bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–02–15
sixty-two papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial presequences are more than just address labels.
  2. Molecular Mechanism of Mitochondrial Complex I Disruption by m.14484T>C Underlying Leber Hereditary Optic Neuropathy.
  3. Super-Refractory Status Epilepticus (SRSE) in a Patient With Compound Heterozygous OPA1 Variants: Case Report and Literature Review.
  4. Optic neuropathy arising from the synergy between YARS2 and mitochondrial COX1 mutations.
  5. In and out of the mitochondrial intermembrane space.
  6. Rhabdomyolysis due to mtDNA pathogenic variants: Report of a subject with a novel MT-CO3 variant and review of the literature.
  7. The bottleneck of fat burning.
  8. Expanding the Phenotypic Spectrum of NDUFS6-Related Disease: From Neonatal Mitochondrial Encephalopathy to Childhood-Onset Axonal Neuropathy.
  9. Mechanisms and disease relevance of mitochondrial translation in humans.
  10. Mitophagy bridges glucose metabolism, inflammation and neuroprotection in astrocytes.
  11. Single-cell mitochondrial lineage tracing: Opportunities and challenges.
  12. p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control.
  13. Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.
  14. Short telomeres in mitochondrial DNA depletion disorders.
  15. Altered senescence and mitochondrial transcriptome defines age-related changes in satellite cells.
  16. Cognate amino acid therapies provide preclinical benefit in 19 C. elegans models of ARS2 deficiency.
  17. Fusion Between Control Mesoangioblasts and mtDNA-Mutant Myotubes Preserves Myotube Morphology and Mitochondrial Network Organization.
  18. Molecular mechanisms of mitochondrial AAA+ proteases.
  19. STIM1-containing contact sites promote direct calcium flux from the endoplasmic reticulum to mitochondria.
  20. Divergent mitochondrial and metabolic adaptations shape selective vulnerability in ALS.
  21. RareCollab -- An Agentic System Diagnosing Mendelian Disorders with Integrated Phenotypic and Molecular Evidence.
  22. Illuminating Mitochondrial RNA G-Quadruplexes as Structural Brakes on RNA Granule Assembly and OXPHOS.
  23. Neuronal intranuclear inclusion disease: a diagnostic pitfall for MELAS.
  24. The importance of mitochondria and mitochondrial calcium signaling in health and disease: an updated outlook on inflammation.
  25. Proximity labeling unveils potential roles of the Miro2-CISD1 network in mitochondrial dynamics and neuronal differentiation.
  26. HuR-Driven Reversible Mitochondrial Shuttling Buffers Cytosolic miRNA Levels in Hepatic Cells.
  27. A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
  28. Mitochondrial Ca2+ efflux controls neuronal metabolism and long-term memory across species.
  29. Mammalian Mitochondrial DNA Accumulates Insertions and Deletions with Age in Energetically Demanding Tissues.
  30. Mitochondrial DNA Analysis Should Be Considered in the Genetic Assessment of Focal Segmental Glomerulosclerosis or Unexplained Chronic Kidney Disease: A Case Report.
  31. Zinc protects against neuroinflammation after spinal cord injury by regulating mitophagy-dependent mtDNA-cGAS-STING signaling.
  32. Statistical interpretation of mtDNA matches in two uncommon types of forensic cases.
  33. Myopathy and ataxia related to impaired mitochondrial function in mevalonate kinase deficiency.
  34. Structural and biochemical basis of ROC-dependent activation of LRRK2.
  35. ASSOCIATION ANALYSIS OF MITOCHONDRIAL HETEROPLASMIC VARIANTS AND CARDIOMETABOLIC TRAITS.
  36. Sarcopenia and Muscle Aging: Updated Insights into Molecular Mechanisms and Translational Therapeutics.
  37. Dissecting Mitochondrial Sulfur Dioxide Generation Mechanism in Rheumatoid Arthritis with a NIR Luminogenic Iridium(III)-Based Probe.
  38. MSTO1-related mitochondrial myopathy and ataxia syndrome: Case series and literature review.
  39. Expanding the Clinical Spectrum of SCN8A-Related Epileptic Encephalopathy: Additional Auditory Impairment, Atypical MRI Abnormalities and Putative Mitochondrial Involvement.
