bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–10–18
57 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial protein import stress in Parkinson's disease: the TOM/TIM-PINK1/Parkin-DELE1/HRI axis linking mitochondrial proteostasis to neuronal death.
  2. Simultaneous Measurement of Mitophagic Flux and Mitochondrial Morphology During Myogenesis.
  3. SPRIZ (CCDC127) protein conserved in deuterostome animals is a rigid OMM-IMM tether that locally sets mitochondrial IMS volume.
  4. Himito: a graph-based toolkit for mitochondrial genome analysis using long reads.
  5. Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
  6. The mitochondrial epigenome and noncoding genome in aging and brain diseases.
  7. Clinical spectrum and genotype-phenotype correlations of MT-CYB-associated mitochondrial disease: from the m.15045G > A variant to the broader disease landscape.
  8. A dedicated motif in human polymerase gamma enables DNA synthesis through replication roadblocks.
  9. Unprecedented atlas explores mitochondria across the tree of life.
  10. ATAD-3 couples plasma membrane injury to mitochondrial Ca2+ signaling.
  11. After delivery: How recipient cells shape the fate and function of transplanted mitochondria.
  12. NAD+ signaling in Parkinson's disease: molecular mechanisms and therapeutic perspectives.
  13. Age, metabolites, and diagnostic discrimination in mitochondrial disease.
  14. Ketogenic Dietary Therapies and β-Hydroxybutyrate as Modulators of Mitochondrial Function: From Molecular Mechanisms to Clinical Translation.
  15. RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.
  16. Mitochondrial apoptosis imaged by high-throughput confocal microscopy.
  17. Modeling human neurodegeneration with iPSCs: opportunities, limitations, and the challenge of aging.
  18. Mitochondria strike two hits to drive the SASP.
  19. Quiescence to proliferation transition regulates asynchronous mitochondrial DNA replication dynamics.
  20. An ALLO-1-associated network links mitochondrial quality control to functional recovery in structurally compromised muscle.
  21. Dynamic protein phosphorylation shapes mitochondrial catalysis, import, and architecture.
  22. Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.
  23. A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone-PPAR signaling.
  24. Tryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1-HSPA9 complex.
  25. Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.
  26. Mechanisms of lipid droplet-mitochondria interactions and their roles in diseases.
  27. Sevoflurane-linked Mitochondrial Disease: Comment.
  28. Tailored Amino Acid Treatment for Pediatric Patients With Mitochondrial Aminoacyl-tRNA Synthetase Deficiencies.
  29. KCNQ1 disruption alters human neuronal development through mitochondrial and insulin signalling pathways.
  30. Quantification of Mitochondrial Oxidative Phosphorylation in Skeletal Muscle.
  31. Mitochondrial Psychobiology.
  32. Mitochondrial dysfunction and PANoptosis-related signaling in acute central nervous system injuries: mechanistic convergence and therapeutic opportunities.
  33. Mitochondria Beyond Bioenergetics: Canonical and Non-Canonical Functions in Ischemic Stroke and Aging.
  34. Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age-Related Bioenergetic Remodeling, and Microglial STING Phenotypes.
  35. Measuring Skeletal Muscle Mitochondrial Architecture in 3D Using Focused Ion Beam Scanning Electron Microscopy (FIB-SEM).
  36. Mitochondrial stress induces transcription of cytosolic and mitochondrial protein synthesis components via NHR-180.
  37. Bulk Differentiation of Human Induced Pluripotent Stem Cells into Contractile Skeletal Muscles.
  38. The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation.
  39. Local ROS and inefficient autophagosome formation limit Optineurin-mediated mitophagy in neurons.
  40. MFN2-associated astrocyte dysfunction contributes to neuronal hyperexcitability and depressive-like behaviors.
  41. Free Mitochondrial DNA and Mitophagy Dysfunction in Diabetic Kidney Disease: A Central Mitochondrial-Inflammatory Axis Driving Progressive Renal Injury.
  42. Muscle stem cells produce a protective Fibrillin-1 matrix to prevent precocious activation.
  43. Novel Compound Heterozygous ATAD3A Variants in Harel-Yoon Syndrome With Congenital Cataracts and Dilated Cardiomyopathy.
  44. Engineering Functional Skeletal Muscle Tissues from Human Induced Pluripotent Stem Cells.
  45. Pleuroparenchymal fibroelastosis in a monogenic mitochondrial DNA depletion syndrome.
  46. Mitochondrial Calcium Uptake Promotes Mitochondrial Activation and Hyperactivated Motility During Human Sperm Capacitation.
  47. Targeting ALCAT1 Ameliorates Cardiomyopathy in Barth Syndrome.
  48. Bidirectional Crosstalk Between cGAS-STING and Necroptosis: From Mitochondrial DNA Release to Inflammatory Disease.
  49. The malonyl-CoA synthetase ACSF3 is required for metabolic editing downstream of biotin carboxylation.
  50. Disease-associated mutations directionally modulate epigenetic age in iPSC-derived tissues.
  51. The role of mitochondrial DNA and RNA in promoting liver disease pathogenesis.
  52. Mitochondrial Dysfunction Across Renal Compartments in Diabetic Kidney Disease.
  53. Neuronal fatty acid bioenergetics: An emerging pathway and potential point in convergence in hereditary spastic paraplegias.
  54. A PPARγ-like signalling axis integrates lipid homeostasis and mitochondrial quality control to preserve neuronal integrity.
  55. Revisiting Inherited Metabolic Diseases (IMDs) Through the Lens of Selective Autophagy.
  56. Reprogramming the Rossmann fold signature motif creates orthogonal redox biocatalysts.
  57. Optimized RNA-seq workflow for routine diagnosis of mitochondrial diseases using aberrant expression analysis and phenotype-driven prioritization.
  1. Front Cell Dev Biol. 2026 ;14 1935788
    Mitochondrial protein import stress in Parkinson's disease: the TOM/TIM-PINK1/Parkin-DELE1/HRI axis linking mitochondrial proteostasis to neuronal death.
    Bo Pang, Xin Li, Yunlong Sun, Lin Ding.
      Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but how impaired mitochondrial homeostasis drives the selective death of dopaminergic neurons is still poorly understood. At the center of this problem lies the mitochondrial protein import machinery-the TOM and TIM23 translocases-which doubles as a stress-sensing hub that coordinates two distinct quality control pathways. When import is compromised, the kinase PINK1 accumulates on the mitochondrial surface, recruits Parkin to ubiquitinate outer membrane proteins, and triggers mitophagy. Meanwhile, the stress sensor DELE1 is cleaved and released to the cytosol, where it activates the HRI kinase to phosphorylate eIF2α and engage the integrated stress response (ISR). These two pathways are not independent. Recent work shows they engage in antagonistic crosstalk: the DELE1-HRI-ISR axis suppresses PINK1/Parkin-dependent mitophagy by preserving mitochondrial import efficiency, acting as a molecular brake on organelle clearance. The balance between these pathways is governed by the SIFI E3 ubiquitin ligase complex, which targets both DELE1 and HRI for degradation. Disruption of SIFI causes progressive neurodegeneration in humans. Here we synthesize the structural, biochemical, and genetic evidence that defines the TOM/TIM-PINK1/Parkin-DELE1/HRI signaling axis, examine how its dysregulation contributes to dopaminergic neuron vulnerability, and evaluate therapeutic strategies targeting mitochondrial import stress in PD.
    Keywords:  DELE1; HRI; PINK1; Parkinson’s disease; integrated stress response; mitochondrial protein import; mitophagy; parkin
    DOI:  https://doi.org/10.3389/fcell.2026.1935788
  2. Methods Mol Biol. 2026 ;3057 189-200
    Simultaneous Measurement of Mitophagic Flux and Mitochondrial Morphology During Myogenesis.
    Fasih A Rahman, Joe Quadrilatero.
      Mitophagy is the selective degradation of mitochondria via autophagy and is essential for maintaining mitochondrial quality and cellular homeostasis as well as being required for skeletal muscle differentiation and myogenesis. While traditional techniques such as immunoblotting, electron microscopy, and live-cell imaging provide valuable insights, they often offer only static or indirect measurements of mitophagy. Mitophagy flux assays capture dynamic turnover events and are, therefore, more informative. In this chapter, we present a streamlined method for monitoring and measuring mitophagic flux in C2C12 myoblasts during differentiation. Further, this approach allows for simultaneous quantification of mitochondrial morphology, providing a powerful platform for studying mitochondrial quality control in vitro.
    Keywords:  Adenovirus; Fluorescence mitophagy reporter; Mitochondrial network analysis; Mitochondrial quality control; Mitochondrial remodeling; Mitophagic flux; Mitophagy; Myogenesis
    DOI:  https://doi.org/10.1007/978-1-0716-5396-8_15
  3. Sci Adv. 2026 Oct 16. 12(42): eaef3522
    SPRIZ (CCDC127) protein conserved in deuterostome animals is a rigid OMM-IMM tether that locally sets mitochondrial IMS volume.
    Raman Shulinski, Roman Loban, Danny Farhat, Benjamín Cartes-Saavedra, Matthew J Magda, Pavel Kotchetkov, Victoria Caminiti, Linda David, Yuri I Wolf, Conor O'Dwyer, Morgan Fullerton, Yan Burelle, Jyh-Yeuan Eric Lee, Andrea Raimondi, Eugene V Koonin, György Hajnóczky, Mary-Ellen Harper, Luca Pellegrini.
      The double-membrane nature of mitochondria generates an intermembrane volume through which ions, reactive oxygen species, and metabolites must flux to reach the matrix or cytosol, but whether this volume is a genetically specified structure remains unknown. We identify SPRIZ (spatial regulator of the intermembrane zone), the product of Ccdc127, a gene conserved across deuterostome animals. SPRIZ assembles into an ∼18-nanometer homodimeric tether anchored in the outer mitochondrial membrane (OMM) and inserted into the inner mitochondrial membrane (IMM) through vertebrate-specific hydrophobic loops, physically spacing the two membranes and setting local intermembrane volume. Cryo-electron tomography of native mitochondria revealed rod-like densities spanning the intermembrane space (IMS), consistent with SPRIZ's predicted rigid coiled-coil architecture and membrane-spanning topology. In mouse liver, two-dimensional morphometry measured ∼3-fold expansion of IMS area with SPRIZ and ∼5.5-fold with lengthened mitochondrial artificial increaser of the IMS (MARTINI); 3D electron tomography confirmed MARTINI's greater OMM-IMM separation and normalized IMS volume. This expansion was functionally validated by increased 14C-mannitol accessibility to the IMS and by impaired mitochondrial Ca2+ uptake. Constitutive Ccdc127/SPRIZ knockout produced viable mice and, in liver mitochondria, preserved overall ultrastructure but caused modest IMS expansion, consistent with loss of local OMM-IMM constraints that stabilize membrane geometry at discrete sites. We therefore identify IMS volume as a genetically encoded and tunable architectural parameter of vertebrate mitochondria. In this model, SPRIZ is a molecular spacing system that locally sets OMM-IMM separation, shaping the environment through which metabolites, ions, and signals diffuse and establishing local gradients within the IMS.
    DOI:  https://doi.org/10.1126/sciadv.aef3522
  4. Nat Commun. 2026 Sep 10. pii: 10668. [Epub ahead of print]17(1):
    Himito: a graph-based toolkit for mitochondrial genome analysis using long reads.
    All of Us Research Program Long Read Working Group
      Understanding the genetic and epigenetic regulation of mitochondrial DNA (mtDNA) is essential for elucidating mechanisms of aging and disease. Long-read sequencing can span the mitochondrial genome and capture base-modification signals, yet analytical tools remain limited. We developed Himito, a graph-based toolkit for analyzing mitochondrial genome using long reads. Himito filters reads originating from nuclear mitochondrial insertions (NUMTs), constructs a sequence graph to represent mtDNA diversity, assembles primary haplotypes, calls variants, and analyzes 5-methylcytosine (5mC) modifications within a unified framework. Benchmarking on reference datasets shows Himito achieves superior performance in assembly and variant calling compared with existing tools. Applied to the All of Us (AoU) v8 dataset, Himito identified pathogenic mtDNA variants, revealed population-scale haplogroup diversity, and uncovered age-related genetic and epigenetic patterns. These results demonstrate that long-read sequencing, combined with graph-based analysis, enables integrated characterization of mitochondrial genomic and epigenomic variation. Himito is available at https://github.com/broadinstitute/Himito .
    DOI:  https://doi.org/10.1038/s41467-026-77418-y
  5. J Cell Sci. 2026 Oct 01. pii: jcs265172. [Epub ahead of print]139(19):
    Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
    Marina R Hanna, James Costanzo, Madison Yarbrough, Melanie Gil, Matthew Murrow, Vivian Gama.
