytic Switches of OGG1 that Protect Mitochondria under Oxidative Stress.
  42. Insulin regulates activity-dependent mitochondrial depolarization and calcium dynamics in dentate granule cells.
  43. Machine learning image analysis predicts Parkinson disease genotype and mitochondrial lysosomal abnormalities in iPS neurons.
  44. Impaired ATP7A-Mediated Copper Homeostasis in the Spinal Cord Promotes Morphine Tolerance.
  45. Familial COQ8B-Associated Glomerulopathy: Divergent Long-Term Outcomes and Adult Detection Through Cascade Testing.
  46. Spatiotemporal Resolution for Neurodegenerative Diseases: Linking Proteinopathy, Cellular Vulnerability, and Disease Trajectories.
  47. Extracellular vesicles coordinate mitochondrial trafficking between Leydig cells and testicular macrophages to sustain testosterone production.
  48. Copper Nanoparticles Enable Multi-Compartment Cuproenzyme Metalation in Cellular Models of Copper Deficiency.
  49. Pulse SILAC Approaches to the Measurement of Cellular Dynamics.
  50. Overexpression of endoplasmic reticulum acetyl-CoA transporter AT-1 alters neuronal metabolism, growth, and synaptic activity.
  51. Mitochondrial pharmacology of cardiovascular and antidiabetic drugs: Mechanistic basis of cardioprotection and cardiotoxicity in the diseased heart.
  52. Mitochondrial remodeling in heart failure with reduced ejection fraction.
  53. Multi-organ imaging genetics: towards an integrated view of brain, body and brain diseases.
  54. Proteostasis stress alters mitochondrial levels and localization of SOD2 during cellular senescence.
  55. Mitochondrial Metabolic Reprogramming in Macrophages: A Key Driver of Rheumatoid Arthritis.
  1. Science. 2026 Oct 22. 394(6822): eaea2181
    BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
    Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.
      The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.
    DOI:  https://doi.org/10.1126/science.aea2181
  2. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613074123
    Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
    Tak Shun Fung, Elias Tzoc-Pacheco, Ruobing Cui, Shelby Brown, Simon Schwörer, Tullia Lindsten, Craig B Thompson, Keunwoo Ryu.
      When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.
    Keywords:  GLS; P5CS; metabolism; mitochondria; mtDNA
    DOI:  https://doi.org/10.1073/pnas.2613074123
  3. Front Pediatr. 2026 ;14 1939961
    Ketogenic diet in treating NADH accumulation caused by complex I dysfunction: the metabolic wisdom of "dredging, not repairing".
    Xiaoying Qiao, Jianxiang Liao.
      Genetic mutations causing Complex I (CI) dysfunction lead to the accumulation of NADH in the mitochondrial matrix due to impaired oxidation. An elevated NADH/NAD⁺ ratio feedback-inhibits key enzymes of the tricarboxylic acid (TCA) cycle, reducing metabolic flux, while concurrent electron transport chain (ETC) blockade exacerbates reactive oxygen species (ROS) generation and oxidative stress. Conventional views propose that the ketogenic diet (KD) bypasses the defective CI to restore downstream ETC electron transfer. However, this perspective harbors an inherent contradiction: CI is the primary entry point for NADH oxidation; bypassing it may sustain some electron flow but fails to consume the accumulated NADH in the matrix, leaving the fate of this critical reducing equivalent inadequately explained. This article proposes the metabolic wisdom of "dredging, not repairing", positing that KD, through metabolic reprogramming, diverts the accumulated NADH into multiple utilizable pathways. These include intra-matrix conversion and consumption (generating NADPH and ketone bodies), pumping malate from the matrix into the cytosol via the reverse malate-aspartate shuttle (rMAS), and further cytosolic malate utilization (gluconeogenesis, NADPH generation, glycerol-3-phosphate shuttle, etc.). This multi-pathway synergy achieves "dredging"rather than "repair". This paper aims to elucidate how KD, via metabolic reprogramming, alleviates the inhibition of the TCA cycle caused by NADH accumulation and restores its flux, thereby offering new insights into metabolic therapeutic strategies for CI-deficient mitochondrial diseases.
    Keywords:  NADH; complex I deficiency; ketogenic diet; metabolic reprogramming; mitochondrial disease
    DOI:  https://doi.org/10.3389/fped.2026.1939961
  4. Science. 2026 Oct 22. 394(6822): 383-384
    A cell death ballet in two acts.
    Cristina Muñoz-Pinedo, Seamus J Martin.
      Two proteins that permeabilize mitochondria promote cell death through distinct mechanisms.
    DOI:  https://doi.org/10.1126/science.aem1247
  5. Nat Rev Neurol. 2026 Oct 23.
    Mitochondrial dysfunction in neurology: biomarkers and clinical implications.
    Elena Rossini, Matteo Garibaldi, Michael G Hanna, Robert D S Pitceathly, Chiara Pizzamiglio.
      Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of disease progression and therapeutic response. Primary mitochondrial diseases are presented as proof-of-concept models of impaired oxidative phosphorylation, providing a framework for biomarker identification and validation with translational relevance to other neurological diseases. Mitochondrial biomarkers can be broadly categorized into four domains: fluid biomarkers, reflecting metabolic alterations and stress signalling; genetic biomarkers, capturing mitochondrial DNA integrity and dynamics; multi-omics approaches, integrating transcriptomic, proteomic and metabolomic signatures; and imaging biomarkers, enabling in vivo assessment of structural and functional consequences of mitochondrial dysfunction. Across disorders, these biomarkers reveal shared disturbances in bioenergetics, redox homeostasis, mitochondrial genome maintenance and inflammatory signalling. However, clinical implementation remains limited by methodological heterogeneity, biological variability and reduced disease specificity. Integrated, multimodal biomarker strategies, combined with longitudinal validation, will be essential for supporting precision medicine and guiding the development of therapies to target mitochondrial pathways in neurology.
    DOI:  https://doi.org/10.1038/s41582-026-01274-z
  6. Nucleic Acids Res. 2026 Oct 13. pii: gkag986. [Epub ahead of print]54(19):
    TargetMITO: a rule-based model for generating functional synthetic mitochondrial targeting sequences in yeast.
    Kewin Gombeau, Raymond Wan, Joshua S James, Déborah Tribouillard-Tanvier, Yizhi Cai.
      Mitochondria are essential organelles containing their own genomes, encoding a few proteins essential for energy production. Most of the mitochondrial proteins are nucleus-encoded, translated as precursors in the cytosol, with a large fraction of these precursors properly addressed by an N-terminal mitochondrial targeting sequence (MTS). These MTS share common features but no consensus sequence can explain their functionality nor the precursors-specific determinants of mitochondrial import. To help understand this mechanism, we created a simple computational model to generate functional synthetic MTS while maintaining a tight control on the design parameters. Using the budding yeast, we demonstrated the presence of precursors-specific import capabilities in addressing artificially nucleus-relocated OXPHOS proteins. Our research confirms the existence of cargo-dependent functional compatibilities and takes us one step closer towards improving gene therapy-based treatment of mitochondrial diseases.
    DOI:  https://doi.org/10.1093/nar/gkag986
  7. Front Physiol. 2026 ;17 1975105
    Rethinking mitochondrial isolation for the next generation of mitochondrial therapies.
    Ethan A Simpson, Celina Phan, Jason P Acker.
      Mitochondrial isolation is fundamental to the study of mitochondrial biology and is increasingly relevant to emerging therapeutic applications such as mitochondrial transplantation. However, isolation procedures can substantially influence mitochondrial yield, purity, structural integrity, and bioenergetic function, making method selection an important determinant of experimental and translational outcomes. This review examines current mitochondrial isolation strategies, including physical disruption, chemical permeabilization, emerging microfluidic and automated dissociation technologies, and downstream separation approaches such as differential centrifugation, density-gradient centrifugation, filtration, and immunoaffinity enrichment. Each approach offers distinct advantages and limitations depending on the biological source, processing requirements, and intended application. Conventional methods remain widely used because of their accessibility and flexibility, but may introduce operator variability, mechanical stress, contamination, or loss of mitochondrial function. More selective purification strategies can improve sample purity, although often at the cost of additional processing time, technical complexity, and reduced recovery. Emerging technologies, including standardized mechanical dissociation and microfluidic disruption, may provide greater control over mitochondrial release, but require broader validation across tissues and sample volumes. A persistent challenge across isolation workflows is balancing mitochondrial recovery with preservation of organelle integrity and function. Future progress will require standardized, scalable isolation strategies that consistently preserve mitochondrial quality across different biological sources and downstream applications. Continued refinement of these approaches will be essential for advancing mitochondrial research and supporting the development of mitochondrial-based therapies.
    Keywords:  bioprocessing; isolation; mitochondria; oxidative injury; stabilization
    DOI:  https://doi.org/10.3389/fphys.2026.1975105
  8. Methods. 2026 Oct 22. pii: S1046-2023(26)00210-0. [Epub ahead of print]
    Confocal microscopy-based radial profile analysis for submitochondrial protein localization.
    Sunmin Kwon, Gun Kim, So Yeong Lee.
      Mitochondria are double-membrane organelles whose functions depend on membrane proteins. Identifying whether proteins localize to the outer mitochondrial membrane (OMM) or inner mitochondrial membrane (IMM) is important but often requires specialized techniques. Here, we developed a confocal laser scanning microscopy (CLSM)-based radial profile analysis for the localization of submitochondrial proteins. Based on this method, cytochrome c oxidase subunit 4 (COX4), adenine nucleotide translocase 2 (ANT2), mitochondrial calcium uniporter (MCU) and calcium-activated potassium channel subunit alpha-1(KCa1.1) signals were spatially distinct from translocase of outer mitochondrial membrane 20 (TOM20) signals in isolated mitochondria. Moreover, osmotic shock increased the apparent spatial separation between OMM- and IMM-associated signals, making it easier to distinguish translocase of inner mitochondrial membrane 23 (TIM23) or pore-forming subunit of the mitochondrial ATP-gated potassium channel (MITOK) signals from TOM20 signals in isolated mitochondria. Our approach provides a practical screening tool for assessing submitochondrial protein localization without specialized instrumentation or expertise.
    Keywords:  Confocal microscopy; Immunofluorescence; Mitochondria; Radial profile analysis; Submitochondrial localization
    DOI:  https://doi.org/10.1016/j.ymeth.2026.10.005
  9. Epigenetics Chromatin. 2026 Jul 26. pii: 44. [Epub ahead of print]19(1):
    Apparent methylation of mitochondrial DNA in WGBS is dominated by technical artifacts.
    Jing-Jing Yin, Zhi-Chao Gong, Shi-Qing Mao.
       BACKGROUND: DNA methylation is a critical epigenetic modification that occurs on cytosine residues and plays essential roles in regulating gene expression, cellular differentiation, and genomic imprinting. However, the existence of cytosine methylation in mitochondrial DNA (mtDNA) remains highly controversial. Whole-genome bisulfite sequencing (WGBS) has been widely used to assess mtDNA methylation, but signals detected in mitochondrial DNA are frequently influenced by technical artifacts.
    RESULTS: We systematically evaluated technical factors that influence mtDNA methylation measurements using zebrafish WGBS datasets derived from a wide range of tissues and experimental conditions, complemented by analyses of human and mouse datasets. mtDNA methylation measurements varied widely among samples within CpG, CHG, and CHH contexts, and mtDNA CpG methylation estimates above 2% were often accompanied by comparable CHG and CHH methylation estimates, even when lambda DNA CpG methylation remained below 2%. Notably, samples lacking documented DNA fragmentation tended to show substantially elevated mtDNA methylation compared with those subjected to fragmentation. Although strand-specific sequencing biases were common, they were not a sufficient cause of elevated false-positive methylation signals. The degree of strand coverage imbalance did not predict high methylation in datasets with documented fragmentation, and high methylation in undocumented samples was preferentially observed where strand coverage was balanced rather than imbalanced. Kit annotations were associated with dataset-level variation in mtDNA methylation, particularly for library preparation kits, but elevated signals were not confined to any single bisulfite conversion or library preparation kit. Cross-species analyses showed that human and mouse datasets displayed comparable patterns of elevated mtDNA methylation.