  40. Growth hormone enhances mitochondria biogenesis and endows mitochondrial thermogenesis in murine adipocytes.
  41. Catalytic relevance of a quinol anion in biological energy conversion by respiratory complex I.
  42. Molecular mechanisms of mitochondrial Ca 2+ exchanger NCLX.
  43. Sialin-STAT3 axis regulates bone homeostasis in mice.
  44. Conformational Remodeling Underlies Activity Loss in Disease-Linked Asparagine Synthetase Variant.
  45. Unveiling Specificity, Redundancy, and Promiscuity of Five Saccharomyces cerevisiae Mitochondrial Carriers.
  46. Mitochondrial CircRNA CircMT-RNR2 Safeguards Antioxidant Defense to Support Fibroblast Functions in Wound Repair.
  47. New Insights on Mitochondria-Targeted Neurological Drugs.
  48. DRP1 in Reproduction and Reproductive Aging.
  49. URMD-Seq: A high-throughput method for scalable detection of ultra-rare mutations in the human mitochondrial genome.
  50. Semaglutide Protects Retinal Ganglion Cells Against Rotenone-Induced Degeneration via Improved Glucose Metabolism.
  51. MELAS Syndrome Presenting with Hypertrophic Cardiomyopathy and Advanced Heart Failure: A Multisystem Diagnostic Challenge.
  52. Missing the rhythm in skeletal muscle mitochondrial respiration.
  53. Distinct effects of ketogenic and non-ketogenic weight-loss diets on hepatic steatosis and mitochondrial metabolism in MASLD.
  54. M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress.
  55. Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation.
  56. Sympathetic innervation regulates metabolic flexibility of skeletal muscle.
  57. Mitochondrial D-loop region methylation differentiates Parkinson's disease from atypical parkinsonism and Parkinson's disease dementia.
  58. A chemical-genetic approach to target voltage-sensitive fluorophores to mitochondria.
  59. Carbon Dots and Mitochondria-Advances in Targeting, Imaging, and Therapeutics.
  60. MitoTex (Mitochondria Texture Analysis User Interface): Open-Source Framework for Textural Characterization and Classification of Mitochondrial Structures.
  61. Sleep in MELAS syndrome.
  62. Optimised measurement of mitochondrial respiratory capacity in frozen rat liver and heart.
  1. Protein Sci. 2026 Mar;35(3): e70491
    Mitochondrial presequences are more than just address labels.
    Erik Marcel Heller, Svenja Lenhard, Doron Rapaport, Johannes Herrmann.
      Most mitochondrial proteins are synthesized in the cytosol as precursor proteins with N-terminal presequences. These presequences serve as targeting signals that facilitate the binding to mitochondrial surface receptors and translocation across the mitochondrial membranes. However, recent studies showed that presequences can be more than address tags. They can contain degradation signals recognized by components of the ubiquitin-proteasome system, and therefore, serve as timers that determine the lifespan of newly synthesized precursor proteins. Moreover, presequences can interact with components of the cytosolic chaperone system to prevent or delay precursor folding. Finally, presequences of some dually localized proteins contain targeting information not only for mitochondria but also for other cellular destinations such as the nuclear lumen or chloroplasts in plant cells. Thus, presequences contain multifaceted information to endow mitochondrial precursor proteins with specific properties that are critical for the early steps of mitochondrial protein biogenesis.
    Keywords:  Presequence; chaperones; mitochondria; proteasome; protein import; ubiquitin ligases
    DOI:  https://doi.org/10.1002/pro.70491
  2. bioRxiv. 2026 Jan 30. pii: 2026.01.28.701874. [Epub ahead of print]
    Molecular Mechanism of Mitochondrial Complex I Disruption by m.14484T>C Underlying Leber Hereditary Optic Neuropathy.
    Pujan Ajmera, Daniel Guion, Steven Barnes, Alfredo A Sadun, Anastassia N Alexandrova.
      Leber's Hereditary Optic Neuropathy (LHON) is a rare genetic condition and severe neurological disorder characterized by dysfunctional mitochondria under extreme oxidative stress, resulting in retinal ganglion cell death and subsequent rapid bilateral loss of central vision. The m.14484T>C mutation in the ND6 subunit of mitochondrial complex I is known for inducing LHON, and is a prevalent LHON-associated mutation, yet its mechanism of impairment at the molecular level is currently unresolved. In this study, we explore the biophysical underpinnings of this mutation and its role in LHON through disruption of human complex I function. We consider, using atomistic simulations, the differential thermodynamics and kinetics of coenzyme Q10 binding between the mutant and wild-type forms, altered dynamics of the complex upon mutation, and key interactions between coenzyme Q10 and complex I binding sites. The hydrogen bond network present near and within the coenzyme Q10 binding domain, along with proper hydration of E-channel residues that couple redox chemistry to proton pumping, is found to be critical for complex I stability and quinone binding, which the ND6-centered mutation disrupts.