      Myeloid cell leukemia 1 (MCL-1) is a canonical anti-apoptotic protein crucial for early neurodevelopment. Loss of MCL-1 results in embryonic-lethal neurodevelopmental defects that cannot be rescued by other anti-apoptotic proteins of the B cell lymphoma 2 (BCL-2) family. Here, we pharmacologically inhibit MCL-1 in human neural progenitor cells and find non-apoptotic roles for MCL-1 in sustaining mitochondrial cristae integrity, fatty acid oxidation and neural progenitor identity. MCL-1 inhibition disrupts mitochondrial ultrastructure, leading to a swollen network with disorganized cristae and destabilized OPA1-MICOS machinery that fails to maintain inner mitochondrial membrane architecture. These structural defects are accompanied by displacement of ACSL1 from the outer mitochondrial membrane, impaired fatty acid oxidation, lipid droplet accumulation and reduced mitochondrial oxygen consumption, revealing a tight link between cristae architecture and metabolic competence. Mechanistically, MCL-1 acts through two coordinated functions: maintaining cristae integrity at the inner mitochondrial membrane and retaining ACSL1 at the outer mitochondrial membrane, both independently of caspase activation. Functionally, MCL-1 inhibition selectively depletes intermediate progenitor cells without affecting proliferation, indicating a direct role in lineage progression. Together, our findings position MCL-1 upstream of OPA1, MICOS and ACSL1, and identify it as a critical coordinator of cristae organization, lipid metabolism and neural progenitor fate. This establishes mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlights non-canonical MCL-1 functions as critical regulators of human brain development.
    Keywords:  ACSL1; Cristae; Intermediate progenitors; MCL-1; MICOS; Mitochondria; Neural progenitor cells; OPA1
    DOI:  https://doi.org/10.1242/jcs.265172
  6. Trends Neurosci. 2026 Oct 10. pii: S0166-2236(26)00189-X. [Epub ahead of print]
    The mitochondrial epigenome and noncoding genome in aging and brain diseases.
    Abd-El-Monsif A Shawky, Hui-Ting Huang, Dhruv Parikh, Kahlilia C Morris-Blanco.
      The mitochondrial genome is a dynamic regulatory platform that extends far beyond its protein-coding capacity. Mitochondrial DNA (mtDNA) harbors epigenetic modifications and produces diverse noncoding RNAs that influence mitochondrial function and cellular homeostasis. Evidence from animal models and human studies indicates that mtDNA methylation, mitochondrial-encoded noncoding RNAs, and cytosolic release of mitochondrial nucleic acids regulate transcription, metabolism, and stress signaling. Furthermore, these mechanisms are altered in aging, neurodegenerative disease, and acute brain injury. In this review, we synthesize emerging insights into how the mitochondrial epigenome and noncoding genome shape mitochondrial function and serve as regulatory interfaces linking cellular stress and neuronal vulnerability in brain aging and disease.
    Keywords:  DNA methylation; double-stranded RNA; long noncoding RNAs; mecciRNAs; mitochondrial epigenetics; neurodegenerative disease
    DOI:  https://doi.org/10.1016/j.tins.2026.09.007
  7. Front Neurosci. 2026 ;20 1968308
    Clinical spectrum and genotype-phenotype correlations of MT-CYB-associated mitochondrial disease: from the m.15045G > A variant to the broader disease landscape.
    Zimeng He, Tongyue Li, Chaolong Xu, Yang Liu, Ying Zou, Zhimei Liu, Jiatong Xu, Xuejing Kang, Huafang Jiang, Danmin Shen, Yunxi Zhang, Hui Xiong, Fang Fang.
       Aim: To characterize the clinical and molecular features associated with the MT-CYB m.15045G > A variant and investigate the clinical spectrum and genotype-phenotype relationships of MT-CYB-associated mitochondrial disease.
    Methods: We performed comprehensive clinical, metabolic, histopathological, genetic, and mitochondrial functional analyses in a patient carrying the m.15045G > A variant. A systematic literature review of previously reported disease-associated MT-CYB variants was conducted, followed by genotype-phenotype comparisons and unsupervised hierarchical clustering integrating clinical, genetic, and functional characteristics.
    Results: The patient presented with exercise intolerance, borderline intellectual functioning, and elevated medium and long-chain acylcarnitines. Muscle biopsy showed mitochondrial myopathic changes, and respiratory chain analysis demonstrated isolated complex III (CIII) deficiency. The m.15045G > A variant showed tissue-specific heteroplasmy of 22.5, 70.5, and 95.5% in blood, urine, and muscle, respectively, providing further evidence for its pathogenicity. Among 34 patients with disease-associated MT-CYB variants, mitochondrial myopathy (MM) was the most common phenotype (50.0%). Patients with MM showed a later age at onset, and muscle-restricted variants were markedly enriched in the MM group (p < 0.001). In contrast, muscle heteroplasmy level, variant type, and isolated CIII deficiency were not significantly associated with phenotype. Hierarchical clustering showed 88.2% concordance with clinical phenotype classification.
    Conclusion: Our findings provide further evidence for the pathogenicity of m.15045G > A and broaden its associated clinical and metabolic features. Tissue-specific distribution of MT-CYB variants showed an association with clinical phenotype, while other genetic and functional factors may collectively contribute to phenotypic variability.
    Keywords:  MT-CYB gene; complex III (cytochrome bc1 complex); genotype–phenotype correlation; m.15045G > A; mitochondrial disease; mitochondrial myopathy
    DOI:  https://doi.org/10.3389/fnins.2026.1968308
  8. bioRxiv. 2026 Sep 28. pii: 2026.09.27.754746. [Epub ahead of print]
    A dedicated motif in human polymerase gamma enables DNA synthesis through replication roadblocks.
    Samuel Miguez-Amil, Araceli Grande-García, Plaza G A Ismael, María Moreno-Morcillo, Ester Casajús-Pelegay, Emma Arean-Ulloa, Carlos Chacón-Sánchez, Grzegorz L Ciesielski, Borja Ibarra, Rafael Fernandez-Leiro.
      Mitochondrial DNA (mtDNA) maintenance is essential for cellular homeostasis, and defects in mtDNA replication are linked to a broad spectrum of mitochondrial diseases. During replication, DNA polymerase γ (Polγ) must traverse duplex junctions and stable secondary structures, yet how the human enzyme overcomes these barriers remains incompletely understood. Here, cryo-electron microscopy structures of Polγ bound to forked DNA, G-quadruplex (G4)-containing DNA and DNA bound to mitochondrial single-stranded DNA-binding protein (mtSSB) reveal a common template-entry path along the catcher domain across distinct substrate and active-site configurations. Within this domain, an arginine-rich helix containing R1026, R1030 and R1034 constitutes a Template Stabilising Motif (TSM). Biochemical reconstitution and DNA-binding experiments show that disrupting the TSM selectively impairs strand displacement, RNA-DNA hybrid displacement and synthesis through G4-forming sequences, while largely preserving synthesis on unstructured templates. Single-molecule optical-tweezers experiments further show that mechanical destabilisation of the fork partially restores mutant strand-displacement activity, whereas force or mtSSB restores primer-extension kinetics on ssDNA templates. Together, these findings establish the role of the TSM in maintaining productive template engagement and identify template stabilisation as a common mechanism enabling Polγ to traverse structurally diverse barriers in mtDNA.
    DOI:  https://doi.org/10.64898/2026.09.27.754746
  9. Nature. 2026 Oct 16.
    Unprecedented atlas explores mitochondria across the tree of life.
    Miryam Naddaf.
      
    Keywords:  Cell biology; Drug discovery
    DOI:  https://doi.org/10.1038/d41586-026-03195-9
  10. Nat Commun. 2026 09 10. pii: 10690. [Epub ahead of print]17(1):
    ATAD-3 couples plasma membrane injury to mitochondrial Ca2+ signaling.
    Shiqi Xu, Yi Peng, Hengda Zhou, Xuecong Ren, Xin Wang, Zhenguang Ying, Meijiao Li, Yujie Sun, Bing Yang, Mao Zhang, Chonglin Yang, Weirui Ma, Suhong Xu.
      Mitochondrial Ca2+ uptake couples cellular Ca2+ signals to mitochondrial metabolism and stress responses and is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here, we identify an ATAD-3-dependent mechanism that promotes mitochondrial Ca2+ uptake following plasma membrane injury in C. elegans. Living imaging reveals robust, albeit delayed, mitochondrial Ca2+ influx following injury in mcu-1 mutants, indicating the existence of a compensatory Ca2+ uptake mechanism. RNAi screen identifies the conserved AAA+ ATPase ATAD-3 as an essential regulator of this pathway, whereas MICU-3 acts as a negative regulator. Wounding induces ATAD-3 oligomerization and mitochondrial enrichment, which are enhanced in mcu-1 mutants. Disrupting ATAD-3 oligomerization or expression of disease-associated ATAD-3 variants abolishes wounding-induced mitochondrial Ca2+ uptake. Structure modeling predicts that oligomeric ATAD-3 adopts a channel-like architecture. These findings uncover ATAD-3 as a context-dependent regulator of mitochondrial Ca2+ homeostasis during cellular stress and provide insight into how this process may be disrupted in disease.
    DOI:  https://doi.org/10.1038/s41467-026-77690-y
  11. Clin Transl Med. 2026 Oct;16(10): e70857
    After delivery: How recipient cells shape the fate and function of transplanted mitochondria.
    Zhi-Yuan Zhang, Bo-Quan Qin, Shi-Zhou Wu, Hui Zhang.
       BACKGROUND: Mitochondrial transplantation is built on a simple idea: failing cells might be rescued by healthy mitochondria. The approach has entered early clinical testing, and encapsulation and cell-type targeting have improved uptake in selected systems. Better delivery, however, does not explain the therapy.
    MAIN BODY: Internalised donor mitochondria encounter an established network, quality-control machinery and sensors for mitochondrial material. Donor material may remain in the endolysosomal system or reach the cytosol. Cytosolic fates include network integration, clearance and a candidate functional contribution without fusion. Intracellular processing may also generate bioactive cargo. These fates imply different mechanisms and evidence requirements. This Review examines how recipient cells shape the contribution of internalised mitochondria, while recognising extracellular routes to benefit. We distinguish direct transplantation evidence from mechanistic support drawn from endogenous mitochondrial biology and natural intercellular transfer. The required donor fate and duration depend on the therapeutic task. Transient rescue may rely on short-term donor function or productive processing in specific models; sustained support may depend on continued donor function, recipient adaptation or redosing. Durable mitochondrial DNA (mtDNA) correction requires donor-mtDNA retention and replication.
    CONCLUSIONS: Linking these tasks to product design, safety assessment and clinical endpoints shifts the question from how many mitochondria enter cells to what they accomplish after arrival.
    KEY POINTS: Recipient-cell handling shapes what transplanted mitochondria do after uptake. Uptake, structural integration and donor mitochondrial DNA retention require distinct evidence. Transient rescue, sustained support and durable mitochondrial DNA correction impose different requirements. Therapeutic goals should guide donor selection, product testing and clinical endpoints.
    Keywords:  endosomal escape; heteroplasmy; innate immunity; mitochondrial fusion; mitochondrial transplantation; mitophagy; translational medicine
    DOI:  https://doi.org/10.1002/ctm2.70857
  12. Front Neurol. 2026 ;17 1943801
    NAD+ signaling in Parkinson's disease: molecular mechanisms and therapeutic perspectives.
    Tianbao Wang, Xue Zhou, Xinhua Chen.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accumulation of α-synuclein (α-syn), mitochondrial dysfunction, and neuroinflammation. Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme involved in cellular energy metabolism, DNA repair, and epigenetic regulation, declines with aging and is markedly reduced in the brains of patients with PD. Emerging evidence suggests that supplementation with NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), exerts neuroprotective effects through multiple mechanisms, such as activation of the mitochondrial unfolded protein response (UPR∧mt), enhancement of autophagy, and suppression of excessive poly(ADP-ribose) polymerase 1 (PARP1) activation. This review summarizes the central role of NAD+ dysregulation in the pathogenesis of PD, with particular emphasis on the interplay between NAD+ depletion, mitochondrial quality control, proteostasis, and neuroinflammation. Furthermore, we discuss recent advances in NAD+-boosting strategies in PD models and clinical studies, highlighting their potential therapeutic implications for PD intervention.
    Keywords:  NAD+; Parkinson's disease; mitochondrial quality control; neuroprotection; nicotinamide riboside
    DOI:  https://doi.org/10.3389/fneur.2026.1943801
  13. Mol Genet Metab. 2026 Oct 05. pii: S1096-7192(26)00571-8. [Epub ahead of print]149(3): 110288
    Age, metabolites, and diagnostic discrimination in mitochondrial disease.
    Didem Tatar, Ercan Yılmaz, Nezihe Köker Özer.
      
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110288
  14. Nutrients. 2026 Oct 02. pii: 3256. [Epub ahead of print]18(19):
    Ketogenic Dietary Therapies and β-Hydroxybutyrate as Modulators of Mitochondrial Function: From Molecular Mechanisms to Clinical Translation.
    Ji-Hoon Na, Young-Mock Lee.