    CONCLUSIONS: Our findings indicate that high mtDNA methylation signals detected in WGBS data are dominated by technical artifacts, particularly DNA fragmentation status and bisulfite conversion efficiency. These results highlight the need for careful interpretation of mitochondrial methylation signals and provide a framework for distinguishing technical noise from potential biological signals in WGBS-based analyses.
    Keywords:  Bisulfite conversion; DNA fragmentation; Epigenetics; Mitochondrial DNA (mtDNA) methylation; Strand bias; Technical artifacts; Whole-genome bisulfite sequencing (WGBS)
    DOI:  https://doi.org/10.1186/s13072-026-00692-z
  10. J Vis Exp. 2026 Oct 21.
    A Droplet Digital Polymerase Chain Reaction Assay for Detecting and Quantifying Pre-Existing Mutations and De Novo Editing Events in Mitochondrial DNA.
    Pei-Lun Kao, Qinglan Ling.
      Development of mitochondria-targeted base editors as a gene therapy strategy for mitochondrial deoxyribonucleic acid (mtDNA)-related diseases, such as MT-ATP6 Leigh syndrome (LS), requires using in vitro models for proof-of-concept evaluations. Here, we developed a droplet digital polymerase chain reaction (ddPCR)-based assay that uses detection probes specific to wild-type, mutant, or edited mtDNA alleles to determine the heteroplasmy level in cells carrying different mtDNA variants. We used a pathogenic human MT-ATP6 allele as an example to demonstrate the development and optimization pipeline of this assay. We optimized assay parameters and designed experiments to validate the precision of the assay in quantifying MT-ATP6 variants and their fraction among the total mtDNA copy number. In addition, our data indicated that this assay is highly sensitive. To allow high-throughput screening, we then developed an R-based analysis pipeline to streamline the analysis workflow for determining MT-ATP6 variant fractional abundance. Our data demonstrated that the assay achieved the high resolution required to differentiate various heteroplasmic MT-ATP6 alleles. Future studies can build upon the current protocol and develop similar ddPCR assays to perform high-throughput screening for the identification of cell lines or tissue samples with specified mtDNA alleles.
    DOI:  https://doi.org/10.3791/73416
  11. Genes Cells. 2026 Nov;pii: e70154. [Epub ahead of print]31(6):
    Characterization of the Trimeric TOM Complex by HS-AFM Single-Molecule Analysis.
    Nanako Kobayashi, Satoshi N Omura, Kana Kuzasa, Kenichiro Imai, Shiho Kawai, Hirotatsu Imai, Romain Amyot, Kenichi Umeda, Osamu Nureki, Toshiya Endo, Noriyuki Kodera, Yuhei Araiso.
      The translocase of the outer mitochondrial membrane (TOM) complex is the entry gate for mitochondrial proteins synthesized in the cytosol. Previous biochemical studies indicated that the TOM complex functions as a trimer and exists in a dynamic equilibrium with a Tom22-lacking dimer in intact mitochondria. In contrast, recent cryo-electron microscopy (cryo-EM) studies revealed near-atomic structures of the Tom22-containing core dimer. However, the relationship between the core dimer and the functional trimer remains unclear. Here, we analyzed the oligomeric organization and structural properties of purified yeast TOM complexes using high-speed atomic force microscopy (HS-AFM). Purified yeast TOM complexes predominantly adopted a trimeric organization but underwent deformation and dissociation during repeated HS-AFM scanning, leaving dimeric and monomeric particles. Trimeric particles exhibited spherical shapes consistent with previous crosslinking models, whereas dissociated dimers closely resembled TOM core-dimer structures determined by cryo-EM. HS-AFM also revealed the peripheral localization of the Tom20 receptor and enabled direct visualization of substrate-TOM interactions, with TOM association accompanied by reduced substrate mobility. Together, these findings provide quantitative and structural evidence for a predominantly trimeric organization of the purified TOM complex and suggest that the trimer contains a stable core-dimer unit with a more loosely associated third Tom40-containing unit.
    Keywords:  Cryo‐EM; HS‐AFM; membrane protein complex; mitochondria; protein translocation
    DOI:  https://doi.org/10.1111/gtc.70154
  12. ACS Synth Biol. 2026 Oct 16. 15(10): 3911-3928
    Harnessing Yeast Mitochondria for the Sustainable Production of High-Value Chemicals.
    Jie Sheng, Xiaochun Zheng.
      In microbial cytoplasmic reaction compartments, competitive pathways and metabolic interactions often hinder the efficient synthesis of target compounds. In contrast, eukaryotic cells can control metabolic complexity by utilizing organelles to segregate biochemical pathways. Mitochondria, known as the "powerhouses of the cell," are rich in a unique set of enzymes, intermediate metabolites, and cofactors that can be exploited for metabolic engineering. However, wider application of mitochondria in metabolic engineering is limited by an insufficient understanding of their unique metabolic traits, the lack of efficient genetic tools, and the difficulty of balancing cell growth and product accumulation. This review outlines yeast mitochondria-related aspects, including their intrinsic properties, mechanisms of protein synthesis and import, recognition and screening of mitochondrial signal peptides, and potential advantages of using mitochondria alone or mitochondria collaborating with other organelles to produce high-value chemicals. Additionally, we discuss challenges in mitochondrial engineering and provide an outlook on future priorities.
    Keywords:  compartmentalization; high-value chemicals; metabolic engineering; mitochondria; mitochondrial engineering; organelles
    DOI:  https://doi.org/10.1021/acssynbio.6c00350
  13. J Cell Biol. 2026 Dec 07. pii: e202511010. [Epub ahead of print]225(12):
    Drosophila dendrites are resilient to adult-onset deficits in mitochondrial dynamics.
    Hailey Q Wang, Demetria G Fortson, Eavan D Burton, Hunter S Whitbeck, Briana M Robles, Kwass Wass, Letitia Bortey, Avi J Adler, Jordan I Kalai, Giovanna Napoleone, Erin L Barnhart.
      Mitochondrial transport, fusion, and fission are necessary for neuronal development, but the role of mitochondrial dynamics in neuronal maintenance remains unclear. In this work, we employed functional in vivo imaging of neurons in the Drosophila visual system, "horizontal system" (HS) cells, to determine how adult-onset deficits in mitochondrial dynamics affect mitochondrial localization, local regulation of ATP, and dendrite maintenance. In mature HS neurons, inhibition of mitochondrial transport or fusion depleted mitochondria from the dendrite over time but, surprisingly, had no effect on dendrite morphology. Moreover, adult-restricted mitochondrial mislocalization affected neither visual stimulus-driven dendritic calcium responses nor local, dynamic regulation of ATP levels. In contrast, when induced during development, the same perturbations caused mitochondrial mislocalization, loss of dendrite complexity, abrogation of stimulus-locked calcium responses and ATP fluctuations, and age-dependent dendrite degeneration. Thus, although mitochondrial dynamics are necessary during neuronal development, mature dendrites are capable of maintaining form and function in vivo upon mitochondrial depletion.
    DOI:  https://doi.org/10.1083/jcb.202511010
  14. Cureus. 2026 Sep;18(9): e116575
    Imaging Characteristics in the Ataxia-Neuropathy Spectrum Related to POLG Mutation.
    Abraham Alhatou, Omar M Alhatou, Mohamed Ghamoodi, Mohammed Alhatou.
      Mutations in the mitochondrial DNA polymerase gamma (POLG) gene cause a broad spectrum of neurodegenerative disorders, including the ataxia-neuropathy spectrum (ANS). Substantial phenotypic heterogeneity and overlapping clinical features can delay diagnosis. We report a 38-year-old woman with no significant past medical history who presented with a three-year history of slowly progressive sensory ataxia that worsened in the dark. Examination revealed mild dysarthria, large-fiber sensory loss, and a positive Romberg sign. Extensive metabolic, toxic, autoimmune, and infectious work-up was unrevealing. Nerve conduction studies confirmed a mild peripheral sensory neuropathy. Brain magnetic resonance imaging (MRI) demonstrated distinct bilateral, symmetric T2-weighted and fluid-attenuated inversion recovery (FLAIR) hyperintensities in the dorsomedial thalami and cerebellar white matter. Whole-exome sequencing confirmed a homozygous W748S mutation in the POLG gene, establishing a diagnosis of POLG-related ANS. This imaging pattern, though not specific to POLG-related disease, may support earlier consideration of targeted genetic testing when present alongside a compatible clinical picture.
    Keywords:  ataxia-neuropathy spectrum; dorsomedial thalamus; mitochondrial disease; polg mutation; sensory ataxia; w748s
    DOI:  https://doi.org/10.7759/cureus.116575
  15. FASEB J. 2026 Oct 31. pii: e72407. [Epub ahead of print]40(20):
    HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
    Ko Suzuki, Jun-Ichiro Takahashi, Kiriko Kaneko, Kazumichi Furuyama.
      Intracellular energy metabolism is strictly regulated by hormones and intracellular metabolites for the appropriate use of energy resources such as carbohydrates and fatty acids. Mitochondria are essential organelles in eukaryotic cells since they contain several metabolic machineries required for oxidative phosphorylation, such as the tricarboxylic cycle, electron transport chain, and fatty acid β-oxidation (FAO). Previously, we reported that FAO activity is increased in CLPX-knockout HepG2 cells (CLPX-KO cells). CLPX is the substrate recognition subunit of the mitochondrial protease ClpXP that regulates intracellular heme levels through the degradation of ALAS1 in the mitochondrial matrix. ALAS1 is the rate-limiting enzyme for heme biosynthesis; thus, we examined whether heme regulates FAO activity. We found that the inhibition of heme synthesis in CLPX-KO cells decreased FAO activity; in contrast, hemin treatment increased FAO activity in wild-type HepG2 cells (CLPX-WT cells). Furthermore, pretreatment of CLPX-WT cells with a chemical inhibitor or specific siRNA targeting the heme degradation enzyme HMOX1 blocked FAO activation induced by hemin, indicating that heme catabolites rather than heme itself are responsible for FAO activation by heme. Among the heme catabolites, we identified carbon monoxide (CO) as an essential metabolite for FAO activation through the activation of the LKB1/AMPK signaling pathway. In this manuscript, we revealed the previously unknown role of CO as an intrinsic inducer of mitochondrial FAO activity and revealed that an excess amount of heme increases FAO activity via CO production by HMOX1.
    Keywords:  AMP‐activated kinase; carbon monoxide; fatty acid oxidation; heme; heme oxygenase; mitochondria
    DOI:  https://doi.org/10.1096/fj.202603280R
  16. J Biol Chem. 2026 Oct 22. pii: S0021-9258(26)02557-3. [Epub ahead of print] 113685
    Acute loss of PLIN5 in brown adipocytes reveals its indispensable role in maintaining mitochondrial function and cold tolerance.
    Violeta I Gallardo Montejano, Chaofeng Yang, Hannah Hurtado, Perry E Bickel.
      Cold exposure induces adaptive molecular and mitochondrial remodeling in brown adipose tissue (BAT) of mice to sustain thermogenesis. We previously showed that the lipid droplet protein Perilipin 5 (PLIN5) is strongly induced in BAT by cold exposure and promotes thermogenic gene expression, mitochondrial remodeling, and uncoupled respiration. However, constitutive BAT-specific PLIN5 deletion impaired mitochondrial function without causing cold intolerance, suggesting physiological compensation, likely via induction of thermogenic genes in white adipose tissue (WAT). To test this possibility, we generated mice with doxycycline-inducible BAT-specific PLIN5 deletion. Acute PLIN5 deletion in adult mice during cold exposure reduced BAT thermogenic gene expression, mitochondrial cristae density, and uncoupled mitochondrial respiration, which resulted in cold intolerance. Unlike constitutive PLIN5 knockout mice, mice acutely rendered deficient of PLIN5 in BAT failed to mount a compensatory thermogenic response in inguinal WAT. Together, these findings demonstrate that PLIN5 is required for mitochondrial homeostasis in brown adipocytes and for adaptive thermogenesis during cold exposure. Notably, by cell fractionation and protease protection assay, we observed that PLIN5 enriches on the outer mitochondrial membrane in BAT during cold exposure. We also observed that the absence of PLIN5 in BAT is not associated with reduced contacts between lipid droplets and mitochondria, thereby suggesting that the role of PLIN5 in adaptive thermogenesis may depend on its translocation to the mitochondrial outer membrane for a purpose unrelated to the formation of contacts between lipid droplets and mitochondria.
    Keywords:  Lipid Droplet; Perilipin 5; adaptive thermogenesis; brown adipose tissue; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2026.113685
  17. Precis Clin Med. 2026 Dec;9(4): pbag028
    Human induced pluripotent stem cells and organoid models in space for investigating severe pediatric metabolic and congenital disorders.
    Sara Benedetti, Hana Štupica, Gian Vincenzo Zuccotti, Volkmar Weissig, Davide Marotta, Carlo Pappone, Alba Tull, Kathleen H Rubins, Afshin Beheshti, Christopher E Mason, Simona Ferraro.
      As biomedical research in space expands, microgravity and spaceflight-associated stressors are revealing cellular responses that may provide new insights into rare and severe metabolic and congenital disorders. Human induced pluripotent stem cells (hiPSCs) and organoids are particularly promising as they enable patient-specific modelling in the space environment. In this review, we examine the current literature on space-based hiPSC experimental models, highlighting their relevance to pediatric disorders with well-defined genetic backgrounds, namely mitochondrial diseases and congenital heart disorders. We summarize the evidence that spaceflight conditions alter mitochondrial function, cytoskeletal organization, oxidative stress, calcium handling, cellular maturation, and gene expression, and discuss how these responses may converge with metabolic disease-associated phenotypes. We highlight both adaptive and pathological responses reported in space-based hiPSC studies and identify key experimental and mechanistic gaps. Finally, we consider how advances in stem cell technologies and space-based biomedical research may enable the development of personalized, patient-specific disease models and therapeutics for rare pediatric diseases, ultimately accelerating translational discovery and clinical innovation.
    Keywords:  3D cell culture; congenital heart defect; hiPSC; mitochondrial disorder; organoids; rare diseases
    DOI:  https://doi.org/10.1093/pcmedi/pbag028
  18. Int J Biol Sci. 2026 ;22(15): 8390-8407
    Extracellular Mitochondrial Components as Emerging Biomarkers and Therapeutic Targets in Human Diseases.
    Kuan-Hao Tsui, Emmanuel Naveen Raj, Andy P Tsai, Boyang Wang, Chen-Yueh Wen, Chia-Jung Li.
      Mitochondria serve as the bioenergetic hub of eukaryotic cells while simultaneously acting as a major source of cellular stress and toxicity. Classical mitochondrial quality control (MQC) has long been viewed as a lysosome-dependent process centered on mitophagy. However, aging is accompanied by progressive lysosomal dysfunction, limiting the efficiency of canonical mitochondrial clearance and contributing to mitochondrial accumulation and cellular deterioration. Emerging evidence suggests that under conditions of lysosomal overload and metabolic stress, cells engage alternative quality-control pathways by selectively exporting mitochondrial components into the extracellular environment through mitochondrial-derived vesicles (MDVs) and exophers. In this review, we integrate current findings to propose a unified framework of age-associated mitochondrial disposition and discuss how cells dynamically balance intracellular degradation with extracellular mitochondrial secretion. We further examine the molecular machinery underlying MDV and exopher biogenesis and evaluate their roles in reshaping intercellular metabolic communication. Particular emphasis is placed on their translational relevance in cancer and neurodegenerative disorders, where extracellular mitochondrial trafficking may contribute to disease progression, therapeutic resistance, and tissue remodeling. We also discuss the technical and analytical bottlenecks that currently constrain this field. Finally, we discuss the emerging potential of mitochondrial secretion pathways as diagnostic biomarkers and therapeutic targets for age-associated diseases.
    Keywords:  intercellular transfer; lysosomes; mitochondrial-derived vesicles; mitophagy
    DOI:  https://doi.org/10.7150/ijbs.140360
  19. Redox Biol. 2026 Oct 16. pii: S2213-2317(26)00440-4. [Epub ahead of print]98 104441
    Phasic metabolic remodeling coordinates cardiac myofibroblast differentiation and function.
    Collin K Wells, Lianay Gutierrez Luque, Daniel C Nguyen, Madison S Teer, Ning Chen, Yania Martinez-Ondaro, Pawel K Lorkiewicz, Richa Singhal, Maleesha De Silva, Bradford G Hill.
      Fibroblast differentiation into matrix-producing, contractile myofibroblasts is accompanied by metabolic reprogramming, but whether these changes precede differentiation or arise from the activated phenotype remains unclear. We integrated time-resolved extracellular flux analysis, transcriptomics, stable isotope-resolved metabolomics, and metabolic interventions to define the relationship between metabolism and myofibroblast differentiation in adult mouse cardiac fibroblasts stimulated with transforming growth factor-β (TGFβ). TGFβ increased glycolysis within 1.5 h, before broad transcriptional remodeling and induction of periostin and α-smooth muscle actin. Mitochondrial respiration initially declined but increased at 48 h as the phenotype emerged, accompanied by smaller, less elongated mitochondria and greater respiratory capacity. [U-13C6]-glucose tracing revealed progressive incorporation of glucose-derived carbon into glycolytic intermediates, nucleotide sugars, and glycerol 3-phosphate, followed later by increased labeling of tricarboxylic acid cycle intermediates. TGFβ-treated fibroblasts also demonstrated enhanced insulin-stimulated glycolysis. Replacing glucose with galactose attenuated collagen and periostin induction, whereas glyceraldehyde 3-phosphate dehydrogenase inhibition prevented induction of collagen, periostin, and α-smooth muscle actin. Conversely, glucose transporter 1 or mutant PFK2 (GlycoHi) overexpression increased glycolysis without inducing myofibroblast markers. Together, these loss- and gain-of-function studies indicate that glycolytic activity is required for complete differentiation but is not sufficient to initiate the phenotype. Inhibition of mitochondrial Complex I or ATP synthase preferentially reduced collagen abundance, while glycolytic and Complex I inhibition diminished TGFβ-induced collagen gel contraction. These findings define a phasic metabolic program in which early glycolytic activation precedes transcriptional and phenotypic remodeling, whereas mitochondrial respiratory capacity increases later and distinct metabolic nodes selectively regulate collagen abundance and contractile behavior.
    Keywords:  Biosynthesis; Fibroblast; Fibrosis; Glycolysis; Mitochondria; Stable isotope
    DOI:  https://doi.org/10.1016/j.redox.2026.104441
  20. Pharmacol Res. 2026 Oct 19. pii: S1043-6618(26)01611-7. [Epub ahead of print]233 109696
    Should mitochondrial membrane potential be reconsidered as a criterion of cell death?
    Petr Mlejnek.
      
    Keywords:  Cell death; Cell death criteria; Cell viability; Flow cytometry; Mitochondrial membrane potential; Plasma membrane permeabilization
    DOI:  https://doi.org/10.1016/j.phrs.2026.109696
  21. Nat Rev Chem. 2026 Oct 22.
    Discussions with the gene editor.
    Feng Zhang, Stephanie Greed.
      
    DOI:  https://doi.org/10.1038/s41570-026-00885-w
  22. Front Mol Biosci. 2026 ;13 1973436
    Lipid droplet-mitochondria crosstalk in osteoarthritis: linking lipid routing to metabolic mismatch.
    Gang Meng, Ruijie Hou, Ping Dong, Qiannan Chen, Xueyuan Li, Kai Hu, Zixuan Du, Rong Wang, Zhaoxin Zhong.
      Osteoarthritis (OA) is a whole-joint disease characterized by metabolic reprogramming beyond structural degeneration. Increasing evidence indicates that lipid droplets (LDs) regulate lipid storage, mobilization and intracellular lipid routing, while alterations in mitochondrial metabolism determine the capacity of chondrocytes to adapt to metabolic stress. However, LD accumulation alone is insufficient to define metabolic dysfunction, as it may represent either adaptive buffering or maladaptive retention. This review proposes a lipid flux-mitochondrial capacity matching framework to integrate lipid handling with mitochondrial oxidative capacity, redox regulation and quality control. We discuss how excessive lipid flux relative to mitochondrial capacity may promote oxidative stress, lipid peroxidation, ferroptosis, senescence and extracellular matrix disruption, whereas balanced lipid utilization supports chondrocyte homeostasis. Current evidence on LD biology, fatty acid oxidation, mitophagy and whole-joint metabolic communication is summarized, with clear distinction between direct OA evidence and findings from other cellular systems. Although organelle contact sites such as PLIN5-FATP4, PLIN3-VDAC3 and ESYT1/2-VAPB represent potential regulators of lipid routing, their functional relevance in OA chondrocytes remains to be established. Future studies integrating isotope tracing, metabolic flux analysis and dynamic organelle imaging are required to clarify how lipid routing and mitochondrial capacity jointly regulate OA progression.
    Keywords:  fatty acid oxidation; ferroptosis; lipid droplets; lipid flux; mitochondrial metabolism; mitophagy; organelle contact sites; osteoarthritis
    DOI:  https://doi.org/10.3389/fmolb.2026.1973436
  23. Autoimmun Rev. 2026 Oct 21. pii: S1568-9972(26)00222-3. [Epub ahead of print] 104208
    Mitochondrial DNA mediated Kupffer cell activation in the pathogenesis and progression of liver diseases.
    Zijun Li, Lifu Zhu, Luqing Pan, Jinjun Ma, Haibo Xie, Jiaxiang Zhang.
      The liver serves as a pivotal metabolic and immunological hub, yet its homeostatic equilibrium is highly susceptible to mitochondrial dysfunction. Recent studies have implicated mitochondrial DNA (mtDNA) as an important damage-associated molecular pattern (DAMP) that links mitochondrial injury to sterile hepatic inflammation and KCs (KCs) activation. This review provides a comprehensive synthesis of the mtDNA mediated KCs across four major hepatic pathologies: Alcohol-associated Liver Disease (ALD), Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), Hepatic Ischemia-Reperfusion Injury (IRI), and Hepatocellular Carcinoma (HCC). We discuss emerging evidence that Z-DNA-binding protein 1 (ZBP1) associated PANoptosis and nerve injury-induced protein 1 (NINJ1) mediated plasma membrane rupture may contribute to inflammatory cell death in severe liver injury, complementing rather than superseding canonical pyroptotic mechanisms. However, the extent to which mtDNA directly activates this axis remains unresolved. Furthermore, we delineate the cell-type-specific dichotomy of cyclic GMP-AMP synthase (cGAS) signaling, which fuels pro-inflammatory storms in KCs via the stimulator of interferon genes (STING) pathway while promoting protective mitophagy in hepatocytes through a STING-independent cGAS-Beclin-1 interaction. In the context of immunometabolism, we also summarize preclinical evidence linking cytidine/uridine monophosphate kinase 2 (CMPK2) dependent mtDNA synthesis to inflammasome activation and mitochondrial calcium uniporter (MCU) acetylation to age-associated mtDNA release during IRI. Finally, we evaluate the clinical translational potential of targeting these molecular hubs and the emergence of cell-free mitochondrial DNA (cf-mtDNA) fragmentomics-including 5' end motif analysis and diversity scoring as a transformative liquid biopsy tool for precision diagnosis. Collectively, available evidence positions mtDNA mediated KCs activation as an important, context-dependent contributor to liver disease and a potential therapeutic target, while underscoring the need for cell-specific and human validation.