      Ketogenic dietary therapies (KDTs) have been used for a century in drug-resistant epilepsy, and β-hydroxybutyrate (BHB), the major ketone body, is recognized as a signaling metabolite. This review examines how KDTs and BHB modulate mitochondrial function and evaluates evidence supporting these mechanisms. BHB is oxidized through D-β-hydroxybutyrate dehydrogenase 1 and succinyl-CoA:3-oxoacid-CoA transferase and alters redox balance and oxidative phosphorylation. It also inhibits class I histone deacetylases, serves as the substrate for lysine β-hydroxybutyrylation, activates hydroxycarboxylic acid receptor 2, and blocks the NLR family pyrin domain-containing 3 inflammasome. These pathways influence redox defense, organelle quality, and inflammation. However, ketogenic feeding suppresses mitochondrial one-carbon metabolism and some signaling effects occur only at BHB concentrations exceeding those typically achieved through dietary ketosis. Clinical benefits are best established in drug-resistant epilepsy and appear genotype-dependent in primary mitochondrial disease, with potential benefit in mitochondrial DNA (mtDNA) variant carriers but possible harm in DNA polymerase gamma-related disease and mtDNA deletion myopathy. Outside neurology, human evidence includes a hemodynamic response to infused 3-hydroxybutyrate in heart failure, sustained glycemic improvement in non-randomized diabetes cohorts, and small trials in psychiatric and oncological populations. Most clinical studies have not directly measured mitochondrial outcomes. Proposed mitochondrial mechanisms of KDTs and BHB remain plausible but are not established explanations for clinical benefit. Genotype-stratified trials, ketone exposure assessment, and direct measurement of mitochondrial variables in patients are needed.
    Keywords:  3-hydroxybutyric acid; diet; drug resistant epilepsy; histone deacetylase inhibition; ketogenic; ketone ester; lysine β-hydroxybutyrylation; mitochondria; mitochondrial diseases
    DOI:  https://doi.org/10.3390/nu18193256
  15. EMBO Mol Med. 2026 Oct 14.
    RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.
    Alba Pesini, Maria J Sanchez-Quintero, Carlos Lopez-Gomez, Eliana Barriocanal-Casado, Agustin Hidalgo-Gutierrez, Eva Nyvltova, Joanna Rorbach, Giulio Kleiner, May T Ting, Christian Garcia, Lucia Dec-Prat, Kurenai Tanji, Christopher B Damoci, Robert McFarland, Robert W Taylor, Michal Minczuk, Antoni Barrientos, Catarina M Quinzii.
      Pathogenic, bi-allelic variants in RMND1 typically manifest as an early-onset multisystemic mitochondrial disease, yet the consequences of RMND1 dysfunction in vivo remain poorly understood. To answer this question, we generated and characterized the first in vivo model of RMND1-related disease, carrying the recurrent p.(Asn238Ser) variant. Homozygous Rmnd1N238S mice exhibit growth defect, premature mortality, and a multisystem phenotype marked by widespread tissue-dependent defects in oxidative phosphorylation assembly and activity. Quantitative proteomic analysis of Rmnd1N238S heart revealed extensive metabolic remodeling, with significant alterations in the abundance of mitoribosomal proteins and factors associated with mitoribosome maturation. Selected changes in mitoribosomal protein abundance were also observed in Rmnd1N238S liver, and RMND1 mutant and depleted human cells. Despite these changes, sucrose-gradient sedimentation did not reveal a gross alteration in mtSSU, mtLSU, or 55S distribution, suggesting that RMND1 dysfunction perturbs mitoribosomal protein homeostasis that could affect late-assembly stages of the mitochondrial ribosome large subunit. Together, our findings establish Rmnd1N238S mice as a robust in vivo model of RMND1-related disease and provide a framework for understanding how RMND1 supports mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s44321-026-00534-1
  16. Sci Data. 2026 Oct 15. pii: 1427. [Epub ahead of print]13(1):
    Mitochondrial apoptosis imaged by high-throughput confocal microscopy.
    Lina Hellwig, Felix J Meigel, Harald Stachelscheid, Steffen Rulands, Philipp Mergenthaler.
      Mitochondrial programmed cell death (i.e. intrinsic apoptosis) is regulated through the formation of pro-apoptotic protein complexes at the mitochondrial outer membrane (MOM), which permeabilize the MOM and commit the cell to die. This step is modulated by mitochondrial dynamics. To capture this, we treated cells with the mitochondrial dynamics inhibitor M1 before inducing apoptosis with actinomycin D (ActD), and imaged them by high-throughput spinning-disk confocal microscopy. In mouse embryonic fibroblasts (MEFs) we followed apoptosis by long-term live-cell imaging, and in human induced pluripotent stem cells (hiPSCs) we stained fixed cells for the pro-apoptotc protein BAX at mitochondria. Here, we provide a description of these two large-scale microscopy datasets. Dataset 1 contains 637,632 images of MEFs imaged as time series after labelling of mitochondrial morphology and integrity with the mitochondrial membrane potential-sensitive dye tetramethylrhodamine-ethylester (TMRE) and apoptosis with Annexin V-FITC. The dataset also contains a digital phase contrast channel which can be useful to track cells. Dataset 2 contains 9,504 images of hiPSCs with immunofluorescence labelling of BAX and COX IV. The datasets are made available through the BioImage Archive repository.
    DOI:  https://doi.org/10.1038/s41597-026-08502-7
  17. J Clin Invest. 2026 Oct 15. pii: e209602. [Epub ahead of print]136(20):
    Modeling human neurodegeneration with iPSCs: opportunities, limitations, and the challenge of aging.
    Shijie Wang, Lisa Elia, Weiyi Liu, Steven Finkbeiner.
      Most neurodegenerative diseases reflect patient-specific combinations of polygenic risk variants interacting with aging and environmental factors, rather than a single causative mutation. Phase III clinical trial failure rates for neurodegenerative indications exceed 95%, reflecting in part the limitations of existing preclinical systems to fully model the human genetic context of disease. Patient-derived induced pluripotent stem cells (iPSCs) have the potential to address this shortcoming by faithfully recapitulating human cell biology and preserving each patient's complete genetic architecture. This Review examines iPSC-based models of neurodegeneration across three themes. First, we discuss mechanisms revealed by these models, from convergent pathways uncovered by familial mutations to early evidence that sporadic disease biology is accessible at sufficient cohort scale. Second, we evaluate culture systems from 2-dimensional monocultures to organoids, examining how increasing complexity expands addressable biological questions while introducing trade-offs. Third, we address the aging problem: reprogramming erases epigenetic signatures of donor aging, removing the cellular context in which late-onset sporadic neurodegeneration emerges. We discuss strategies approximating aging in iPSC-derived neurons and highlight direct conversion strategies that preserve native epigenetic age, enabling access to age-dependent phenotypes. We propose a framework matching model systems to biological questions, improving mechanistic understanding and therapeutic development.
    DOI:  https://doi.org/10.1172/JCI209602
  18. Dev Cell. 2026 Oct 14. pii: S1534-5807(26)00358-8. [Epub ahead of print]61(10): 1945-1946
    Mitochondria strike two hits to drive the SASP.
    Jun Bum Park, Zhixun Dou.
      Senescent cells develop a persistent inflammatory signature with broad consequences for tissue function and disease. Martini et al.1 show that mitochondrial citrate metabolism drives inflammation through a pathway that acts independently of mitochondrial DNA-driven immune signaling yet cooperates with it to amplify the inflammatory response.
    DOI:  https://doi.org/10.1016/j.devcel.2026.09.010
  19. Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2602028123
    Quiescence to proliferation transition regulates asynchronous mitochondrial DNA replication dynamics.
    Kiyoshi Miyagawa, Noriko Hosoya.
      Each human cell contains hundreds to thousands of mitochondrial DNA (mtDNA) copies, only a small fraction of which replicates independently of the cell cycle. An asynchronous replication of the leading and lagging strands has been proposed to represent a major replication mode in mitochondria, complicating the investigation of mechanisms that regulate mtDNA replication. Using single-DNA-molecule analysis that distinguishes the origins and timing of replication of each strand, we show that the mitochondrial DNA replication machinery responds to the transition from quiescence to proliferation by dynamically dissociating strand-specific replication rates and modulating the physiological requirements for factors involved in replication and transcription. During this response, the requirement for mitochondrial RNA polymerase (POLRMT) in replication initiation increases, whereas that for primase-polymerase (PrimPol), which is thought to function in DNA repriming at DNA lesions, eventually decreases. Thus, precise quantification of mtDNA replication rates at the single-strand level reveals the temporally dynamic nature of the mtDNA replication machinery during the transition from quiescence to proliferation.
    Keywords:  asynchronous replication; mitochondrial DNA; quiescence
    DOI:  https://doi.org/10.1073/pnas.2602028123
  20. Commun Biol. 2026 Oct 06. pii: 1348. [Epub ahead of print]9(1):
    An ALLO-1-associated network links mitochondrial quality control to functional recovery in structurally compromised muscle.
    Anwesha Sarkar, Lilla Biriczová, Natalia A Szulc, Pankaj Thapa, Remigiusz Serwa, Wojciech Pokrzywa.
      Muscle function can recover before damaged contractile structures are fully repaired, but the mechanisms enabling this recovery remain poorly understood. Using a temperature-sensitive Caenorhabditis elegans model of UNC-45 dysfunction, in which impaired myosin chaperoning triggers muscle proteotoxic stress and reversible paralysis, we show that coordinated movement recovers while sarcomere disorganisation persists. Quantitative proteomics identified ALLO-1, a selective-autophagy receptor previously characterised for paternal organelle clearance during embryogenesis, as induced during recovery from UNC-45dependent muscle stress. Functional and proteomic analyses revealed an ALLO-1-associated regulatory network comprising IKKE-1, SIP-1, DIM-1 and CAR-1 that modulates mitochondrial stress responses and muscle recovery. Loss of ALLO-1 or its associated factors altered mitochondrial homoeostasis and delayed functional recovery, whereas muscle-specific ALLO-1a restoration improved recovery, preserved mitochondrial network integrity, and modulated mitochondrial turnover despite reduced respiratory capacity. These findings identify ALLO-1 as a regulator of mitochondrial stress adaptation that enables functional recovery before completing structural repair.
    DOI:  https://doi.org/10.1038/s42003-026-11093-z
  21. bioRxiv. 2026 Sep 29. pii: 2026.09.28.755151. [Epub ahead of print]
    Dynamic protein phosphorylation shapes mitochondrial catalysis, import, and architecture.
    Andrew J Smith, Patrick Forny, Sean W Rogers, Merima Forny, David J Pagliarini.
      Phosphorylation is a pervasive mitochondrial protein post-translational modification, yet the extent of its influence over mitochondrial functions remains unclear. To identify dynamic mitochondrial phosphoisoforms, we profiled the phosphoproteome of AML12 cells following individual genetic perturbations of 10 resident mitochondrial phosphatases. Guided by these results, we investigated the functional implications of phosphorylation on mitochondrial processes related to catalysis, import, and morphology. We find that phosphorylation of adenylate kinase 2 suppresses its nucleotide binding and catalytic activity. Elevated phosphorylation proximal to the mitochondrial targeting sequence of branched chain ketoacid dehydrogenase kinase disrupts its import and processing, resulting in enhanced catabolism of branched chain amino acids. Most notably, we discover extensive phosphorylation on proteins involved in mitochondrial cristae architecture, including multiple members of the MICOS complex and ATP synthase, upon silencing the phosphatase PGAM5. Collectively, our work connects reversible phosphorylation and resident phosphatases to the regulation of diverse mitochondrial processes.
    HIGHLIGHTS: Perturbation of 10 mitochondrial resident phosphatases maps dynamic phosphosites.AK2 S151 phosphorylation tunes catalysis by augmenting adenine nucleotide binding.MTS-proximal BCKDK phosphorylation impairs protein import and gates BCAA catabolism.MIC19 and ATP5I phosphorylation remodels cristae and modulates bioenergetics.
    DOI:  https://doi.org/10.64898/2026.09.28.755151
  22. Nat Metab. 2026 Oct 14.
    Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.
    Xingxiu Pan, Austin L Zuckerman, Karl N Miller, Marcos G Teneche, Subrata Munan, Andrew Pon, Niklas B Thompson, Rasangi M Perera, Roya AminiTabrizi, Adarsh Rajesh, Sara Violante, Jiwu Wang, Justin R Cross, Peter D Adams, Hardik Shah, Valentin Cracan.
      An elevated NADH/NAD+ ratio (NADH-reductive stress) is a hallmark of mitochondrial dysfunction, yet how it drives pathologies ranging from primary mitochondrial disorders to ageing remains poorly understood1,2. Here, we show that mitochondrial respiratory chain inhibition in primary human fibroblasts induces NADH-reductive stress that coexists with profound NADPH depletion. Using the Escherichia coli soluble transhydrogenase (EcSTH)3 to model this redox coupling in cells with intact mitochondria, we demonstrate that perturbation of both NAD(H) and NADP(H) redox pairs elicits metabolomic and transcriptomic reprogramming, culminating in proliferation arrest with senescence features. Notably, normalizing the NADH/NAD+ ratio alone while NADPH depletion persists fails to rescue proliferation in EcSTH-expressing primary human cells, unlike in transformed HeLa cells. Stable isotope tracing reveals that primary fibroblasts rely more on NADPH-driven reductive carboxylation than HeLa cells, explaining why NADH/NAD+ normalization alone is insufficient for rescue. To test this NADPH dependency, we develop a constitutively active Staphylococcus aureus NAD kinase (SaNADK) that expands the mammalian NADP(H) pool. In fibroblasts, SaNADK restores reductive carboxylation and de novo pyrimidine biosynthesis, and reverses proliferation arrest and senescence features. Furthermore, hepatic SaNADK expression in aged male mice partially alleviates transcriptional signatures of inflammation and metabolic dysregulation. Together, these findings establish EcSTH and SaNADK as xenotopic tools for dissecting NAD(P)H redox coupling and provide a framework for counteracting ageing-associated metabolic decline.
    DOI:  https://doi.org/10.1038/s42255-026-01640-7
  23. Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2619615123
    A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone-PPAR signaling.
    Kentaro Hirose, Xiaoxin Chen, Chakrapani Kalyanaraman, Mark T Waddingham, Makoto Nakamura, Feng Zhang, Christina Chen, Shun Yao, Steven Chang, Hongyao Yu, Jiajia Wang, Emanuele Barca, Haruko Nakano, Austin Hsu, Sheamin Khyeam, Sara Gonzalez Ortega, Kazuki Tajima, Takeshi Yoneshiro, Hao Zhang, Arun Padmanabhan, Shingo Kajimura, Saptarsi Haldar, Atsushi Nakano, Masatoshi Murai, Yoshitaka Fujihara, Kinya Otsu, Catarina M Quinzii, Matthew P Jacobson, Guang Hu, James T Pearson, Guo N Huang.
      Increased mitochondrial biogenesis and aerobic respiration in postnatal mammalian organs are essential for adaptation to extrauterine life, yet the functions of many tissue-enriched, developmentally regulated mitochondrial proteins remain poorly defined. By integrating mitochondrial proteome annotations with mouse and human transcriptomic datasets, we identified Coenzyme Q10a (Coq10a), a striated muscle-enriched mitochondrial protein, as a regulator of postnatal cardiac growth. Coq10a, the mammalian homolog of the yeast ubiquinone-binding protein Coq10p, is highly induced in the heart after birth through thyroid hormone-, Nkx2.5-, and Tbx5-dependent regulation. To define its physiological function, we generated three independent Coq10a-deficient mouse models. Both global and cardiomyocyte-specific loss of Coq10a promoted postnatal cardiac hypertrophy without impairing basal cardiac function or mitochondrial respiration. Instead, Coq10a deficiency altered intracellular ubiquinone partitioning, resulting in increased ubiquinone accumulation in a microsomal membrane fraction. Transcriptomic analyses revealed enrichment of PPAR-associated metabolic gene sets and induction of established PPAR-responsive genes in Coq10a-deficient hearts. Pharmacological inhibition of PPARα and PPARγ, but not PPARδ, attenuated the hypertrophic phenotype. Molecular dynamics simulations, docking analyses, and mutagenesis identified PPARα residues that contribute to differential responsiveness to ubiquinone. Although Coq10a-deficient hearts maintained near-normal function under basal conditions, they exhibited increased susceptibility to pressure-overload stress. Together, these findings establish Coq10a as a regulator of intracellular ubiquinone partitioning and support a model linking altered mitochondrial lipid distribution and PPAR-associated signaling to postnatal cardiac growth. More broadly, they demonstrate how tissue-enriched mitochondrial proteins can mediate organ-specific physiological functions beyond energy production.
    Keywords:  Coq10a; PPAR signaling; cardiac hypertrophy; mitochondria; ubiquinone
    DOI:  https://doi.org/10.1073/pnas.2619615123
  24. Nat Chem Biol. 2026 Oct 16.
    Tryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1-HSPA9 complex.
    Rachel E Hayward, Raymond F Berkeley, Zijian Gao, Maximilian Garhammer, Marc A Morizono, Evert Njomen, Haoxin Li, Kristen E DeMeester, Victor Cociorva, Mark A Herzik, F Ulrich Hartl, Bruno Melillo, Benjamin F Cravatt.
      Activity-based protein profiling has identified hundreds of human proteins from diverse classes that react at cysteine residues with stereochemically defined electrophilic compounds (stereoprobes). The structure-activity relationships underlying these stereoprobe-protein interactions, however, remain poorly understood. Here, we show that the protein interaction landscape of tryptoline acrylamide stereoprobes can be profoundly altered by structural modifications distal to the acrylamide reactive group. Most stereoprobe liganding events occurred at nonorthosteric sites and evaded assignment by the machine learning-based cofolding model Boltz-2, which instead tended to misplace stereoprobes in orthosteric pockets (an outcome we term 'orthostery burnout'). We found that stereoprobes reacting with C124 in the nucleotide exchange factor GRPEL1 disrupt interactions with the mitochondrial HSP70 chaperone HSPA9/mortalin, leading to impairments in mitochondrial protein import and mitophagy induction. Our results highlight tryptoline acrylamides as a versatile source of covalent ligands targeting nonorthosteric sites on proteins, including tool compounds that perturb the mitochondrial HSP70 chaperone system.
    DOI:  https://doi.org/10.1038/s41589-026-02348-1
  25. Biochem Pharmacol. 2026 Oct 13. pii: S0006-2952(26)00887-7. [Epub ahead of print] 118545
    Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.
    Zhi-Yuan Zhang, Bo-Quan Qin, Shi-Zhou Wu, Hui Zhang.
      Neurons must sustain functional mitochondria far from the cell body. Mitofusin 2 (MFN2), a dynamin-like large guanosine triphosphatase (GTPase), coordinates outer mitochondrial membrane remodeling with axonal transport, bioenergetic support, inter-organelle communication, and stress-responsive quality control. Studying these activities separately obscures how disruption of one protein produces diverse neuronal phenotypes. We propose a testable conformational-allocation framework in which molecular state distributions and transition kinetics bias MFN2 participation across cellular outputs. Integrating structural and functional evidence, we distinguish experimentally resolved mechanisms from working models. Variants associated with Charcot-Marie-Tooth disease type 2A (CMT2A) are compared by the molecular step or functional output affected. Fusion loss alone does not capture this mechanistic diversity. Structure-guided docking supports local compatibility at a shallow, conformationally conditional C-terminal surface, without establishing native accessibility, affinity, or therapeutic response. CMT2A provides the strongest context for intervention, combining causal genetics, direct mitofusin engagement studies, and multiscale rescue. Amyotrophic lateral sclerosis (ALS) provides secondary preclinical evidence, whereas Alzheimer's and Parkinson's diseases remain exploratory. The mitofusin pathway is chemically tractable, but paralog selectivity and state-dependent target engagement remain unresolved. A state- and variant-informed strategy may better match intervention to the affected output than indiscriminate enhancement of fusion.
    Keywords:  Axonal transport; Charcot–Marie–Tooth disease type 2A; Conformational allocation; Mitochondrial dynamics; Mitofusin 2; Pharmacological modulation
    DOI:  https://doi.org/10.1016/j.bcp.2026.118545
  26. Pharmacol Res. 2026 Oct 14. pii: S1043-6618(26)01592-6. [Epub ahead of print]233 109677
    Mechanisms of lipid droplet-mitochondria interactions and their roles in diseases.
    Yang Ding, Xiao-Hong Xie, Yang-Kun Li, Zhen-Hua Xiao, Zong-Bao Wang, Lin-Xi Chen, Shu-Zhi Wang.
      Lipid droplets (LDs) coordinate cellular lipid utilization, energy homeostasis, redox balance, and autophagy through dynamic inter-organelle communication with mitochondria. This review summarized recent advances in the molecular mechanisms regulating LD-mitochondria interactions and discusses how their dysregulation contributes to disease progression. Accumulating evidence has indicated that the contacts between LD and mitochondria are dynamically regulated through specialized membrane contact sites and protein complexes, such as Perilipin (PLIN) family of proteins, Mitofusin2 (Mfn2), and Rab GTPases. Rather than being a passive structural association, this interaction serves as a regulatory hub that integrates fatty acid (FA) transport, metabolic adaptation, and stress responses. It enables bidirectional regulation of lipid metabolism, allowing cells to flexibly and efficiently switch between lipid storage and FA oxidation in response to metabolic signals. Disruption of this inter-organelle communication impairs intracellular lipid utilization, compromises mitochondrial function, and exacerbates oxidative stress and ferroptosis. Such dysfunction is increasingly recognized as a core mechanism underlying metabolic disorders, cardiovascular diseases and neurodegenerative diseases. In the future, integration of protein regulation, gene editing technologies, and precision therapeutic approaches may enable specific targeting of LD-mitochondria communication, thereby offering new avenues for the treatment of relevant diseases.
    Keywords:  Cardiovascular diseases; Lipid droplet; Metabolic diseases; Mitochondria; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.phrs.2026.109677
  27. Anesthesiology. 2026 Oct 12.
    Sevoflurane-linked Mitochondrial Disease: Comment.
    José Luis Ramírez, Antonieta Mahfoud, Liliana Casique, Alexander Canache, Anahy Jimenez, Emirjes Maza.
      
    DOI:  https://doi.org/10.1097/ALN.0000000000006328
  28. J Inherit Metab Dis. 2026 Nov;49(6): e70254
    Tailored Amino Acid Treatment for Pediatric Patients With Mitochondrial Aminoacyl-tRNA Synthetase Deficiencies.
    I J J Muffels, G Kok, Z Tang, L S Medeiros, F O Poswar, W P Vermeij, R Rodenburg, K Smit, S K Sukumaran, S B Wortmann, L Averdunk, J Munch, J Pak-Lam Ho, A M K Kwok, E E S Nieuwenhuis, P M van Hasselt, I V D Schwartz, C M A Lubout, A M Bosch, K Koop, E M M Hoytema van Konijnenburg, S A Fuchs.
      Aminoacyl-tRNA synthetases (ARSs) facilitate the loading of transfer RNAs with their cognate amino acids in the cytosol (ARS1), mitochondria (ARS2), or both (dual ARS). ARS deficiencies are clinically heterogeneous and can cause severe, occasionally fatal disease. Supplementation with cognate amino acids to prevent local amino acid depletion has shown promise in ARS1 deficiencies, but its potential in ARS2 deficiencies remains largely unexplored. We investigated the effects of cognate amino acid depletion on mitochondrial function in fibroblasts from seven patients with ARS2 deficiencies using Seahorse respirometry and imaging flow cytometry. During amino acid depletion, patient fibroblasts showed decreased mitochondrial membrane potential and reduced basal and maximal respiratory capacity. We additionally evaluated oral cognate amino acid supplementation in nine patients with SARS2, EARS2, LARS2, WARS2, FARS2, or VARS2 deficiencies. Supplementation was well tolerated, with no adverse effects observed. Several patients showed clinical improvements during treatment, including improved development, increased growth, and/or improved cardiac function. In two patients, treatment discontinuation coincided with severe neurological regression. Together, these findings demonstrate that assessing mitochondrial function during cognate amino acid depletion provides a novel functional assay for ARS2 deficiencies that may aid variant interpretation and supports a biological rationale for cognate amino acid supplementation. Clinical supplementation was well tolerated and showed preliminary beneficial effects. These findings support further investigation of cognate amino acid supplementation as a potential supportive treatment strategy for patients with ARS2 deficiencies.
    Keywords:  amino acid supplementation; aminoacyl‐tRNA synthetase deficiency; genetic disease; metabolic disorder; mitochondrial disease; seahorse
    DOI:  https://doi.org/10.1002/jimd.70254
  29. Commun Biol. 2026 Oct 13. pii: 1341. [Epub ahead of print]9(1):
    KCNQ1 disruption alters human neuronal development through mitochondrial and insulin signalling pathways.
    Dorothea Schall, Baran E Güler, Siamand Alibrahim, Mahmudul Hasan, Naeem Ahmad, Joanna Widomska, Claudio Acuna, Mairéad Sullivan, Ralph Röth, Chang Liu, Linda Blaier, Katalin Vincze, Karin Burau, Simone Macri, Daniela Mauceri, Marcin Luzarowski, Ágota Apáti, János M Réthelyi, Geert Poelmans, Gudrun A Rappold, Barbara Franke, Jeffrey C Glennon, Simone Berkel.
      KCNQ1 encodes a voltage-gated potassium channel implicated in peripheral and neurological disorders, but its role in human neurodevelopment remains unclear. We generated KCNQ1 knockout (KO) human induced pluripotent stem cells and differentiated them into neural stem cells (NSCs) and cortical neurons. KCNQ1-deficient NSCs show impaired neurite outgrowth, linked to reduced cell adhesion and disrupted neural cell adhesion molecule signalling, a phenotype reproduced by pharmacological KCNQ1 inhibition. Multi-omics and follow-up analyses reveal mitochondrial dysfunction, including reduced mitochondrial copy number and ATP synthase expression. KO cells also show impaired insulin signalling, with diminished insulin receptor gene expression and altered RAS-MAPK and PI3K-AKT pathways. In differentiated neuronal cultures, KCNQ1 loss decreases synaptic activity and maintains an immature transcriptional profile. Together, these findings identify a role for KCNQ1 in regulating cell adhesion, mitochondrial function, insulin signalling, and neuronal maturation, expanding our understanding of processes that may contribute to neurological manifestations associated with KCNQ1-related disorders.
    DOI:  https://doi.org/10.1038/s42003-026-11111-0
  30. Methods Mol Biol. 2026 ;3057 201-223
    Quantification of Mitochondrial Oxidative Phosphorylation in Skeletal Muscle.
    Aditya N Brahmbhatt, Christopher G R Perry.