    Keywords:  Inflammatory response; Kupffer cells; Liver diseases; Mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.autrev.2026.104208
  24. Adv Sci (Weinh). 2026 Oct 18. e77242
    A Micropeptide Component of the OGDH Complex Modulates ATP Production in the TCA Cycle.
    Xinqiang Yin, Weiyan Qi, Lifen Lin, Huilin Zheng, Guoxiang Zhao, Quan Chen, Guoqiang Shao, Yifan Wu, Jialiang Hu, Hanmei Xu.
      Since its elucidation, the tricarboxylic acid (TCA) cycle has been regarded as a fully defined enzymatic pathway. Here, we report the discovery of a previously unrecognized micropeptide component of this central metabolic system. Through analyzing ribosome profiling data from the mouse sORFs.org database, we discovered APPM (ATP production-promoting micropeptide), a 29-amino acid peptide encoded by a non-canonical small open reading frame within the mouse Ctsb gene. APPM localizes to the mitochondrial matrix and inner membrane, where it directly binds to the E1 subunit (OGDH) of the α-ketoglutarate dehydrogenase complex (OGDHc). This interaction modulates OGDHc enzymatic activity, thereby regulating NADH and ATP production. We identified tyrosine-13 as the critical residue mediating the APPM-OGDH interaction and functional activation. Exogenous APPM administration increased ATP levels in vivo and, in a mouse model of heart failure, restored cardiac function, outperforming the reference drug trimetazidine. Collectively, our findings identify APPM as the first micropeptide regulator of the OGDH complex, expanding the known repertoire of the TCA cycle and presenting a potential therapeutic strategy for diseases characterized by bioenergetic insufficiency.
    Keywords:  APPM; ATP synthesis; OGDHc; TCA cycle; mitochondrial function
    DOI:  https://doi.org/10.1002/advs.77242
  25. Autophagy. 2026 Oct 20.
    PRKN dephosphorylation by PTEN-L couples mitophagy inhibition to GSDME pyroptosis suppression.
    Chenghao Yan, Xu Liu, Xinyu Gong, Xiaofang Wu, Haodong Xu, Liming Wang.
      Mitochondrial damage is a potent trigger of inflammatory cell death; however, how damaged mitochondria transduce stress signals to initiate cell death execution, and how this process is finely regulated, remain incompletely understood. We recently identified that the PINK1-PRKN axis, activated upon mitochondrial depolarization, not only initiates mitophagy but also drives pyroptosis via the ubiquitination and degradation of MCL1, which in turn promotes BAX and BAK1 activation, leading to CASP3 activation and GSDME cleavage. PTEN-L functions as a negative regulator of this pathway by directly dephosphorylating PRKN, which concurrently suppresses both mitophagy and pyroptosis, thereby coupling organelle quality control to inflammatory cell death.
    Keywords:  GSDME-dependent pyroptosis; PINK1-PRKN axis; PTEN-L dephosphorylation; mitochondrial damage; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2751925
  26. Exp Neurol. 2026 Oct 18. pii: S0014-4886(26)00446-2. [Epub ahead of print]408 116078
    A critical mechanistic synthesis of PINK1-mediated mitophagy signaling and its therapeutic targeting in Parkinson's disease neurodegeneration.
    Abida Khan, Talha Jawaid, Zia Ur Rehman, Mohammed Kanan Alshammari, Md Afroz Bakht, Faiyaz Shakeel, Mohammed Zawiah, Mohd Imran.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with loss of dopaminergic neurons, mitochondrial dysfunction and disruption of cellular homeostasis. PTEN-induced kinase 1 (PINK1) plays a crucial role in mitochondrial quality control by regulating mitophagy, mitochondrial dynamics, and calcium signaling to maintain neuronal bioenergetic homeostasis. This review critically evaluates the molecular pathways underlying PINK1-mediated mitochondrial integrity and the mechanisms by which loss-of-function mutations contribute to the pathogenesis of PD. Familial early-onset PD is strongly associated with pathogenic PINK1 mutations identified through genetic studies. Therapeutic approaches targeting the PINK1 pathway are examined, including adeno-associated virus (AAV)-based gene delivery, direct small-molecule PINK1 activation (MTK458), and indirect modulation of mitophagy and mitochondrial homeostasis by compounds such as curcumin, resveratrol, cannabidiol, gastrodin, and quercetin. Moreover, the complementary restoration of mitochondrial homeostasis through the modulation of downstream targets, such as transcription factor EB (TFEB) activation and BCL2-interacting protein 3-like (BNIP3L/NIX)-mediated mitophagy, is discussed as an indirect therapeutic strategy. Another important finding is that PD is a biologically and clinically heterogeneous disease that requires biomarker-directed and genotype-stratified therapeutic development. Finally, major translational issues are critically evaluated, including challenges related to blood-brain barrier penetration, target specificity, and long-term safety of mitochondrial modulators.
    Keywords:  Mitochondrial dysfunction; Mitophagy; Oxidative stress; PINK1/Parkin; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.expneurol.2026.116078
  27. Middle East J Dig Dis. 2026 Apr;18(2): 105-108
    Mitochondrial Neurogastrointestinal Encephalopathy: A Case Report from Northeast of Iran.
    Masoud M Malekzadeh, Maryam Anvari, Hadi Bagherihosseini, Azita Ganji.
      Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare autosomal recessive disorder often misdiagnosed due to its heterogeneous presentation. We describe a 21-year-old man with a long history of episodic nausea and vomiting, weight loss, and intermittent diarrhea since childhood, initially misdiagnosed as Crohn's disease following a colonoscopy-induced perforation. Despite treatment with adalimumab, his gastrointestinal symptoms persisted. Subsequent investigations revealed dilated stomach and duodenum, and new neurological findings (ptosis, nasal speech) prompted further evaluation. Brain magnetic resonance imaging (MRI) showed leukoencephalopathy, leading to the definitive diagnosis of MNGIE. This case highlights the importance of considering mitochondrial disorders in young patients with refractory gastrointestinal dysmotility and concomitant neurological features to prevent diagnostic delays and unnecessary interventions.
    Keywords:  Gastrointestinal dysmotility; Iran; Mitochondrial neurogastrointestinal encephalopathy
    DOI:  https://doi.org/10.34172/mejdd.3386
  28. EMBO J. 2026 Oct 21.
    Lipid-fuelled synaptic plasticity: integrating membrane turnover, β-oxidation, and protein lipidation.
    Saber H Saber, Benjamin Matthews, Sevannah A Steeves, Yara Abosnwber, Tristan P Wallis, Frédéric A Meunier.
      Synaptic plasticity requires the coordinated regulation of membrane remodelling, energy production, and protein turnover. However, how these processes are integrated at the molecular level remains unclear. Here, we propose that activity-dependent lipid flux represents a central mechanism linking these processes. Saturated free fatty acids (sFFAs) released from membrane phospholipids, triglycerides, or from extracellular uptake can be activated to acyl-CoA and directed to mitochondrial β-oxidation and synaptic protein lipidation. These represent two emerging pathways adding to the complexity of roles played by sFFAs, including membrane fluidity and receptor activation. Recent work identifies DDHD2 as a mechanistic entry point into this broader synaptic lipid network. We position DDHD2-dependent lipid mobilisation in the wider context of glia-neuron lipid transfer and ApoE/sortilin-dependent fatty acid uptake. Key unresolved questions include the source and fate of fatty acids, the relative contribution of β-oxidation versus glycolysis to ATP production, and whether these pathways are altered in neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s44318-026-00944-4
  29. Nature. 2026 Oct 21.
    GRP75-dependent SIMPA mediates inter-organellar quality control.
    Fan Yu, Lingyu Jiang, Hanyu Liu, Song Yang, Yuan Yuan, Hongzhen Jin, Jinming Liu, Xi Liu, Yu Dong, Dongfeng Ren, Jie Kang, Yan Huang, Qi Meng, Feng Bai, Yanjun Li, Shuoguo Li, Huadong Liu, Wei Zhao, Jia Xiao, Quan Chen.
      Mitochondria are bound by a double membrane and are semiautonomous organelles, rendering them highly vulnerable to global and internal proteostatic stress1. Multiple surveillance mechanisms at proteostatic and inter-organellar levels have evolved to maintain mitochondrial integrity and cellular health2-7. However, the precise mechanisms by which proteostatic damage relays stress signals across organelles and how the quality surveillance machinery coordinates these functions remain unknown. Here we report that under proteostatic stress, damaged mitochondrial proteins are sequestered to form stress-induced mitochondrial protein aggregates (SIMPAs) that activate specific quality control mechanisms in a spatially confined manner without perturbing the mitochondrial network. Quantitative proteomic and correlative light-electron microscopy analysis revealed that SIMPA mediates inter-organellar communication via mitochondria-endoplasmic reticulum contact sites or mitochondrial-associated membranes. Mechanistically, GRP75 coordinates SIMPA biogenesis and focally activates endoplasmic reticulum unfolded protein response pathways via mitochondria-endoplasmic reticulum contact sites or mitochondrial-associated membranes for the targeted clearance of SIMPAs. Functionally, in both cellular and liver disease models, we found that a GRP75-dependent SIMPA signalling cascade attenuates mitochondrial stress and preserves mitochondrial integrity under proteotoxic stress. Overall, we show that SIMPAs, functioning as protein condensates, serve as a central cross-compartment communication hub for mitochondrial quality control, supporting cellular and organismal fitness.
    DOI:  https://doi.org/10.1038/s41586-026-10733-y
  30. Anal Chem. 2026 Sep 29. 98(38): 28542-28550
    Spatial Control of Cleavage Site Accessibility via 12S rRNA Gating on Tetrahedral Nucleic Acid Scaffold Enables Mitochondrial APE1 Imaging for In Vivo Neuroblastoma Risk Stratification.
    Fei Zhang, Yingyu Zhang, Xianwei Zhang, Qionglin Wang, Na Zhao, Jianying Ren, Man Zhang, Peng Wang, Mengxin Zhang, Wancun Zhang.
      Mitochondrial apurinic/apyrimidinic endonuclease 1 (APE1) mislocalization is closely linked to tumor progression and prognosis. Yet, its ubiquitous distribution across mitochondria, cytoplasm, and nucleus makes specific in situ imaging of mitochondrial APE1 highly challenging. Herein, we fabricate a sequentially activated biosensor (C-12S-tFNA) with 12S rRNA-gated spatial regulation of APE1 cleavage site (apurinic/apyrimidinic site, AP site) accessibility, where cytochrome c (cyt c) acts as the targeting motif to drive precise mitochondrial enrichment. In the initial state, the AP site is structurally locked to prevent nonspecific cleavage by extramitochondrial APE1. After entering the mitochondria, mitochondrial 12S rRNA, which is consistently expressed across diverse cell types, hybridizes with the AP-site-containing strand via base complementarity, leading to AP site unlocking. The exposed AP site is subsequently cleaved by mitochondrial APE1, separating the fluorophore-quencher pair and generating a fluorescent signal. Benefiting from the 12S rRNA-gated design, false-positive signals can be effectively suppressed. Experimental findings demonstrate that C-12S-tFNA exhibits high sensitivity (LOD: 0.002 U/mL) and exceptional specificity for mitochondrial APE1. Notably, it distinguishes high-risk from low-risk neuroblastoma (NB) in vivo without the need for surgically resected or biopsied tissue, while exhibiting favorable biocompatibility. Collectively, C-12S-tFNA enables noninvasive, activity-based mitochondrial APE1 imaging and holds promise for improving precision risk stratification in NB.
    DOI:  https://doi.org/10.1021/acs.analchem.6c04619
  31. Biomacromolecules. 2026 Oct 12. 27(10): 6339-6350
    2-Aminoisobutylic Acid-Stabilized Helical Peptides for Selective Mitochondrial Gene Delivery.
    Kota Nomura, Kayo Terada, Yosuke Murakami, Tomohiro Umeno, Ayaka Tateishi, Makoto Oba, Keiji Numata.
      Efficient gene delivery to mitochondria remains a major challenge in the development of organelle-targeted therapeutics. Here, we report the rational design and evaluation of helix stabilized mitochondria-targeting peptides (MTPs) via the incorporation of 2-aminoisobutyric acid (Aib), a noncanonical residue known to promote helical structure and increase membrane permeability. Three essential peptides were newly synthesized by systematically substituting alanine or glycine residues with Aib in a peptide derived from the mitochondrial outer membrane protein mitoNEET. Structural analyses using molecular dynamics (MD) simulations and circular dichroism (CD) spectroscopy confirmed increased helical content in the Aib-substituted peptides. Compared with the unmodified peptide, the Aib-substituted peptides exhibited significantly increased HeLa cell uptake and mitochondrial localization. Furthermore, conjugation of the designed MTPs with a cationic arginyl-histidine repeat peptide enabled efficient delivery of plasmid DNA into mitochondria, leading to successful expression of mitochondrial-localized reporter genes. These findings demonstrate that Aib-induced helix stabilization is a powerful strategy for increasing mitochondrial gene delivery and provide a versatile platform for peptide-based mitochondrial therapeutics.
    Keywords:  2-aminoisobutyric acid (Aib); drug delivery system; mitochondria-targeting peptides (MTPs); peptide design
    DOI:  https://doi.org/10.1021/acs.biomac.6c00322
  32. Circ Genom Precis Med. 2026 Oct;19(5): e005673
    Pyrophosphatase 2 Deficiency: Clinical Presentation, Diagnosis and Management.
    Hayley Nehoff, Ian Crozier, Hilary Vernon, Christine James, Ana I Fernández-Ávila, Michael Bowes, Esther Gomez-Gonzalez, Colin Phoon, Kristy DiLoreto, Martin E Matsumura, Désirée Y van Haaften-Visser, Cameron Seaman, Matthew R Edwards, Deborah J Morris-Rosendahl, Kathleen Simonetti, Alyssa L Rippert, Rebecca C Ahrens-Nicklas, Cassandra Tormey, Emily Bogush, Aaina Kochhar, Johan L K Van Hove, Alicia M Kamsheh, Bridget A Leone, Saskia B Wortmann, Robert G Weintraub, W Reid Thompson, Eric S Silver, Warren A Zuckerman, John Pearson, Jan Till, Kathryn Chatfield, Amy Goldstein, Robert McFarland, Johannes A Mayr, Kit Doudney.
       BACKGROUND: PPA2 (pyrophosphatase 2) deficiency is a relatively newly recognized condition caused by biallelic variants in the PPA2 gene. The gene encodes the mitochondrial enzyme PPA2, involved in the production of orthophosphate in the mitochondrial matrix. Affected individuals typically present with sudden cardiac death or acute heart failure following common viral illnesses in infants and toddlers, or following exposure to small amounts of alcohol as teenagers. The condition has a high mortality rate in these situations. Here, we explore the clinical presentations and current management of these patients with a view to guiding future emergency clinical management of cases.
    METHODS: Case records from published and unpublished affected individuals diagnosed with PPA2 deficiency were compiled in a retrospective cohort study of genotypes, phenotypes and clinical management protocols in individuals with biallelic (likely) pathogenic PPA2 variants.
    RESULTS: We collated 93 affected individuals from 53 families, 14 of which have not previously been reported. Patient presentation is invariably acute, often associated with fatigue, vomiting, seizures and collapse. Generally, presenting individuals received standard emergency management with cardiopulmonary resuscitation and appropriate management of arrhythmia, and here we present compiled clinical management protocols for emergency and ongoing treatment of PPA2-deficient patients. A pronounced inheritance rate of pathogenic alleles from carrier parents is noted, and further research is warranted to confirm and investigate any selective advantage for gametes carrying pathogenic PPA2 variants.
    CONCLUSIONS: PPA2 deficiency has a high mortality rate following exposure to common childhood viruses in children around and under the age of 3 and in teenagers exposed to ethanol. We have presented current therapeutic approaches gathered from a worldwide survey of clinicians treating their patients, possible pathogenic mechanisms and inheritance peculiarities of the condition and provide a comprehensive review of the current recommendations surrounding patients' clinical management.
    Keywords:  cardiopulmonary resuscitation; fibrosis; mitochondria; pyrophosphatases; vomiting
    DOI:  https://doi.org/10.1161/CIRCGEN.125.005673
  33. Cell Press Blue. 2026 Oct 07. pii: 100129. [Epub ahead of print]
    Context-specific hypermetabolism in humans with mitochondrial defects.
    Evan D Shaulson, Alexander J Sercel, Shannon Rausser, Samantha Leonard, Kathryn Whyte, Faris Zuraikat, Heather Seid, Qiuhan Huang, Alex Junker, Darshana Kapri, Mangesh Kurade, David Shire, Joanna Chen, Caroline Trumpff, Catherine Kelly, Natalia Bobba-Alves, Kris Englestad, Herman Pontzer, Wei Shen, Seth A Creasy, Edward L Melanson, Michael Rosenbaum, Marie-Pierre St-Onge, Dympna Gallagher, Michio Hirano, Martin Picard.
      Pathogenic mitochondrial DNA (mtDNA) defects test how impaired oxidative phosphorylation reshapes human energy expenditure. We studied adults with confirmed mtDNA defects (MitoD) and healthy controls using whole-room indirect calorimetry, doubly labeled water, quantitative magnetic resonance, actigraphy, autonomic monitoring, mood assessments, plasma inflammatory markers, and growth differentiation factor 15 (GDF15). Under behaviorally clamped conditions, fat-free mass-adjusted 24-h energy expenditure (24-h EE) was consistently higher in MitoD, with higher non-resting expenditure per unit wrist acceleration by day, and blunted sleep-related metabolic suppression at night. In contrast, free-living total daily energy expenditure (TDEE) was similar between groups despite lower physical activity in MitoD, consistent with behavioral compensation within a constrained energy budget. Plasma GDF15 was ~5-fold higher in MitoD and tracked with disease severity, systemic inflammation, fatigue, energetic burden, and lower habitual activity. These findings identify a persistent energetic burden in MitoD that is buffered in daily life and associated with elevated GDF15.
    Keywords:  GDF15; doubly labeled water; energy expenditure; fatigue; hypermetabolism; metabolic phenotyping; mitochondrial disease; resting energy expenditure; sickness behavior; whole-room indirect calorimetry
    DOI:  https://doi.org/10.1016/j.cpblue.2026.100129
  34. Stem Cells Int. 2026 ;2026 1130043
    Human Induced Pluripotent Stem Cells in Rare Neurological Disorders: Opportunities and Challenges for Disease Modeling and Drug Discovery.
    Anja Harej Hrkać, Valentino Rački, Andrej Belančić, Jasna Kriz, Dinko Vitezić, Jasenka Mršić-Pelčić, Ganesh Acharya, Mukesh Varshney, Kristina Pilipović.
      Rare disease is a condition that affects a small fraction of the population. In most cases, it has a known genetic cause but could also be associated with other contributing factors. As the affected individuals may exhibit diverse symptoms due to the genetic and phenotypic heterogeneity, non- or misdiagnosis of rare diseases is common. Their low incidence and prevalence present an obstacle to developing new therapies despite a major unmet need with only a few treatment options available. This is particularly relevant to rare neurological disorders as there are major difficulties in studying the mechanisms of initiation and progression of the central nervous system (CNS) disorders. Recent advances in biotechnology, specifically the use of human induced pluripotent stem cells (iPSCs) for modeling diseases, have been instrumental in providing a flexible platform that not only reflects the effects of genetic disturbances on the development of CNS disorders but also is capable of providing insights into complex multifactorial disorders. Whether the human iPSCs are harvested from the affected individuals or using the gene-editing tools on cells from healthy individuals, valuable models can now be made available for studying these orphan conditions. In this narrative review, we explore the benefits of using human iPSC models over the existing platforms of other primary cell lines and animal models for the disease modeling and drug discovery and discuss the limitations and future aspects of the iPSC use in the investigation of rare neurological disorders.
    Keywords:  disease models; genetic heterogeneity; induced pluripotent stem cells; nervous system diseases; rare diseases
    DOI:  https://doi.org/10.1155/sci/1130043
  35. Adv Sci (Weinh). 2026 Oct 18. e78349
    AKAP1 Protects Retinal Ganglion Cells and Preserves Vision by Improving Mitochondrial and Synaptic Health in Glaucomatous Neurodegeneration.
    Tonking Bastola, Keun-Young Kim, Ziyao Shen, Guy A Perkins, Muna Poudel, Yoonjin Lim, Hyejeong Choi, Soo-Ho Choi, Mark H Ellisman, Robert N Weinreb, Won-Kyu Ju.
      Glaucoma, a leading cause of irreversible blindness, is characterized by progressive loss of retinal ganglion cells (RGCs) and lacks effective neuroprotective therapies. Despite evidence implicating mitochondrial dysfunction in glaucoma, the mechanisms linking elevated intraocular pressure, synaptic dysfunction, mitochondrial failure, and RGC death remain incompletely understood. Here we identify the mitochondrial scaffold protein A-kinase anchoring protein 1 (AKAP1) as a critical regulator of RGC resilience in glaucoma. AKAP1 expression is reduced in glaucomatous retinas and correlates with disrupted mitochondrial dynamics, oxidative stress, synaptic impairment, and visual decline. AAV2-mediated restoration of AKAP1 preserves RGC survival and visual function in two independent experimental glaucoma models. These data suggest that retinal AKAP1 promotes mitochondrial fusion, cristae integrity, and bioenergetic capacity in the inner retina and in stressed cultured RGCs, and is accompanied by increased mitochondrial content in presynaptic terminals of the inner plexiform layer. Retinal AKAP1 is further associated with higher PKA abundance, normalized CaMKII and synapsin phosphorylation, preserved synaptophysin, and lower complement C1q and glial activation markers; these associations do not, by themselves, establish causality. These findings identify AKAP1 as a candidate regulator of mitochondrial and synaptic homeostasis and highlight AAV2-AKAP1 gene therapy as a promising neuroprotective strategy for vision preservation in glaucoma.
    Keywords:  biology; cell biology; mitochondrial biogenesis; mitochondrion; neurodegeneration; neuroprotection; neuroscience; retinal ganglion; synaptophysin
    DOI:  https://doi.org/10.1002/advs.78349
  36. Signal Transduct Target Ther. 2026 Oct 20. pii: 458. [Epub ahead of print]11(1):
    Mitophagy coordinates organelle crosstalk in health and diseases.
    Mengyao Wu, Pengyi He, Yajun Lian, Tuo Zhang, Yiqi Wu, Lu Wang, Daolin Tang, Yongming Yao, Renqi Yao.