      Mitochondrial oxygen consumption stimulated by ADP and inorganic phosphate is often measured as an index of ATP synthesis derived from oxidative phosphorylation. This measurement is typically performed by monitoring the rate at which oxygen disappears from a solution containing isolated mitochondria or either intact or permeabilized cells and tissue. Termed "respirometry," this method has become increasingly popular in numerous research disciplines focused on cellular metabolism, including the broader field of skeletal muscle physiology. Here, we describe how respirometry is performed in permeabilized skeletal muscle fiber bundles. This technique involves mechanically separating skeletal muscle fibers followed by exposure to a cell membrane-permeabilizing agent (e.g., saponin). This technique is thought to preserve the mitochondrial network, morphology, and interactions with surrounding intracellular structures. The method can be performed on small tissue samples and permits flexibility in designing substrate titration protocols to target specific mitochondrial pathways.
    Keywords:  Mitochondria; Permeabilized fibers bundles; Polarographic oxygen sensor; Respirometry; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-1-0716-5396-8_16
  31. Neurosci Biobehav Rev. 2026 Oct 13. pii: S0149-7634(26)00494-X. [Epub ahead of print] 107036
    Mitochondrial Psychobiology.
    Ana C Andreazza, Alexander Behnke, Juan P Bolanos, Jaime de Juan-Sanz, Elissa Epel, Michele K Evans, Lisa Feldman Barrett, Lauren E Gyllenhammer, Yusuke Hirabayashi, Michio Hirano, Fiona Hollis, D Parker Kelly, Christopher Kempes, Iris-Tatjana Kolassa, Nick Lane, Mary Kay Lobo, Lilianne R Mujica-Parodi, Aoife O'Donovan, Dost Ongur, Martin Picard, Sarah D Pressman, Carmen Sandi, Orian Shirihai, Caroline Trumpff, Lukas Van Oudenhove, Tor D Wager.
      A field that uses mitochondria to unify biological and psychological sciences and to better understand the basis of health has emerged-Mitochondrial Psychobiology. Mitochondria are the body's cellular hubs for energy transformation and signaling. Mitochondria regulate functions as diverse as metabolism, gene expression, and stress adaptation; consequently, their dysregulation is linked to most chronic illnesses and aging. Here, we propose that mitochondria provide a mechanistic bridge between body and the measurable functions of the mind, including perception, cognition, emotion, and behavior. From this perspective, mitochondria provide a scientifically tractable interface through which bioenergetic processes relate to subjective experiences and behaviors. We outline foundational principles for Mitochondrial Psychobiology, discuss the key gaps that the field needs to address to advance our understanding of mind-mitochondria relationships across the lifecourse, and review emerging approaches to probe the mind-mitochondria connection across levels. This stimulating scientific challenge is a unique opportunity to train the next generation of interdisciplinary scientists, resolve conceptual and technical challenges spanning temporal and spatial scales, and develop a more accurate, holistic model of health. Rooted in general energetic principles, mitochondrial psychobiology is poised to productively steer biomedicine over the coming decades.
    Keywords:  bioenergetics; brain; environment; evolution; mitochondria; modeling; psychopathology; regulation; resilience; robustness; stress; transdisciplinary
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.107036
  32. Front Mol Neurosci. 2026 ;19 1982074
    Mitochondrial dysfunction and PANoptosis-related signaling in acute central nervous system injuries: mechanistic convergence and therapeutic opportunities.
    Hongbo Zhang, Ruoxin Tu, Dawei Zhang, Hao Tian, Hongna Yin.
      Acute central nervous system (CNS) injuries comprise a heterogeneous group of disorders caused by vascular or traumatic factors, including ischemic stroke, intracerebral hemorrhage (ICH), traumatic brain injury (TBI), and spinal cord injury (SCI). These injuries initiate secondary cascades that combine metabolic failure, oxidative stress, neuroinflammation, and regulated cell death. Mitochondrial dysfunction is positioned near the center of these processes because impaired bioenergetics, excessive mitochondrial reactive oxygen species (mtROS), abnormal fission and fusion, defective mitophagy, and mitochondrial DNA (mtDNA) release can simultaneously disturb cellular homeostasis and activate inflammatory signaling. PANoptosis is an inflammatory form of regulated cell death that integrates pyroptotic, apoptotic, and necroptotic machinery through PANoptosome complexes. Emerging evidence suggests that mitochondrial stress can create conditions that favor PANoptotic convergence by increasing mtROS and damage-associated molecular patterns (DAMPs), activating DNA-sensing and inflammasome pathways, and sustaining receptor-interacting protein kinase and caspase signaling. This review examines the potential mechanistic links between mitochondrial dysfunction and PANoptosis-related signaling across ischemic stroke, ICH, SCI, and TBI. We summarize changes in mitochondrial bioenergetics, oxidative stress, dynamics, mitophagy, mitochondria-derived vesicles (MDVs), and mitochondrial transfer, and evaluate how these changes intersect with PANoptosis-related signaling. Importantly, we distinguish direct evidence of PANoptosis from studies that only demonstrate coordinated changes in individual death pathways. We also assess therapeutic strategies that target mitochondrial oxidative stress, dynamics, mitophagy, biogenesis, mitochondrial DAMP signaling, and mitochondrial transplantation and transfer. Current findings support mitochondria as a promising upstream intervention point, but complete causal evidence linking mitochondrial damage to defined PANoptosome assembly remains limited in acute CNS injury. Clarifying cell-specific and time-dependent mechanisms will be essential for translating this framework into effective neuroprotective strategies.
    Keywords:  PANoptosis; PANoptosome; acute central nervous system injury; mitochondrial dysfunction; mitochondrial quality control; neuroinflammation
    DOI:  https://doi.org/10.3389/fnmol.2026.1982074
  33. Aging Dis. 2026 Oct 09.
    Mitochondria Beyond Bioenergetics: Canonical and Non-Canonical Functions in Ischemic Stroke and Aging.
    Paweł Berezka, Natalia Piekarczyk, Jan Jacek Kaczor.
      Ischemic stroke remains a leading cause of death and long-term disability worldwide, yet effective neuroprotective therapies beyond reperfusion strategies are still lacking. Emerging evidence highlights mitochondria as central regulators of neuronal fate, expanding their traditional role in cellular energy homeostasis through ATP production by oxidative phosphorylation (OXPHOS). Together with calcium buffering and redox regulation, these represent canonical mitochondrial functions. Mitochondria also regulate cellular adaptation to stress through mitochondrial quality control (MQC), mitochondrial ferritin-dependent iron buffering, signaling mediated by mitochondrial metabolites and mitochondrial DNA (mtDNA), and intercellular organelle transfer. These non-canonical functions link mitochondrial state to ferroptotic cell death, innate immune activation, and epigenetic regulation of nuclear responses. During cerebral ischemia, mitochondrial dysfunction involves impaired OXPHOS, the generation of reactive oxygen species (ROS), opening of the permeability transition pore, disruption of organelle dynamics, and dysregulation of non-canonical functions, collectively promoting neuronal injury, inflammation, and impaired recovery. These disturbances are further exacerbated by aging, which compromises MQC mechanisms, including fusion/fission balance, mitophagy, and biogenesis, and increases neuronal vulnerability. Mitochondrial signals, including mtDNA, cardiolipin, and ROS, also contribute to inflammasome activation and glial metabolic reprogramming, linking mitochondrial injury to neuroinflammation. Moreover, mitochondrial ferritin and iron buffering may influence oxidative damage and ferroptosis. Therefore, integrating canonical and non-canonical mitochondrial functions provide a broader framework for understanding ischemic injury and underscore the potential of MQC, redox regulation, iron homeostasis, and mitochondrial transfer as therapeutic targets and strategies for stroke recovery.
    DOI:  https://doi.org/10.14336/AD.2026.0679
  34. Aging Cell. 2026 Oct;25(10): e70771
    Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age-Related Bioenergetic Remodeling, and Microglial STING Phenotypes.
    McKenna M Somerville, Sydney S Lin, Scott W Ballinger, Alecia K Gross.
      Mitochondria are central regulators of retinal bioenergetics and innate immune signaling, yet how mitochondrial genetic background and aging jointly influence immunometabolic responses in the retina remains poorly defined. Here, we investigated the effects of mitochondrial DNA (mtDNA) variation on retinal function and the combined effects of mtDNA variation and age on bioenergetic composition, mtDNA damage, and the microglial expression and intracellular localization of stimulator of interferon genes (STING) protein. Using mitochondrial-nuclear eXchange (MNX) mice harboring identical C57BL/6J nuclear genomes but distinct C57 or C3H mtDNA haplotypes, we assessed oxidative phosphorylation complex composition, electrophysiological function, mtDNA damage, and microglial STING dynamics across the lifespan and following acute intraocular pressure (IOP) elevation. Aging was associated with increased mtDNA damage and remodeling of oxidative phosphorylation complex composition, characterized by reduced Complex III and V abundance and increased Complex IV. Despite these age-associated changes, photoreceptor- and retinal ganglion cell-associated retinal responses were preserved at early ages, whereas bipolar cell-associated responses differed by mtDNA background. Microglial STING expression increased with age. Acute IOP elevation was associated with differential microglial STING dynamics and STING association with lysosomal compartments decreased with age. Together, these findings demonstrate that mitochondrial genetic background and aging influence retinal bioenergetics and neuroimmune protein expression and identify mtDNA variation as a modifier of age-associated microglial STING expression in the retina.
    Keywords:  metabolism; microglia; neuroinflammation; retina
    DOI:  https://doi.org/10.1111/acel.70771
  35. Methods Mol Biol. 2026 ;3057 171-187
    Measuring Skeletal Muscle Mitochondrial Architecture in 3D Using Focused Ion Beam Scanning Electron Microscopy (FIB-SEM).
    Hailey A Parry, Brian Glancy.
      Recent advances in volume electron microscopy have permitted unprecedented visualizations and in-depth quantitative analyses of mitochondrial network structure in skeletal muscle. Nanoscale, 3D analyses of skeletal muscle mitochondria have provided novel insights into how mitochondria interact among themselves and with other skeletal muscle cell organelles, such as the sarcoplasmic reticulum and the sarcomere. The identification of mitochondria within volume electron microscopy datasets and the downstream analyses of segmented structures remain two major bottlenecks in the analysis of 3D mitochondrial network structure at the nanoscale. Here, we provide a step-by-step guide on how to use machine learning programs to segment skeletal muscle mitochondria from volume electron microscopy datasets, followed by instructions on several types of 3D analyses of individual mitochondria and mitochondrial network structure that can be performed using ImageJ. We highlight key quality-control steps to ensure precise and accurate segmentation and analyses and to enhance reproducibility across groups.
    Keywords:  Focus Ion Beam Scanning Electron Microscopy; Mitochondria; Skeletal muscle; Volume electron microscopy
    DOI:  https://doi.org/10.1007/978-1-0716-5396-8_14
  36. Cell Rep. 2026 Oct 14. pii: S2211-1247(26)01240-4. [Epub ahead of print]45(10): 118161
    Mitochondrial stress induces transcription of cytosolic and mitochondrial protein synthesis components via NHR-180.
    Avijit Mallick, Theresa Ramalho, Levi Ali, Yunguang Du, Duy Hoang, Rui Li, Pooja Rai, Sookyung Kim, Rakeyah Ahsan, Ala M Shaqra, Andreas Bergmann, Celia A Schiffer, Lihua Julie Zhu, Brian Kelch, Kuang Shen, Cole M Haynes.
      The mitochondrial unfolded protein response (UPRmt), which promotes mitochondrial biogenesis and proteostasis, is regulated by the transcription factor ATFS-1. In C. elegans, impaired atfs-1 expression perturbs mitochondrial function and slows development. Here, using an RNAi suppressor screen, we find that inhibition of the nuclear hormone receptor NHR-180 increases mitochondrial function and developmental rate in atfs-1(null) worms. NHR-180 levels increase and become more nuclear-localized during mitochondrial dysfunction, inducing transcription of genes required for protein synthesis on cytosolic and mitochondrial ribosomes. The NHR-180 ligand-binding domain interacts with AMP, suggesting that NHR-180 may link cellular energy status to protein synthesis during mitochondrial stress. However, NHR-180-dependent activity is associated with exacerbated mitochondrial dysfunction. Consistent with these findings, inhibition of the S6 kinase homolog RSKS-1 increases mitochondrial function in atfs-1(null) worms. S6 kinase inhibition also increases respiration and mitochondrial DNA (mtDNA) content in mammalian ATF5-knockout cells and oxidative phosphorylation (OXPHOS)-deficient models.
    Keywords:  ATFS-1; CP: molecular biology; NHR-180; OXPHOS; RSKS-1, S6K, ATF5; mitochondria; mtDNA; protein synthesis
    DOI:  https://doi.org/10.1016/j.celrep.2026.118161
  37. Methods Mol Biol. 2026 ;3057 55-67
    Bulk Differentiation of Human Induced Pluripotent Stem Cells into Contractile Skeletal Muscles.
    Yu-Shen Cheng, Farah Ulfat Jamee, Muhammad Irfanur Rashid, Hidetoshi Sakurai, Kazunori Shimizu, Yohei Okada.