      Eukaryotic cells contain various membrane- and non-membrane-bound organelles, whose spatial and functional organization underpins intracellular homeostasis. Organelle coordination is governed by complex signaling and metabolic networks, often facilitated by direct physical contacts and molecular exchange. Mitochondria, as central hubs of bioenergetic and metabolic activity, are essential to functional coordination among cellular organelles. They engage in diverse cellular processes, encompassing ATP production, biosynthesis of key metabolites, calcium ion buffering, redox balance, and cellular turnover. To preserve their integrity and functionality, dysfunctional mitochondria undergo selective elimination via mitophagy, a specialized form of macroautophagy. Mitophagy plays dual roles in maintaining mitochondrial fidelity and actively shapes interorganelle communication. Through bidirectional signaling, mitophagy influences the activity of multiple organelles, including the endoplasmic reticulum, nucleus, lysosomes, peroxisomes, and lipid droplets. This interorganelle crosstalk is essential for adapting to metabolic stress, maintaining redox balance, and coordinating cell fate decisions. In this review, we explore the intricate signaling networks connecting mitophagy with various organelles and discuss how these interactions influence organ function and overall cellular health. We also highlight emerging small-molecule modulators of mitophagy, providing insight into potential therapeutic strategies aimed at restoring or enhancing organelle communication in pathological conditions.
    DOI:  https://doi.org/10.1038/s41392-026-02812-3
  37. J Biol Chem. 2026 Oct 21. pii: S0021-9258(26)02533-0. [Epub ahead of print] 113661
    Phosphorylation of the mitochondrial calcium uniporter beta subunit matrix domain locks a conformation that suppresses mitochondrial calcium flux.
    Danielle M Colussi, Zoya Lehman, David Zhuang, Peter B Stathopulos.
      Mitochondrial calcium (Ca2+) uptake is a central regulator of metabolism, signal transduction and cell death pathways. The mitochondrial calcium uniporter complex (mtCU) mediates this flux through a tetrameric pore comprised of MCU and MCU beta (MCUb) subunits. The large, matrix-oriented amino (N)-terminal domains (NTDs) of both paralogs are critical regulatory hubs, responsive to both ion binding and post-translational modifications. Despite high sequence identity between the MCU and MCUb NTDs, we previously identified significant disparities in regulatory ion-binding mechanisms. Further, while phosphorylation of MCU-NTD at Ser92 by protein kinase C (PKC) is known to induce a conformational change that regulates mtCU flux, whether the conserved post-translational modification site on MCUb serves a similar or divergent regulatory role remains unexplored. Here, using a colorimetric phosphate release and phosphoprotein staining assays, solution NMR spectroscopy and LC-MS/MS, we reveal that PKCδ phosphorylates MCUb-NTD at Ser77. Moreover, an S77D phosphomimetic induced structural and molecular dynamics behaviour consistent with the phosphorylated state. Remarkably, the S77D substitution alone was sufficient to drive the MCUb-NTD into a conformation analogous to the Ca2+-bound state, in silico and in vitro, bypassing the requirement for ion binding. This phosphorylation-induced transition exhibited increased thermal stability but weakened hetero-oligomerization with MCU-NTD compared to wild-type. Functionally, MCUb-S77D reduced mitochondrial Ca2+ uptake in HEK293T and HeLa cells without altering colocalization with MCU. Collectively, our results show that Ser77 phosphorylation locks the MCUb-NTD into a Ca2+-insensitive conformation that mimics the Ca2+-bound state, potentiating the suppression of mitochondrial Ca2+ flux.
    DOI:  https://doi.org/10.1016/j.jbc.2026.113661
  38. PLoS One. 2026 ;21(10): e0352911
    Structure bioinformatics of eight human ATP synthase F0 subunits and their AlphaFold3-predicted reduced-hydrophobicity QTY analogues.
    Ziyu Wang, Edward Chen, Shuguang Zhang.
      Human mitochondrial ATP synthase is an essential rotary motor enzyme that produces most of the cellular ATP through oxidative phosphorylation. Its membrane-embedded F0 sector contains highly hydrophobic transmembrane subunits that are challenging to study in aqueous environments without detergents. We applied the QTY code to eight human ATP synthase F0 subunits: ATP6, ATP8, ATPK, ATP68, ATPMK, AT5G1, AT5G2, and AT5G3. Hydrophobic amino acids leucine (L), isoleucine (I), valine (V), and phenylalanine (F) in transmembrane regions were systematically replaced with hydrophilic glutamine (Q), threonine (T), and tyrosine (Y). Four native subunits with available CryoEM structures from human ATP synthase (PDB: 8H9S) were superposed with their AlphaFold3-predicted QTY analogues. For subunits without complete CryoEM structures, AlphaFold3-predicted native structures were superposed with their AlphaFold3-predicted QTY analogues. Additional structural analyses were included, and key structural and functional regions, including ATP68 and the ATP6-c-ring interface, were modeled. The native ATP synthase F0 subunits superposed well with their respective QTY analogues. For the CryoEM-native comparisons, RMSD values ranged from 0.565 Å to 6.952 Å. For the AlphaFold3-native comparisons of subunits without CryoEM structures, RMSD values ranged from 0.204Å to 0.297Å. Considering all eight subunits, despite substantial QTY substitutions in the transmembrane regions, ranging from 38.89% to 50.79%, the QTY analogues retained similar overall folds, molecular weights, and isoelectric points. Hydrophobic surface analysis showed that the QTY analogues had reduced hydrophobic surfaces compared with their native counterparts. These structural bioinformatics studies suggest that the QTY code is applicable to ATP synthase F0 subunits to generate more hydrophilic, water-soluble analogues while preserving overall structural similarity. These results extend the application of the QTY code to the membrane-embedded F0 sector of ATP synthase and provide a foundation for future experimental studies for these QTY analogues expressed, purified, and evaluated for self-assembly.
    DOI:  https://doi.org/10.1371/journal.pone.0352911
  39. Trends Genet. 2026 Oct 21. pii: S0168-9525(26)00242-8. [Epub ahead of print]
    Mitochondrial genome homeodynamics across scales.
    Juan C Landoni, Suliana Manley.
      Mechanisms that maintain the mitochondrial genome, termed mitochondrial DNA homeodynamics, span vastly different spatial and temporal scales. A multiscale framework may help to reconcile seemingly disparate mechanisms, unifying canonical and emerging processes and providing a shared conceptual and mechanistic foundation for future investigations.
    DOI:  https://doi.org/10.1016/j.tig.2026.09.006
  40. Mitochondrion. 2026 Oct 23. pii: S1567-7249(26)00117-0. [Epub ahead of print] 102227
    Grouped but not unified: mechanistic diversity in mitochondrial skeletal disorders.
    N Sushma Sri, Sai Latha Sabbu, Katta M Girisha, Aarti Sevilimedu.
      Mitochondrial disease is a term assigned to a diverse group of genetic disorders caused by impaired mitochondrial function, resulting in defective oxidative phosphorylation and ATP synthesis, with clinical manifestations that affect primarily energy-demanding tissues such as the brain and muscle. However, a subset of these conditions is characterized by prominent primary skeletal manifestations and has been designated Mitochondrial Skeletal disorders (MSDs). Since the initial review of MSDs in 2020, the number of genes in this category has expanded considerably, based on the updated Nosology of Genetic Skeletal disorders (2023) and MitoCarta3.0 (2021). In this review, we evaluate the clinical, genetic and functional evidence supporting the inclusion of the new genes and revisit the question of a shared mechanistic basis underlying this growing subgroup. Clinically, MSDs display pleiotropic and variable phenotypes, including dysplasia, craniofacial abnormalities and growth restriction. Functionally, the implicated proteins perform diverse essential roles in the mitochondria, extending beyond protein homeostasis to include maintenance of mtDNA integrity, mitochondrial metabolism, and membrane dynamics and composition. We hypothesize that these primary mitochondrial defects converge on the downstream activation of mitochondria-driven inflammatory pathways, disrupting osteogenic differentiation and bone formation through key signaling pathways (Wnt and Hedgehog), and transcription factors (RUNX2). However, consolidating this hypothesis will require deeper mechanistic studies using in vivo models, perturbation studies and multi-omic integration, ultimately enabling a more informed path towards the development of targeted therapeutic interventions.
    Keywords:  Genetic skeletal disorder; Inflammation; Mitochondrial dysfunction; Mitochondrial skeletal disorders (MSD); Protein homeostasis; Skeletal dysplasia; mtDNA maintenance and integrity
    DOI:  https://doi.org/10.1016/j.mito.2026.102227
  41. J Med Chem. 2026 Oct 22. 69(20): 23517-23539
    Development of Organocatalytic Switches of OGG1 that Protect Mitochondria under Oxidative Stress.
    Maeve Long, James Tribble, Rahul Upadhyay, Alice Eddershaw, Nicholas D D'Arcy-Evans, Alan Nicol, Sara Cano, Emma Scaletti Hutchinson, Alicia Del Prado, Hannah Stigsdotter, Natálie Rudolfová, Dinesh Nirmalan, Elisée Wiita, Ingrid Almlöf, Richard Svensson, Andreas Krämer, Anas Bitar, Oryn Purewal-Sidhu, Oliver Mortusewicz, Olov Wallner, Opher Gileadi, Evert J Homan, Stefan Knapp, Pawel Baranczewski, Laurie H Sanders, Miguel de Vega, Pål Stenmark, Alexandra Stolz, Thomas Helleday, Michael Sundström, Pete Williams, Maurice Michel.
      Mitochondrial dysfunction is a major component of neurodegeneration. The mitochondrial genome is prone to oxidative damage, and repair proteins are important to maintain mitochondrial DNA integrity. OGG1 initiates base excision repair of oxidative DNA lesions in both nuclear and mitochondrial genomes. While inhibitors of OGG1 have been extensively explored, pharmacological activation of OGG1 through catalytic reprogramming remains underdeveloped. Herein, we report the discovery of mitochondrial enriched organocatalytic switches of OGG1. Biochemical analysis, mutational profiling, and X-ray crystallography confirmed active-site binding and preferential stimulation of β-elimination over glycosylase turnover, effectively reprogramming OGG1. We demonstrate that ORCAs protect mitochondrial function and morphology under oxidative stress, specifically affecting mitochondrial membrane potential and fragment number while attenuating metabolic stress. Mechanistically, ORCAs improved NAD levels in mouse dissociated cortical neurons and provided neuroprotection in a retina axotomy model. Together, the findings position OGG1-ORCAs as potential novel therapies for the treatment of age-related diseases and neurodegeneration.
    Keywords:  DNA glycosylase; OGG1; base excision repair; mitochondrial function; neurodegeneration; organocatalytic switches
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c00526
  42. J Neurosci. 2026 Oct 19. pii: e0291262026. [Epub ahead of print]
    Insulin regulates activity-dependent mitochondrial depolarization and calcium dynamics in dentate granule cells.
    Beatriz Ferrán, Hadyn M Rose, Jenna Gray, Traci L Redwine, Sophia Pham, Oliver Rubin, Heather C Rice, William E Sonntag, Carlos Manlio Díaz-García.
      Systemic insulin resistance is associated with reduced hippocampal energy metabolism and cognitive impairment both in humans and animal models. However, whether insulin rapidly regulates neuronal metabolic stability during activity remains unclear. Here, we examined insulin signaling and queried the corresponding mitochondrial responses in dentate granule cells (DGCs) of adult female mice. This layer of excitatory neurons within the hippocampus plays an essential role in learning and memory. Insulin robustly increased Akt phosphorylation in dentate gyrus tissue when insulin degradation was inhibited, and this response was attenuated by genetic deletion of the insulin receptor in DGCs, consistent with cell-autonomous signaling. We found that insulin did not alter mitochondrial membrane potential at rest, but significantly limited activity-evoked mitochondrial depolarization induced by neuronal stimulation. However, this change had no measurable impact on cytosolic ATP availability and was instead associated with Ca2+ dynamics. Removing Ca2+ ions from the extracellular solution, or disrupting mitochondrial Ca2+ uptake, prevented insulin modulation of the mitochondrial membrane potential. Furthermore, insulin limited cytosolic Ca2+ accumulation through an insulin receptor-dependent mechanism that persisted despite Akt inhibition. Insulin also accelerated the clearance of mitochondrial Ca2+ transients in active neurons, which occurred without changes in either neuronal excitability or pyruvate dehydrogenase phosphorylation. Together, these findings identify endogenous insulin degradation as a key regulator of hippocampal insulin signaling, and reveal a previously unrecognized interaction between insulin and Ca2+ signaling in stimulated DGCs. This work also establishes a direct link between central insulin signaling and the maintenance of mitochondrial electrochemical homeostasis in the adult brain.Significance Statement Insulin signaling is known to influence synaptic plasticity, yet its direct effects on neuronal metabolism remain poorly defined. Here, we show that endogenous insulin degradation limits insulin signaling in adult hippocampal tissue. This finding suggests that inhibitors of the insulin degrading enzyme may hold the potential to improve the efficacy of insulin-based interventions aimed at improving learning and memory. Acute insulin signaling does not modify neuronal excitability, or cytosolic ATP availability. Instead, it stabilizes mitochondrial membrane potential and reduces calcium accumulation in active dentate granule cells. By identifying an insulin-dependent mechanism that regulates the electrochemical homeostasis of mitochondria in active neurons, this work provides insight into how brain insulin resistance may contribute to cognitive dysfunction in aging and neurometabolic disorders.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0291-26.2026
  43. NPJ Parkinsons Dis. 2026 Aug 01. pii: 255. [Epub ahead of print]12(1):
    Machine learning image analysis predicts Parkinson disease genotype and mitochondrial lysosomal abnormalities in iPS neurons.
    Yan Li, Maximilian Powell, Jessica Chedid, Ratneswary Sutharsan, Adahir Labrador-Garrido, Dad Abu-Bonsrah, Chiara Pavan, Tyra Fraser, Dmitry Ovchinnikov, Melanie Zhong, Ryan Davis, Dario Strbenac, Jennifer A Johnston, Lachlan H Thompson, Deniz Kirik, Clare L Parish, Glenda M Halliday, Carolyn M Sue, Nicolas Dzamko, Gautam Wali.
      Mitochondrial and lysosomal dysfunction are central features of Parkinson's disease (PD) across major genetic forms including PRKN, SNCA, and LRRK2. We applied cell morphomics, a machine-learning-based framework combining high-content imaging with quantitative feature extraction, to analyse mitochondrial and lysosomal morphology at single-cell resolution in iPS cell-derived cortical neurons from PD patients and healthy controls (13 lines total). Supervised machine-learning models distinguished PD neurons from controls with high accuracy (AUC = 0.87) and reliably separated individual genotypes. Feature importance and attribution analysis revealed genotype-specific organelle biases in the relative contribution of mitochondrial and lysosomal features, with mitochondrial features dominating classification in PRKN neurons, balanced mitochondrial and lysosomal contributions in SNCA neurons, and a greater lysosomal contribution in LRRK2 neurons. Multi-class models retained strong performance, and findings were reproduced across two independent laboratories using different dyes and imaging conditions. These results demonstrate that morphomics provides a robust and scalable framework to quantify genotype-specific organelle abnormalities in PD neurons and supports its application for cellular stratification and biomarker discovery.
    DOI:  https://doi.org/10.1038/s41531-026-01458-w
  44. J Mol Cell Biol. 2026 Oct 22. pii: mjag043. [Epub ahead of print]
    Impaired ATP7A-Mediated Copper Homeostasis in the Spinal Cord Promotes Morphine Tolerance.
    Haiyue Guo, Fan Hu, Li Wan, Zirui Wang, Mengyao Zhang, Kai Wang, Xianlin Xu, Wentao Liu, Chun-Yi Jiang.
      Morphine tolerance remains a major clinical challenge in pain management, and its underlying mechanisms are still not fully understood. Here, we show that tolerance-inducing morphine administration persistently suppressed the P-type ATPase copper transporter ATP7A, resulting in copper accumulation within spinal dorsal horn neurons and a consequent increase in reactive oxygen species (ROS). Intrathecal delivery of the copper chelator ammonium tetrathiomolybdate markedly attenuated the development of morphine tolerance. Mechanistically, excess cytosolic copper promotes ROS production, leading to mitochondrial dysfunction and elevated mitochondrial ROS generation. Unexpectedly, we found that the transport of copper from the cytosol into mitochondria mitigated morphine-induced ROS accumulation. Pharmacological treatment with DC_AC50, a small molecule that enhances mitochondrial copper delivery by inhibiting the copper-trafficking proteins ATOX1 and CCS, effectively reduced morphine-evoked ROS levels. Conversely, inhibition of the mitochondrial copper chaperone COX17 exacerbated ROS buildup in both cytosolic and mitochondrial compartments following morphine exposure. Collectively, these findings identify spinal copper homeostasis as a previously unrecognized and potentially actionable therapeutic target for mitigating opioid tolerance.
    Keywords:  ATP7A; Copper accumulation; Mitochondria; Morphine tolerance; ROS
    DOI:  https://doi.org/10.1093/jmcb/mjag043
  45. Nephrology (Carlton). 2026 Oct;pii: e70299. [Epub ahead of print]31(10):
    Familial COQ8B-Associated Glomerulopathy: Divergent Long-Term Outcomes and Adult Detection Through Cascade Testing.
    Zeynep Ural, Ülver Derici.
      COQ8B (formerly ADCK4)-associated glomerulopathy is an autosomal recessive primary coenzyme Q10 deficiency that typically presents with proteinuria, focal segmental glomerulosclerosis and progressive kidney dysfunction during childhood or adolescence. We report extended longitudinal follow-up of a family carrying the homozygous COQ8B c.1339dupG, p.(Glu447Glyfs*10) variant, demonstrating marked intrafamilial phenotypic heterogeneity despite an identical genotype. Two homozygous siblings developed kidney failure in childhood or adolescence and underwent living-related kidney transplantation, with prolonged allograft survival and no clinical recurrence of the native disease. In contrast, a third homozygous sibling was identified through cascade testing at age 24 with preserved kidney function and non-nephrotic proteinuria and has remained free of kidney failure for more than 10 years. The fourth sibling, who was heterozygous, remained clinically unaffected and both heterozygous parental donors maintained normal kidney function without proteinuria during long-term follow-up. This family illustrates the broad clinical spectrum of COQ8B-associated glomerulopathy and shows that identical homozygous variants may be associated with markedly divergent long-term kidney trajectories. Cascade testing may identify mildly affected adults before advanced kidney impairment and should be considered an integral component of familial evaluation in genetically defined glomerular disease.
    Keywords:  COQ8B; cascade testing; coenzyme Q10; focal segmental glomerulosclerosis; proteinuria
    DOI:  https://doi.org/10.1111/nep.70299
  46. Neurosci Bull. 2026 Oct 23.
    Spatiotemporal Resolution for Neurodegenerative Diseases: Linking Proteinopathy, Cellular Vulnerability, and Disease Trajectories.
    Mengyuan Dong, Chunrong Wang, Zhao Chen, Siyu Ding, Linliu Peng, Hong Jiang.
      Neurodegenerative diseases (NDs) are a heterogeneous group of disorders characterized by selective and progressive degeneration of specific neuronal populations, often accompanied by glial dysfunction. Despite extensive investigation, proposed pathogenic models remain insufficient to fully explain selective vulnerability and stereotyped spatiotemporal patterns of neurodegeneration across diseases. Spatial omics technologies preserve anatomical context and enable interrogation of cell-type composition, molecular heterogeneity, and intercellular interactions within neural systems. In this review, we synthesize current concepts and technological advances in spatial omics and discuss how these approaches are reshaping our understanding of NDs. Spatial omics provides an integrative framework for linking pathological protein aggregation with selective cellular vulnerability, microenvironment-dependent interactions, and disease progression across molecular, cellular, and anatomical scales. We highlight emerging insights into pathology-associated gene modules, neuron-glia interactions, and mechanisms underlying regional vulnerability. Finally, we discuss multimodal data integration and future directions for translating spatially resolved molecular maps into mechanistic understanding.
    Keywords:  Neurodegenerative diseases; Selective vulnerability; Spatial omics; Spatiotemporal neurodegeneration
    DOI:  https://doi.org/10.1007/s12264-026-01726-y
  47. Extracell Vesicles Circ Nucl Acids. 2026 ;7(3): 1331-1335
    Extracellular vesicles coordinate mitochondrial trafficking between Leydig cells and testicular macrophages to sustain testosterone production.
    Marco G Alves, Ruben J Moreira, Ana Gabriela Henriques, Rita Ferreira, Pedro F Oliveira.
      
    DOI:  https://doi.org/10.20517/evcna.2026.61
  48. ACS Chem Biol. 2026 Sep 18. 21(9): 2441-2450
    Copper Nanoparticles Enable Multi-Compartment Cuproenzyme Metalation in Cellular Models of Copper Deficiency.
    Harman Kaur, John Soukar, Nikita Gudekar, Vinit C Shanbhag, Michael J Petris, Akhilesh K Gaharwar, Vishal M Gohil.
      Copper (Cu) is an essential trace element that serves as a cofactor for enzymes involved in diverse metabolic pathways and processes across multiple subcellular compartments. Mutations that cause systemic or subcellular Cu deficiency result in fatal pediatric disorders, including Menkes disease and related mitochondrial disorders. Treatment of these disorders requires pharmacological agents that can transport Cu across membranes; however, the only approved drug, Cu histidinate, shows limited efficacy. Using genetic models of Menkes disease, we recently demonstrated that the Cu ionophore elesclomol (ES) efficiently restores the activity of mitochondrial and cytosolic cuproenzymes, but its ability to metalate cuproenzymes within secretory compartments is low. To overcome this limitation, we investigated Cu nanoparticles (Cu-NPs) as a facile means of delivering Cu to multiple subcellular compartments simultaneously. Cu-NPs were synthesized by chemical reduction to produce spherical nanoparticles with an average size of 80 nm. Biophysical characterization of Cu-NPs revealed zero-valent Cu and a neutral zeta potential, compatible with biological interactions and in vivo circulation. In cellular models of Cu deficiency, Cu-NPs were shown to internalize via clathrin-mediated endocytosis and restore the activity of cuproenzymes in mitochondrial, cytosolic, and secretory compartments. Importantly, biomarkers of Cu toxicity were not activated under these conditions, indicating a favorable therapeutic index. Overall, these findings highlight Cu-NPs as versatile Cu delivery agents with therapeutic potential for Cu deficiency disorders.
    DOI:  https://doi.org/10.1021/acschembio.6c00564
  49. Adv Exp Med Biol. 2026 ;1359 533-543
    Pulse SILAC Approaches to the Measurement of Cellular Dynamics.
    Justin Snider, Daifeng Wang, Daniel F Bogenhagen, John D Haley.
      The global measurement of assembly and turnover of protein-containing complexes within cells has advanced with the development of pulse stable isotope labelled amino acid approaches. Stable isotope labeling with amino acids in cell culture (SILAC) allows the incorporation of "light" 12-carbon amino acids or "heavy" 13-carbon amino acids into cells or organisms and the quantitation of proteins and peptides containing these amino acid tags using mass spectrometry. The use of these labels in pulse or pulse-chase scenarios has enabled measurements of macromolecular dynamics in cells, on time scales of several hours. Here, we review advances with this approach and alternative or parallel strategies. We also examine the statistical considerations impacting datasets detailing mitochondrial assembly, to highlight key parameters in establishing significance and reproducibility.