      Effective treatments for various muscular disorders and a clear understanding of their disease pathology remain lacking owing to the limitations of traditional animal models and two-dimensional (2D) cell cultures. Human induced pluripotent stem cells (hiPSCs) offer promising platforms for disease modeling and regenerative medicine. However, existing protocols for skeletal muscle differentiation are often labor-intensive and yield inconsistent results. Here, we utilized a piggyBac transposon-based system to generate bulk MYOD1-hiPSCs, eliminating the need for clonal selection and enabling rapid, efficient, and reproducible skeletal muscle differentiation. Furthermore, we established a protocol for generating functional three-dimensional (3D) skeletal muscle tissues that exert contractile force in response to electrical stimulation, highlighting their physiological relevance. This system provides a simple and valuable tool for disease modeling, drug screening, and the study of sporadic muscle disorders using patient-derived hiPSCs.
    Keywords:  3D culture; Bulk culture; Contraction; Disease modeling; MYOD1-hiPSC; Skeletal muscle differentiation
    DOI:  https://doi.org/10.1007/978-1-0716-5396-8_5
  38. Cell Rep. 2026 Oct 16. pii: S2211-1247(26)01233-7. [Epub ahead of print]45(10): 118154
    The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation.
    Pham Thuy Tien Vo, Julien Cicero, Zichen Wang, Hiroyuki Hakozaki, Thomas S Hoang, Sendi Rafael Adame-Garcia, Dana J Ramms, Kuniaki Sato, Erica Stevenson, Yuan Zhou, Katie Fan, Juliette A Bokor, Vasiliya Kril, Cara Schiavon, Scott B Biering, Danielle L Swaney, Nevan J Krogan, Johannes Schöneberg, Uri Manor, J Silvio Gutkind.
      The stimulator of interferon genes (STING) pathway is essential for mounting robust innate immunity, yet its chronic activation can drive detrimental inflammation. Although multiple cell-autonomous mechanisms that restrain STING signaling have been reported, whether inflammatory mediators within the tissue microenvironment regulate STING activation remains elusive. Using herpes simplex virus type 1 infection as a model of STING activation, we revealed that the COX2-PGE2-PKA axis functions as a critical negative regulator of STING-mediated antiviral innate immunity. Mechanistically, PGE2 acts through the EP4-PKA cascade to induce PTEN-induced kinase 1 (PINK1)-mediated mitophagy by phosphorylating STOML2 at Ser29. This pathway facilitates the clearance of damaged mitochondria that serve as a source of immunostimulatory cytosolic mitochondrial DNA, thereby attenuating downstream STING activation and type I interferons while promoting viral replication. Together, these findings establish mitochondrial quality control as the mechanistic link between PGE2 signaling and mtDNA-dependent STING activation and identify the COX2-PGE2-PKA pathway as a druggable therapeutic target to enhance STING-mediated innate immunity.
    Keywords:  CP: immunology; EP4; STING signaling; antiviral innate immunity; cyclooxygenase-2; herpes simplex virus type 1; mitochondrial DNA; mitophagy; prostaglandin E2; protein kinase A; type I interferons
    DOI:  https://doi.org/10.1016/j.celrep.2026.118154
  39. bioRxiv. 2026 Oct 03. pii: 2026.01.16.700014. [Epub ahead of print]
    Local ROS and inefficient autophagosome formation limit Optineurin-mediated mitophagy in neurons.
    Jordan R Green, Anne E Ojo, Molly K Gooden, Lillian D Papell, Titilola D Kalejaiye, Chantell S Evans.
      Mitophagy is a quality control mechanism that maintains neuronal health by removing damaged mitochondria. In neurons, mitophagy can be driven by Optineurin (OPTN), a selective autophagy receptor recruited in response to oxidative stress. However, mechanistic studies of mitophagy have relied mainly on non-neuronal cell lines and acute damage paradigms. It remains unknown whether these findings translate to neurons under physiological stress conditions. Here, we investigated the temporal dynamics of OPTN-dependent mitophagy under mild oxidative stress using live-cell imaging in primary rat hippocampal neurons. We found that autophagosomes failed to readily engulf OPTN-positive (OPTN+) mitochondria, revealing a previously unidentified rate-limiting step in neuronal OPTN-mediated mitophagy. Additionally, OPTN+ mitochondria colocalized with acidified lysosomes over timescales significantly longer than previously reported. These OPTN+ mitochondria displayed locally elevated reactive oxygen species (ROS). Scavenging mitochondrial ROS increased lysosomal colocalization with damaged mitochondria and accelerated mitophagy progression. Together, these findings indicate that redox signaling contributes to the slow timescale of OPTN-mediated mitophagy in neurons.
    DOI:  https://doi.org/10.64898/2026.01.16.700014
  40. Sci Adv. 2026 Oct 16. 12(42): eaed8795
    MFN2-associated astrocyte dysfunction contributes to neuronal hyperexcitability and depressive-like behaviors.
    Feng-Xia Ma, Min Wang, Shuo-Yan Fang, Xiao-Xin Wang, Shen-Han Xu, Xin-Xin Zhao, Yu-Xiao Liu, Cong Wang, Chen Qiao, Qiu-Ling Wang, Lei Cao.
      Astrocyte pathology is increasingly recognized as a key factor in the pathogenesis of major depressive disorder (MDD), where disrupted glutamate clearance and impaired neuron-glia interactions contribute to synaptic dysfunction. However, the molecular mechanisms leading to astrocyte loss remain largely undefined. Mitochondrial dysfunction is a hallmark of MDD, yet most studies have focused on neuronal mitochondria, leaving astrocytic mitochondrial dynamics insufficiently investigated. Here, we identify mitofusin-2 (MFN2)-associated astrocyte dysfunction in depression. SMART-seq profiling of hippocampal astrocytes from chronic social defeat stress (CSDS) mice revealed Mfn2 up-regulation, accompanied by excessive mitochondrial fusion, impaired mitophagy, and astrocyte loss. Elevated MFN2 expression was detected in plasma, postmortem brain tissue, and iPSC-derived astrocytes from patients with MDD. Astrocyte-specific knockdown of Mfn2 restored mitochondrial morphology and mitophagy, thereby preserving astrocyte viability and alleviating depressive-like behaviors. Using mass spectrometry-based label-free proteomics, in vivo calcium imaging, and functional assays, we demonstrated that β-arrestin2 deficiency reduced STAT1 stability, releasing its transcriptional repression on Mfn2. Normalization of MFN2 expression through astrocytic Mfn2 knockdown or Stat1 overexpression reduced extracellular glutamate accumulation and prevented neuronal hyperexcitability in CSDS mice. Collectively, our findings define astrocytic MFN2-associated astrocyte dysfunction as a central pathological event in depressive behaviors, with the β-arrestin2-STAT1 pathway acting as an upstream regulatory mechanism. This work reveals an astrocytic pathway in depression and highlights a potential therapeutic target that directly addresses astrocyte pathology, beyond the neuron-centered focus of current antidepressant treatments.
    DOI:  https://doi.org/10.1126/sciadv.aed8795
  41. Cells. 2026 Sep 24. pii: 1746. [Epub ahead of print]15(19):
    Free Mitochondrial DNA and Mitophagy Dysfunction in Diabetic Kidney Disease: A Central Mitochondrial-Inflammatory Axis Driving Progressive Renal Injury.
    Aasthika Das, Eric Lalu, Vikky Awasthi, Cyrine Ben Dhaou, Hebaalaha Hussein, Glenn Gerhard, Karim Bahmed, Iris Lee, Vishwajeet Puri, Rihab Bouchareb.
      Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease and end-stage renal failure worldwide despite significant advances in glucose-lowering and renoprotective therapies. Emerging evidence identifies mitochondrial dysfunction as a central pathogenic mechanism linking metabolic stress to chronic inflammation and progressive renal injury. In the diabetic kidney, hyperglycemia, lipotoxicity, and oxidative stress impair mitochondrial quality control pathways, particularly mitophagy, a targeted mitochondrial degradation pathway, leading to the accumulation of dysfunctional mitochondria and increased mitochondrial reactive oxygen species production. A critical consequence of mitochondrial damage is the cytosolic release of mitochondrial DNA (mtDNA), which acts as a potent damage-associated molecular pattern and can activate innate immune pathways, including cGAS-STING, NLRP3 inflammasome, and Toll-like receptor 9 signaling. Persistent mtDNA-driven immune activation promotes sterile inflammation, cellular senescence, extracellular matrix remodeling, and renal fibrosis, thereby establishing a vicious cycle that accelerates DKD progression. In this review, we examine the emerging role of the mitochondrial DNA-inflammatory axis in DKD, highlighting the interplay between mitophagy dysfunction, mtDNA release, innate immune activation, and fibrotic remodeling. We further discuss the potential of circulating and urinary mtDNA as biomarkers of disease activity and evaluate therapeutic strategies targeting mitochondrial quality control, oxidative stress, and mtDNA-sensing pathways. Collectively, these findings position mtDNA as a critical mechanistic link between mitochondrial dysfunction and chronic inflammation, and support targeting the mitochondrial-immune axis as a promising strategy for precision therapies in DKD.
    Keywords:  DKD; Kidney; inflammation; mitochondrial DNA
    DOI:  https://doi.org/10.3390/cells15191746
  42. Sci Adv. 2026 Oct 16. 12(42): eaeb8190
    Muscle stem cells produce a protective Fibrillin-1 matrix to prevent precocious activation.
    Eleni Chrysostomou, Oussama Smail, Artemis Vlachopoulou, Takuto Hayashi, Nicolas Tcheng, Nicol Voermans, Dieter P Reinhardt, Frederic Relaix, Philippos Mourikis.
      Diverse biological mechanisms regulate muscle stem cell quiescence, including inhibition of differentiation, adhesion, and translational control. Here, we identify the matrix glycoprotein Fibrillin-1 (FBN1) as a Notch-regulated, cell-autonomous effector, essential for maintaining quiescence. Known for its causal role in Marfan syndrome (MFS), our work positions FBN1 as a critical niche component that protects muscle stem cells from aberrant growth factor signaling. Targeted deletion of Fbn1 in muscle stem cells leads to dose-dependent quiescence defects, characterized by loss of cellular projections, depletion of the stem cell pool, and progressive decline in muscle function. Consistently, human MFS muscle biopsies show abnormally activated satellite cells, implicating stem cell imbalance in the development of MFS-associated myopathy. Mechanistically, the loss of FBN1 up-regulates transforming growth factor-β (TGFβ) signaling, and pharmacological blockade of TGFβ signaling rescues the cellular and physiological defects of FBN1-deficient muscle. These findings reveal a new quiescence-preserving mechanism through extracellular matrix-mediated shielding from mitogenic signals and position stem cell dysfunction as a driver of MFS myopathy.
    DOI:  https://doi.org/10.1126/sciadv.aeb8190
  43. Am J Med Genet A. 2026 Oct 12.
    Novel Compound Heterozygous ATAD3A Variants in Harel-Yoon Syndrome With Congenital Cataracts and Dilated Cardiomyopathy.
    Tingting Wen, Hongyu Chen, Lan Yu, Xianghong Zhang.
      Harel-Yoon syndrome is a rare mitochondrial disorder caused by pathogenic variants in ATAD3A, typically characterized by neonatal respiratory insufficiency, cataracts, developmental delay, hypotonia, and cerebellar atrophy. We report a pediatric patient with compound heterozygous missense variants in ATAD3A (c.655C>T, p.R219C and c.980G>C, p.R327P) who presented with an atypical phenotype manifested as early-onset congenital cataracts and progressive dilated cardiomyopathy. Notably the patient did not show typical neurological manifestations nor the cardiac presentations of hypertrophic cardiomyopathy. The maternally inherited c.655C>T variant was absent from population databases, while paternally inherited c.980G>C was previously associated with Harel-Yoon syndrome. In silico protein structure modeling demonstrated that the mutant ATAD3A hexamer showed a looser and more disorganized conformation compared to that of the wild-type, suggesting functional impairment. This case expands the phenotypic spectrum of ATAD3A-related disorders and highlights the importance of long-term surveillance in patients with ATAD3A variants, even in the absence of classical neurological features. In addition, our findings support the inclusion of ATAD3A in the genetic differential diagnosis for patients with congenital cataracts and cardiomyopathy.
    Keywords:   ATAD3A ; Harel‐Yoon syndrome; compound heterozygous variants; congenital cataracts; dilated cardiomyopathy
    DOI:  https://doi.org/10.1002/ajmg.a.70327
  44. Methods Mol Biol. 2026 ;3057 35-53
    Engineering Functional Skeletal Muscle Tissues from Human Induced Pluripotent Stem Cells.
    Amber Detwiler, Alastair Khodabukus, Nenad Bursać.
      In vitro cell culture models of human skeletal muscle offer a valuable platform for studies of pathology and discovery of new therapeutics. However, traditional two-dimensional cell culture models suffer from limited durability and challenges with assessment of skeletal muscle contractile function. Furthermore, finite proliferation potential and scarce availability of patient-derived primary myoblasts limit experimental throughput when using these cells. Here, we describe a method for using human induced pluripotent stem cells (hiPSCs) to generate functional three-dimensional skeletal muscle tissues. Briefly, transient overexpression of Pax7 in hiPSC-derived paraxial mesoderm cells permits efficient formation of myogenic progenitor cells (iMPCs), which are then combined with hydrogel matrix to form cylindrically shaped skeletal muscle (iSKM) "myobundles." After 2 weeks of differentiation, iSKM myobundles contain aligned and densely packed multinucleated myotubes that, in response to electrical stimulation, exhibit robust calcium transients and positive force-frequency and force-length relationships. The methods detailed here have been successfully utilized to model and study limb-girdle muscular dystrophy type R2/2B and can be applied for studies of skeletal muscle regeneration and testing of candidate gene and cell therapies for disease. Collectively, iSKM myobundle engineering is a powerful in vitro methodology expected to significantly advance human skeletal muscle research and therapy.