    DOI:  https://doi.org/10.1007/978-3-032-29437-1_32
  50. iScience. 2026 Nov 20. 29(11): 117722
    Overexpression of endoplasmic reticulum acetyl-CoA transporter AT-1 alters neuronal metabolism, growth, and synaptic activity.
    Eric R McGregor, Cassandra J McGill, Nicholas L Arp, Josef P Clark, Dominique A Baldwin, Yusi Cui, Alexander Nassar, Di Kuang, Gonzalo Fernandez-Fuente, Yun Hwa Choi, Keenan S Pearson, Jason K Nagorski, Lingjun Li, Judith A Simcox, Jing Fan, Luigi Puglielli, Rozalyn M Anderson.
      Acetyl-CoA is a molecule central to cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 mutations have been linked to peripheral neuropathy, developmental delay with premature death, and intellectual disability with progeria. Here, we show that AT-1 overexpression impacts diverse phenotypes related to neuronal function and plasticity. Differences in ribosomal, synaptic processing, and metabolic pathways were identified at transcriptomic and proteomic levels. Metabolic adaptations included changes in mitochondrial membrane potential, architecture, and respiration, and tracing experiments revealed changes in the fate of glucose favoring glycogen storage over the pentose phosphate pathway. Altered redox was linked to NAD-dependent proteins SIRT1 and CtBP2. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization. Metabolic adaptation was coincident with decreased synaptic activity, indicating that neuronal communication is coordinated, in part, through acetyl-CoA metabolism.
    Keywords:  acetyl-CoA; glucose utilization; lipids; metabolism; mitochondria; neuron
    DOI:  https://doi.org/10.1016/j.isci.2026.117722
  51. Biochim Biophys Acta Mol Basis Dis. 2026 Oct 21. pii: S0925-4439(26)00371-6. [Epub ahead of print]1873(2): 168505
    Mitochondrial pharmacology of cardiovascular and antidiabetic drugs: Mechanistic basis of cardioprotection and cardiotoxicity in the diseased heart.
    Gino A Kurian.
      Mitochondrial function is a central determinant of cardiomyocyte survival, yet mitochondrial pharmacology remains under-integrated into cardiovascular and antidiabetic drug classification, safety assessment, and therapeutic decision-making. Many cardiometabolic drugs exert direct or indirect effects on mitochondrial bioenergetics, redox balance, calcium handling, quality control, and genome stability effects that can confer protection in some contexts while precipitating toxicity in others. In diseased myocardium, where mitochondrial reserve is constrained by ischemia, metabolic stress, ageing, or heart failure, these drug-mitochondria interactions frequently dictate clinical benefit or harm beyond the nominal drug class. This review synthesises the mitochondrial actions of widely used cardiovascular and antidiabetic therapies, including statins, renin-angiotensin-aldosterone system inhibitors, β-blockers, metformin, sodium-glucose cotransporter-2 inhibitors, and incretin-based agents, across acute and chronic exposure windows. We integrate key mechanistic domains encompassing electron transport chain modulation, redox and cofactor reprogramming, calcium permeability transition coupling, mitochondrial dynamics, mitophagy, and stress signalling, and relate these signatures to clinically relevant cardiometabolic disease contexts. We propose a unifying framework in which mitochondrial reserve capacity and quality control competence function as the central decision node determining whether pharmacologic mitochondrial engagement is adaptive or injurious. Finally, we outline principles for mitochondria-conscious prescribing, risk stratification, and drug development, and propose that systematic incorporation of mitochondrial endpoints into clinical trials and safety pipelines is essential for advancing precision cardiometabolic therapy.
    Keywords:  Antidiabetic therapies; Cardiometabolic drugs; Cardiovascular pharmacology; Mitochondrial bioenergetics; Mitochondrial dysfunction; Mitochondrial quality control; Precision cardiometabolic medicine
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168505
  52. Front Physiol. 2026 ;17 1958014
    Mitochondrial remodeling in heart failure with reduced ejection fraction.
    Xin Chen.
      Extensive mitochondrial remodeling occurs during heart failure with reduced ejection fraction (HFrEF), yielding either protective adaptations that mitigate dysfunction or detrimental alterations that accelerate disease progression. Central to this remodeling are maladaptive metabolic reprogramming, featured by aberrant fuel preference and electron transport chain deficiency, which underlie the depletion of bioenergetic reserves. Concurrently, alterations in reactive oxygen species (ROS)-producing sites and antioxidant system elevate mitochondrial ROS production while diminishing ROS scavenging capacity, fostering a progressively deteriorating redox environment that perpetuates mitochondrial dysfunction. Additional maladaptive changes, including impaired mitochondrial biogenesis, fission-biased mitochondrial dynamics, mitophagy dysregulation, increased mitochondrial membrane permeability, and activation of pro-inflammatory responses, further disrupt mitochondrial homeostasis and exacerbate cardiac injury. Conversely, remodeling of the mitochondrial Ca2+ transport system provides adaptive restriction of mitochondrial Ca2+, conferring protection against apoptosis. In this review, I will summarize recent evidence demonstrating the molecular and pathophysiological mechanisms related to mitochondrial remodeling in HFrEF. I will delineate the signaling axes and factors that mediate distinct mitochondrial functions and specify how they are remodeled during the progression of heart failure. Different HFrEF etiologies are associated with distinct mitochondrial pathologies, and these will be comprehensively reviewed. I will also discuss the therapeutic potential of mitochondrial targeting in preclinical models and how these insights are translated into novel clinical strategies to improve heart failure management.
    Keywords:  electron transport chain; heart failure; metabolic reprogramming; mitochondrial dynamics; mitochondrial membrane permeability transition; mitochondrial remodeling; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3389/fphys.2026.1958014
  53. Nat Rev Neurol. 2026 Oct 19.
    Multi-organ imaging genetics: towards an integrated view of brain, body and brain diseases.
    Zirui Fan, Bingxin Zhao.
      Population-based cohorts that combine genetic data with whole-body multimodal imaging are transforming how we map the genetic architecture of the brain in its broader bodily context. Historically, imaging genetics has focused largely on single organs, especially the brain, with separate efforts targeting the heart, skeleton and other organs for systemic diseases, and limited integration across organ systems. Yet, strong brain-body interactions and the high multimorbidity of brain and systemic diseases highlight the need for a brain-centred multi-organ perspective. Here we introduce the emerging field of brain-focused multi-organ imaging genetics, outlining key data resources and interdisciplinary analytical frameworks for large-scale multi-organ genetic discovery and reviewing the genetic associations between brain diseases and imaging phenotypes across organ systems. We discuss how these advances support a whole-body integrated view of brain health and disease and how they are beginning to reshape clinical translation for neurological conditions. We outline a roadmap for agentic artificial intelligence co-scientists that work alongside human researchers throughout the scientific discovery process, arguing that such systems will be essential for achieving an integrated understanding of brain health and disease, both as tools for individual researchers and as a collaborative infrastructure for the whole field.
    DOI:  https://doi.org/10.1038/s41582-026-01276-x
  54. Cell Struct Funct. 2026 Oct 20.
    Proteostasis stress alters mitochondrial levels and localization of SOD2 during cellular senescence.
    Yasuhiro Takenaka, Masataka Hirasaki, Yoshihiko Kakinuma.
      Proteostasis decline is a hallmark of aging and contributes to stress-induced premature senescence (SIPS) through proteotoxic stress and mitochondrial dysfunction. Although mitochondria-derived reactive oxygen species (ROS) are critically involved in SIPS, the behavior of nuclear-encoded mitochondrial antioxidant proteins under proteostasis impairment remains poorly understood. Here, we investigated the dynamics of superoxide dismutase 2 (SOD2) during SIPS induced by the proteasome inhibitor MG132 or the lysosomal inhibitor bafilomycin A1 (BAFA1) in human fibroblasts. Both MG132 and BAFA1 induced cellular senescence and caused an early reduction of SOD2 protein levels in the mitochondrial fraction without a corresponding decrease in SOD2 mRNA or total cellular SOD2 protein levels. Immunofluorescence analysis revealed that SOD2 was partially dissociated from mitochondria under these conditions, indicating impaired mitochondrial localization rather than decreased protein abundance. Quantitative colocalization analysis confirmed a significant reduction in SOD2-mitochondria overlap, which was partially restored by short-term co-treatment with antimycin A (AA), a mitochondrial electron transport chain inhibitor that attenuates excessive ROS production. Furthermore, mislocalized SOD2 was frequently associated with aggregate-like structures, and biochemical analyses demonstrated an increase in high-molecular-weight SOD2-containing complexes under proteostasis stress. These findings suggest that proteostasis disruption is associated with early changes in the intracellular distribution and aggregate-associated accumulation of SOD2, leading to a transient reduction of mitochondrial SOD2 and potentially contributing to mitochondrial oxidative imbalance and the progression of cellular senescence.Key words: cellular senescence, MnSOD, SOD2, mitochondria, oxidative stress, proteostasis, MG132, proteasome.
    Keywords:  MG132; MnSOD; SOD2; cellular senescence; mitochondria; oxidative stress; proteasome; proteostasis
    DOI:  https://doi.org/10.1247/csf.26039
  55. J Inflamm Res. 2026 ;19 645321
    Mitochondrial Metabolic Reprogramming in Macrophages: A Key Driver of Rheumatoid Arthritis.
    Jingjing Zhao, Fuwei Pan, Guangshuai Nie, Fuzeng Zheng, Lin Wang, Chongtao Han.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovitis and progressive cartilage and bone destruction. Synovial macrophages are central coordinators of inflammatory signaling, stromal activation, and osteoclastogenesis, yet their pathogenic functions cannot be explained by extracellular cytokine networks alone. Increasing evidence indicates that macrophage activation is coupled to cell-intrinsic mitochondrial metabolic reprogramming. Within the hypoxic, nutrient-variable, and inflammatory RA synovium, macrophages undergo coordinated changes in glycolysis and oxidative phosphorylation, tricarboxylic acid cycle flux, mitochondrial reactive oxygen species production, fission-fusion dynamics, mitophagy, and mitochondrial DNA homeostasis. These alterations reshape bioenergetics while generating metabolites and organelle-derived danger signals that engage hypoxia-inducible factor 1α, nuclear factor-κB, the NOD-like receptor family pyrin domain-containing 3 inflammasome, and cyclic GMP-AMP synthase-stimulator of interferon genes signaling. The resulting metabolic-inflammatory circuits can stabilize pathogenic macrophage states and propagate inflammation to fibroblast-like synoviocytes, endothelial cells, and osteoclast-lineage cells. This review integrates current evidence on macrophage heterogeneity, mitochondrial remodeling, and intercellular signaling in RA. We further evaluate mitochondria-targeted antioxidants, metabolic modulation, restoration of mitochondrial quality control, inhibition of mitochondrial danger-signal sensing, and multistage nanodelivery. Particular emphasis is placed on evidence strength, macrophage-subset specificity, and the distinction between disease-driving abnormalities and compensatory adaptations. Finally, we outline the biomarkers, human-tissue validation, spatial multi-omics, and delivery strategies required to translate macrophage mitochondrial immunometabolism into precision therapy for RA.
    Keywords:  immunometabolism; mitochondrial metabolism; mitochondrial quality control; rheumatoid arthritis; synovial macrophages; targeted therapy
    DOI:  https://doi.org/10.2147/JIR.S645321
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