    Keywords:  Disease modeling; Human induced pluripotent stem cells; Hydrogel; Myopathy; Skeletal muscle; Tissue engineering
    DOI:  https://doi.org/10.1007/978-1-0716-5396-8_4
  45. Eur Respir J. 2026 Oct 11. pii: 2600791. [Epub ahead of print]
    Pleuroparenchymal fibroelastosis in a monogenic mitochondrial DNA depletion syndrome.
    Sandra von Hardenberg, Pia Maier, Leonard Christian, Anibh Martin Das, Lavinia Neubert, Jannik Ruwisch, Katrin Peters, Dirk Schramm, Matthias Griese, Britta Skawran, Marlies Eilers, Danny Jonigk, Norman Junge, Aiden Haghikia, Tobias Hegelmaier, Winfried Hofmann, Benjamin Seeliger, Diane Miriam Renz, Amelie Stalke, Lara Hartmayer, Alexander Duscha, Martin Schulze, Nataliya DiDonato, Holger Prokisch, Bernd Auber, Lars Knudsen, Jonas C Schupp, Nicolaus Schwerk.
       BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare, most often idiopathic fibrotic lung disease with poor prognosis, mainly affecting adults. Biallelic pathogenic variants in the deoxyguanosine kinase gene (DGUOK) cause a mitochondrial DNA (mtDNA) depletion syndrome, predominantly affecting infants with severe hepatic and neurological disease. Neither detailed pulmonary manifestations nor a pulmonary-dominant phenotype has been reported.
    METHODS: We describe nine patients with PPFE and DGUOK-associated mitochondriopathy. Clinical, radiological, histopathological, and genetic data were systematically collected from all patients. Functional studies, single-nucleus RNA sequencing (snRNAseq), immunofluorescence staining, transmission electron microscopy, respiratory chain enzyme activity assays and mtDNA recovery experiment were conducted on patient-derived fibroblasts, muscle or lung tissues. mtDNA content quantification was performed on whole genome sequencing data.
    RESULTS: All patients (ages 5-36 years) carried biallelic pathogenic DGUOK variants, including an unreported intronic alteration in seven. All presented with progressive dyspnea, weight loss and some with pneumothoraces. Chest computed tomography and lung biopsies demonstrated features of PPFE. snRNAseq of lung tissue from four pediatric patients identified Aberrant Basaloid cells at the fibrotic edge, together with a transcriptional signature of nuclear DNA damage response. Ultrastructural analysis confirmed mitochondrial abnormalities in alveolar type 2 and Aberrant Basaloid cells.
    CONCLUSION: This study provides evidence that mitochondrial dysfunction can contribute to early-onset PPFE independent of age, with a DNA damage response signature in aberrant epithelial cell populations previously described only in adult fibrotic lung disease. DGUOK deficiency and other hereditary mitochondrial disorders should be considered in children and young adults presenting with PPFE of unknown origin.
    DOI:  https://doi.org/10.1183/13993003.00791-2026
  46. bioRxiv. 2026 Oct 02. pii: 2026.09.28.755036. [Epub ahead of print]
    Mitochondrial Calcium Uptake Promotes Mitochondrial Activation and Hyperactivated Motility During Human Sperm Capacitation.
    Pilar Irigoyen, Juan J Ferreira, Adriana Cassina, Shweta Bhagwat, Nikita Peramsetty, Rossana Sapiro, Celia M Santi.
      Capacitation is a post-ejaculatory maturation process by which sperm become hyperactive and undergo the acrosome reaction, both of which are required to fertilize an oocyte. Two key features of capacitation are increased intracellular calcium via the calcium channel CatSper and changes in mitochondrial function. In mouse spermatozoa, CatSper-dependent calcium entry promotes mitochondrial calcium uptake and mitochondrial activation, contributing to hyperactivated motility and fertilization ability. Whether this mechanism is conserved in human spermatozoa was unknown. Here, we assessed mitochondrial function and mitochondrial calcium in paired non-capacitated and capacitated human spermatozoa from normozoospermic donors. Capacitation increased mitochondrial respiratory control ratio, coupling efficiency, mitochondrial membrane potential, and mitochondrial calcium. The increase in mitochondrial calcium required extracellular calcium and was prevented by pharmacological inhibition of CatSper or the mitochondrial calcium uniporter (MCU). Inhibition of CatSper or mitochondrial calcium uniporter also attenuated the capacitation-associated increase in mitochondrial membrane potential and reduced hyperactivated motility without affecting progressive or total motility. Pharmacological disruption of mitochondrial function reduced capacitation-associated hyperactivated motility without affecting the acrosome reaction. Together, these findings support a conserved pathway in human and mouse spermatozoa in which CatSper-mediated calcium entry promotes MCU-dependent mitochondrial calcium uptake and mitochondrial activation, contributing to the acquisition of hyperactivated motility during capacitation. These findings identify mitochondrial calcium handling as a potential target for modulating human spermatozoa function.
    DOI:  https://doi.org/10.64898/2026.09.28.755036
  47. bioRxiv. 2026 Sep 28. pii: 2026.09.24.754267. [Epub ahead of print]
    Targeting ALCAT1 Ameliorates Cardiomyopathy in Barth Syndrome.
    Jun Zhang, Qianqian Ye, Xi Fang, Wendong Huang, Yuguang Shi.
       Background: Barth syndrome (BTHS) is an X-linked mitochondrial disorder caused by loss-of-function mutations in TAFAZZIN ( TAZ ), resulting in defective cardiolipin (CL) remodeling, cardiomyopathy, and premature death. The mechanisms linking TAZ deficiency to impaired mitochondrial quality control remain incompletely understood, and there are no disease-modifying therapies available for BTHS. Here, we investigated the role of Acyl-CoA Lysocardiolipin Acyltransferase-1 (ALCAT1), a stress-inducible phospholipid-remodeling enzyme, in BTHS cardiomyopathy.
    Methods: Inducible TAZ knockdown ( TAZ KD ) and cardiomyocyte-specific TAZ knockout ( TAZ cKO ) mice were used to determine the effects of genetic ALCAT1 deletion or pharmacological inhibition with Juvenatin, a highly selective small molecule ALCAT1 inhibitor. Cardiac function, exercise capacity, mitochondrial function, lipid remodeling, lysosomal function, and mitophagic flux were assessed.
    Results: ALCAT1 was markedly upregulated in TAZ -deficient hearts. Genetic ALCAT1 deletion attenuated cardiac dysfunction in TAZ KD mice. Juvenatin similarly improved cardiac function in TAZ KD mice and reversed established cardiomyopathy in TAZ cKO mice. Genetic or pharmacological ALCAT1 inhibition improved mitochondrial ultrastructure and respiration and reduced mitochondrial oxidative stress. These benefits occurred without correcting the characteristic CL abnormalities caused by TAZ deficiency. Instead, ALCAT1 deletion or inhibition corrected pathological phosphatidylinositol remodeling, normalized phosphoinositide signaling, and restored lysosomal function and mitophagic flux, leading to improved mitochondrial quality control in TAZ -deficient cells.
    Conclusions: ALCAT1 contributes to BTHS cardiomyopathy through a CL-independent pathway involving dysregulated phosphatidylinositol/phosphoinositide signaling, lysosomal dysfunction, and impaired mitophagy. Genetic and pharmacological targeting of ALCAT1 restores mitochondrial and cardiac function despite persistent CL abnormalities, establishing ALCAT1 as a promising disease-modifying therapeutic target for BTHS.
    DOI:  https://doi.org/10.64898/2026.09.24.754267
  48. Drug Des Devel Ther. 2026 ;20 649776
    Bidirectional Crosstalk Between cGAS-STING and Necroptosis: From Mitochondrial DNA Release to Inflammatory Disease.
    Hongquan Wang, Zhiji Wang, Hui Zhang, Zhihang Yang, Shuang Zhao, Yuzi Jin.
      The cGAS-STING pathway, a cornerstone of cytosolic DNA sensing, and necroptosis, a pro-inflammatory regulated cell death modality, are increasingly recognized as intimately interconnected axes that profoundly influence disease pathogenesis. This review synthesizes current knowledge on their bidirectional crosstalk, emphasizing the molecular underpinnings and therapeutic implications. We detail how cGAS -STING activation can precipitate necroptosis through type I interferon and TNF-α synergy, as well as transcriptional upregulation of ZBP1, with mitochondrial damage and mtDNA release serving as critical upstream triggers. Reciprocally, in certain necroptotic settings, phosphorylated MLKL can permeabilize mitochondrial membranes to liberate mtDNA, although this is not yet established as an obligatory feature of all MLKL-dependent necroptosis, which activates cGAS-STING independently of plasma membrane rupture, while RIPK3 can drive mitochondrial dysfunction to similar effect. This reciprocal engagement often escalates into a self-amplifying feedback loop that drives chronic inflammation and tissue injury across diverse pathologies, including neurodegenerative disorders, sterile organ injury, and cancer, though it can also be harnessed for antitumor immunity. However, this crosstalk is context-dependent rather than uniformly amplifying: in some settings, STING activation restrains necroptosis, as observed during Staphylococcus aureus pneumonia and in human monocytes. The review further evaluates emerging pharmacological strategies that target this interface, ranging from direct inhibitors of STING or MLKL to agents that preserve mitochondrial integrity, and discusses the context-dependent challenges of therapeutic intervention. By framing the cGAS -STING-necroptosis axis as a central hub integrating innate immune sensing with inflammatory cell death, we underscore its significant potential as a therapeutic target for inflammation-associated diseases.
    Keywords:  MLKL; ZBP1; cGAS-STING; interplay; mtDNA; necroptosis; regulated cell death
    DOI:  https://doi.org/10.2147/DDDT.S649776
  49. J Biol Chem. 2026 Oct 14. pii: S0021-9258(26)02520-2. [Epub ahead of print] 113648
    The malonyl-CoA synthetase ACSF3 is required for metabolic editing downstream of biotin carboxylation.
    Joseph Choi, Jasmine Encarnacion, Daria Kurganova, Susanna Scafidi, Michael J Wolfgang.
      Acsf3, a mitochondrial malonyl-CoA synthetase, is mutated in the human inborn error Combined Malonic and Methylmalonic Aciduria. To clarify its role in mammalian metabolism, we generated Acsf3 knockout mice. We show that the loss of Acsf3 results in high concentrations of malonate and methylmalonate and exhibit expected defects in mitochondrial metabolism, but the KO mice are largely healthy similar to the human inborn error. Acsf3 KO mice exhibit redundancy in malonyl-CoA synthetase activity suggesting a genetic modifier of disease severity. Malonate and methylmalonate are metabolic poisons generated as a by-product of biotin dependent carboxylation that require metabolic editing. Indeed, the liver-specific loss of the biotin ligase, Holocarboxylase Synthetase (hlcs), inhibits all biotin dependent carboxylation and results in broad changes in liver mRNA, protein, posttranslational and metabolic regulation. Loss of Hlcs suppresses the metabolic deficits in Acsf3KO liver due to the inhibition of malonate and methylmalonate generation. Mice with a double knockout of Acsf3 and Hlcs maintained mitochondrial lipoylation demonstrating the highly redundant generation of mitochondrial malonyl-CoA. These data define the role of Acsf3 in metabolic editing of malonate and methylmalonate to maintain mitochondrial metabolism in the face of endogenously produced anti-metabolites.
    Keywords:  biotin; metabolic disease; metabolomics; mitochondrial metabolism; proteomics; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.jbc.2026.113648
  50. bioRxiv. 2026 Oct 04. pii: 2026.09.30.755445. [Epub ahead of print]
    Disease-associated mutations directionally modulate epigenetic age in iPSC-derived tissues.
    Nicholas J Skvir, Todd W Dowrey, Samuel F Cranston, Elise MacDonald, Richard Giadone, Dakota Jones, Carly S Golden, Braden Pate, Madeline Labott, Maria A Serrano, Konstantinos-Dionysios Alysandratos, Kim Vanuytsel, George J Murphy.
      Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) resets epigenetic age, creating a major challenge for modeling age-associated cellular states and limiting the use of iPSCs in aging research beyond the genetic component. Recent work has shown that healthy organoids can re-accumulate age-associated epigenetic states over extended culture; whether disease-associated genetic states can directionally reshape these trajectories after reprogramming remains unknown. Here, we present a reproducible, in-vitro approach to re-establish epigenetic aging trajectories using iPSC-derived organoid systems, as quantified by multiple epigenetic clock models. We first demonstrate that epigenetic age progressively increases with serial passaging in a lung organoid model (alveolospheres). We then show that disease-associated mutations in multiple models drive additional, cell-intrinsic shifts in epigenetic age, implicating disease state as an independent modulator of epigenetic clocks. Together, these findings reinforce that iPSC-derived organoids recapitulate epigenetic aging trajectories over time, while highlighting disease state as a potent and potentially tractable modulator of epigenetic age in vitro. By enabling more faithful modeling of age-associated cellular states, this approach expands the utility of iPSC-based systems for dissecting the molecular mechanisms that regulate human aging.
    DOI:  https://doi.org/10.64898/2026.09.30.755445
  51. Front Cell Dev Biol. 2026 ;14 1855694
    The role of mitochondrial DNA and RNA in promoting liver disease pathogenesis.
    Sanjeevani Raj, Anjali Warhade, Nikkee Kumari, Shweta Pandey, Mrigya Babuta.
      Mitochondria are a semi-autonomous organelle due to their unique structural organization and independent genetic system, and they play diverse roles in maintaining cellular homeostasis. The liver is the central metabolic organ and performs myriad functions, including energy production, metabolism, and detoxification. Liver diseases account for approximately two million mortalities per year. Mitochondrial dysfunction and damage are implicated in promoting the pathogenesis of different liver diseases. Mitochondria and mitochondrial nucleic acids, namely, mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), have emerged as regulators of innate immunity. Here, we first review the structural organization of mitochondria and the molecular mechanisms governing mitochondrial biogenesis, replication, and transcription. Next, we describe the mechanistic details by which mitochondrial dysfunction causes the release of mtDNA and mtRNA into the cytosol and extracellular milieu. Some of the mechanisms are through the opening of mitochondrial permeability transition pore (mPTP), voltage-dependent anion channel (VDAC) oligomerization, prohibitin (PHB1/2), mitochondria-derived vesicles (MDV), dysfunction of the mtRNA degradosomes, and senescence-associated secretory phenotype (SASP). Cell death pathways such as necrosis, necroptosis, and pyroptosis, in addition to perpetuating inflammation, also release mtDNA and mtRNA into the extracellular milieu. The released mtDNA and mtRNA act as damage associated molecular patterns (DAMPs) that engage various cytosolic DNA and RNA sensors and pattern recognition receptors (PRRs) such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), toll-like receptor 9 (TLR9), toll-like receptor 3 (TLR3), Z-DNA-binding protein 1 (ZBP1), NOD-like receptor protein 3 (NLRP3), absent in melanoma 2 (AIM2), retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5), protein kinase R (PKR) and activate different signaling cascades downstream. This review provides a contemporary, comprehensive analysis of the available literature on the roles of mtDNA and mtRNA in liver diseases, including metabolic dysfunction-associated steatotic/steatohepatitis (MASLD/MASH), alcohol-associated liver disease (ALD), drug-induced liver injury (DILI), viral hepatitis, and hepatocellular carcinoma (HCC). Thus, the review highlights the potential of both mtDNA and mtRNA to serve as biomarkers of the pathological conditions of the liver, and the way the mitigation of mitochondrial dysfunction and the release of mtDNA or mtRNA can serve as potential therapeutic targets.
    Keywords:  DAMP; DNA-sensing receptors; MDV; MQC; Mitobiogenesis; megamitochondria; mt-dsRNA; ox-mtDNA
    DOI:  https://doi.org/10.3389/fcell.2026.1855694
  52. Diabetes. 2026 Oct 12. pii: dbi260024. [Epub ahead of print]
    Mitochondrial Dysfunction Across Renal Compartments in Diabetic Kidney Disease.
    Abigail Shapiro, Ratnakar Tiwari, Alexander Staruschenko.
       ARTICLE HIGHLIGHTS: Mitochondrial dysfunction in diabetic kidney disease is compartment and stage specific, reflecting differences in renal cell metabolism, function, and injury response. This article introduces a framework for interpreting mitochondrial dysfunction across renal cell types and disease stages. Proximal tubular stress progresses from increased transport demand to mitochondrial injury and impaired quality control. Distal nephron, immune, and interstitial mitochondrial mechanisms remain incompletely defined. In glomerular endothelial cells and podocytes, mitochondria primarily regulate stress and injury signaling. Cell-specific mitochondrial phenotyping may reveal reversible pathways and guide more precise therapeutic strategies in diabetic kidney disease.
    DOI:  https://doi.org/10.2337/dbi26-0024
  53. Biochim Biophys Acta Mol Cell Biol Lipids. 2026 Oct 10. pii: S1388-1981(26)00061-2. [Epub ahead of print]1872(1): 159775
    Neuronal fatty acid bioenergetics: An emerging pathway and potential point in convergence in hereditary spastic paraplegias.
    Nyakuoy Yak, Merja Joensuu.
      The human brain is an energetically demanding organ. Neurons have traditionally been considered to rely predominantly on glucose to sustain neuronal activity under normal physiological conditions. However, recent advances challenge this long-standing view, demonstrating that neurons can oxidise endogenous and exogenous long-chain fatty acids through mitochondrial β-oxidation to create energy. In this mini-review, we discuss the emerging role of neuronal fatty acid β-oxidation and how fatty acid metabolism is integrated with glycolysis, lipid storages, and mitochondrial energy production. We further explore the ER-lipid droplet-mitochondria nexus as a metabolic hub coordinating fatty acid mobilisation, storage, and oxidation, and investigate how abnormalities in these organelles and their inter-organelle coupling converge across hereditary spastic paraplegia subtypes to disrupt neuronal lipid metabolism and mitochondrial bioenergetics. Finally, we discuss how these emerging mechanisms may reveal new therapeutic opportunities for hereditary spastic paraplegias.
    Keywords:  Bioenergetics; Fatty acid; HSP; Hereditary spastic paraplegia; Lipid metabolism; Neuronal bioenergetics; SPG; β-Oxidation
    DOI:  https://doi.org/10.1016/j.bbalip.2026.159775
  54. bioRxiv. 2026 Sep 29. pii: 2026.09.28.755091. [Epub ahead of print]
    A PPARγ-like signalling axis integrates lipid homeostasis and mitochondrial quality control to preserve neuronal integrity.
    Dikaia Tsagkari, Maria Markaki, Tao Zhang, Ellen Nollen, Nektarios Tavernarakis.
      Peroxisome proliferator-activated receptor gamma (PPARγ) is a central regulator of lipid metabolism and a critical mediator of neuroprotection, yet the mechanisms linking these functions remain unclear. Here, we identify the Caenorhabditis elegans nuclear receptor SEX-1 as a functional PPARγ-like regulator and define a pathway that coordinates lipid metabolism with mitochondrial homeostasis to preserve neuronal function. Integrating comparative genomics, multi-omics profiling, meta-analysis, and experimental validation, we show that SEX-1 orchestrates membrane sphingolipid metabolism, lipid droplet (LD) dynamics, and mitochondrial quality control through interconnected lipogenic and autophagic programs. Loss of sex-1 disrupts this metabolic network, resulting in aberrant LD accumulation, mitochondrial dysfunction, and widespread alterations in sphingolipid metabolism. These defects compromise the structural integrity and thermosensory function of amphid neurons during early adulthood, while the capacity of SEX-1 to restrict neuronal lipid droplet accumulation declines with age. Notably, genetic modulation of sphingolipid metabolic pathways rescues neuronal defects, establishing a causal link between lipid metabolic homeostasis and neuronal maintenance. Together, our findings identify a PPARγ-like signalling axis that integrates sphingolipid metabolism, organelle quality control, and neuronal homeostasis, providing a mechanistic framework for understanding how metabolic regulation promotes neuroprotection.
    DOI:  https://doi.org/10.64898/2026.09.28.755091
  55. J Inherit Metab Dis. 2026 Nov;49(6): e70259
    Revisiting Inherited Metabolic Diseases (IMDs) Through the Lens of Selective Autophagy.
    Marianna Maddaluno, Laura Cinque, Viviana Cetrangolo, Chiara De Leonibus.
      Selective autophagy is increasingly recognized as a fundamental quality-control mechanism that complements bulk autophagy by enabling the targeted degradation of specific intracellular cargos, including mitochondria, endoplasmic reticulum (ER), lipid droplets, glycogen, peroxisomes, ferritin, ribosomes, and protein aggregates. Cargo selectivity is mediated by selective autophagy receptors (SARs), which link damaged or superfluous substrates to the autophagic machinery through LC3/GABARAP interactions, thereby coordinating cargo sequestration. Recent studies have revealed substantial mechanistic differences between bulk and selective autophagy, highlighting the specialized signaling pathways, receptor networks, and transcriptional programs that regulate selective cargo clearance. Dysregulation of these pathways has emerged as a key contributor to the pathogenesis of inherited metabolic diseases (IMDs), a heterogeneous group of genetic disorders characterized by defective metabolism and multisystem involvement. This review summarizes the molecular mechanisms underlying major forms of selective autophagy, including mitophagy, pexophagy, glycophagy, lipophagy, ER-phagy, and ferritinophagy. It also discusses their relevance across IMD classes, such as mitochondrial disorders, lysosomal storage disorders, and peroxisomal diseases, among many others. Furthermore, selective autophagy is highlighted as a potential therapeutic target, with modulation of autophagy receptors and signaling pathways offering promising strategies to restore cellular homeostasis and improve disease manifestations in IMDs.
    Keywords:  bulk autophagy; inherited metabolic diseases (IMDs); selective autophagy; selective autophagy cargos (SACs); selective autophagy receptors (SARs)
    DOI:  https://doi.org/10.1002/jimd.70259
  56. Nat Commun. 2026 09 12. pii: 10770. [Epub ahead of print]17(1):
    Reprogramming the Rossmann fold signature motif creates orthogonal redox biocatalysts.
    Yu Ping, Jin Young Kim, Minh-Anh L Dinh, Emma Luu, Suphanida Worakaensai, Shiding Zhang, William B Black, Emma Monge, Hans Jefferson C Ng, Sean Perea, Yulai Zhang, Youtian Cui, Edward King, Justin B Siegel, Han Li.
      Biological reducing power is carried by nicotinamide adenine dinucleotide (phosphate) (NAD(P)/H), which supports cellular functions and cannot be specifically directed to engineered metabolic pathways. Nicotinamide mononucleotide (NMN(H)) has emerged as an orthogonal redox cofactor to address this. Herein, to create NMN(H)-specific enzymes that no longer interact with cellular NAD(P)/H pools, we perturb the ancient, conserved GxGxxG motif in Rossmann fold enzymes that enables persistent NAD(P)/H recognition. We build variants NRC-01 and NRC-02 on phosphite dehydrogenase (PTDH), which eliminate electron leaking to NAD(P)H-dependent side reactions while driving NMNH-dependent biotransformation with ~240-fold higher productivity than existing catalysts. Testing the design principle on 12 other vastly diverse enzymes yields additional NMN(H)-orthogonal enzymes catalyzing valuable biomanufacturing reactions, and reveals a potential rule predicting the translatability of this method. Rosetta modeling, structural alignment, and experimental results reveal that Rossmann fold reprogramming, paired with engineered structural reinforcement, may offer a general route to orthogonal redox biocatalysts.
    DOI:  https://doi.org/10.1038/s41467-026-77633-7
  57. Eur J Hum Genet. 2026 Oct 12.
    Optimized RNA-seq workflow for routine diagnosis of mitochondrial diseases using aberrant expression analysis and phenotype-driven prioritization.
    Lucile Riera-Navarro, Eléonore Birgy, Samira Ait-El-Mkadem Saadi, Alexandre Janin, Annabelle Chaussenot, Sarra Bouri, Konstantina Fragaki, Bruno Francou, Patrick Edery, Elsa Kaphan, Gaetan Lesca, Fabienne Ory Magne, Pascal Cintas, Julien Maquet, Celia Hoebeke, Aline Cano, Alain Fouilhoux, Marion Aubert Mucca, Olivier Patat, Véronique Paquis-Flucklinger, Sylvie Bannwarth, Vincent Procaccio, Marco Lorenzi, Cécile Rouzier.
      Mitochondrial diseases (MD) are the most common inherited metabolic disorders and show marked clinical and genetic heterogeneity. Despite widespread use of whole-exome (WES) and whole-genome sequencing (WGS), nearly half of patients remain without molecular diagnosis, partly due to difficulties in interpreting variants affecting RNA splicing or gene expression. RNA sequencing (RNA-seq) has shown promise in research settings, few studies have evaluated its feasibility in routine clinical diagnostics under technical and financial constraints. We evaluated the implementation of RNA-seq in a routine diagnostic workflow for MD using fibroblasts from 38 patients, including 8 analyzed with a candidate-gene approach and 30 with an untargeted strategy. To optimize the workflow and improve sensitivity in untargeted analyses, we focused on aberrant expression detection using OUTRIDER with complementary analytical strategies, including multiple testing correction restricted to disease-relevant gene sets and Z-score-based outlier detection combined with phenotype-driven prioritization using Human Phenotype Ontology terms. This combined strategy enabled diagnostic performance comparable to previously published studies while optimizing resources. Pathogenicity was confirmed in 75% of targeted cases (6/8). In the untargeted cohort, new molecular diagnoses were established in 13% of patients (4/30), despite fewer samples than typically recommended and minimizing costs. Our study demonstrates that RNA-seq is feasible and clinically informative in a routine diagnostic setting despite analytical and financial constraints. RNA-seq represents a valuable complement to WES/WGS for improving variant interpretation and diagnostic yield in MD. We propose a practical framework for its implementation alongside genome sequencing in routine diagnostics.
    DOI:  https://doi.org/10.1038/s41431-026-02256-x
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