    DOI:  https://doi.org/10.64898/2026.01.28.701874
  3. Ann Clin Transl Neurol. 2026 Feb 11.
    Super-Refractory Status Epilepticus (SRSE) in a Patient With Compound Heterozygous OPA1 Variants: Case Report and Literature Review.
    Pouria Mohammadi, Lara Basovic, Christopher Michael McGraw.
       OBJECTIVE: Super-Refractory Status Epilepticus (SRSE) is a rare, life-threatening neurological emergency with unclear etiology in many cases. Mitochondrial dysfunction, often due to disease-causing genetic variants, is increasingly recognized as a cause, with each gene producing distinct pathophysiological mechanisms.
    METHODS: We describe the detailed clinical, neurophysiological, neuroimaging, and molecular findings of a 19-year-old female with SRSE associated with compound heterozygous variants in OPA1, a key gene for mitochondrial inner membrane fusion and cristae maintenance. In addition, a literature review was performed, identifying 16 previously published cases reporting one or both of the variants observed in the present case.
    RESULTS: Despite a longstanding history of generalized hypotonia, celiac disease, optic atrophy, cerebellar ataxia, and progressive motor decline, the proband had no prior history of seizures. She developed super-refractory status epilepticus with occipital-predominant epileptiform activity and MRI showing transient diffusion restriction in the right parieto-occipital cortex and cerebellum. Genetic testing revealed a frameshift variant (p.Val903GlyfsTer3) and a missense variant (p.Ile382Met) in the GTPase domain, known to impair mitochondrial fusion. Unlike POLG or MELAS-associated seizures, typically driven by severe mtDNA depletion and respiratory chain failure, OPA1 dysfunction usually spares mtDNA copy number but disrupts mitochondrial dynamics. In severe biallelic loss-of-function, a "second-hit" stressor may trigger a diffuse energy crisis and catastrophic seizures.
    INTERPRETATION: This case of mitochondrial SRSE in a patient with no known infectious, autoimmune, or structural cause emphasizes the possible role of genetic background and mitochondrial disorders in the development of the disease. This case highlights a rare mitochondrial subtype of RSE, emphasizing the need to consider energy metabolism defects in unexplained refractory status epilepticus.
    Keywords:  OPA1; SRSE; mitochondrial disease; mitochondrial dynamics; super‐refractory status epilepticus
    DOI:  https://doi.org/10.1002/acn3.70287
  4. J Genet Genomics. 2026 Feb 08. pii: S1673-8527(26)00047-0. [Epub ahead of print]
    Optic neuropathy arising from the synergy between YARS2 and mitochondrial COX1 mutations.
    Huiying Li, Cheng Ai, Xiaofen Jin, Jing Wang, Jun Yu, Yinlong Gao, Douglas C Wallace, Min-Xin Guan.
      Leber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy. Here, we investigate the mechanism underlying the interaction between nuclear modifier and mtDNA mutation(s) that manifests optic neuropathy in vivo to develop an effective therapeutic approach for this disease using mouse models bearing LHON-linked Yars2G186V or COIV421A mutation alone and double mutations. Yars2G186V alters mitochondrial translation and assembly and activities of complex I, III, and IV, while COIV421A reduces complex IV activity. However, a single Yars2G186V or COIV421A mutation causes mild declines in ATP production and yields relatively mild degeneration of retinal ganglion cells (RGCs). Notably, the synergy between COIV421A and Yars2G186V mutations aggravates mitochondrial dysfunction and oxidative stress. Interestingly, COIV421A mainly promotes apoptosis, and Yars2G186V contributes to ferroptosis. The combination of two mutations accelerates the degeneration of RGCs and photoreceptors. Strikingly, AAV-mediated Yars2 expression in the mouse retina carrying both Yars2G186V and COIV421A mutations corrects the defective translation and ferroptosis arising from the Yars2G186V mutation and remarkably improves mitochondrial function and causes morphologic and functional recovery of RGCs and photoreceptors. These findings provide mechanistic insights into the pathophysiology of LHON arising from nuclear modifiers and mtDNA mutation(s) and potential therapeutic strategies for LHON and other mitochondrial diseases.
    Keywords:  Apoptosis; Ferroptosis; Gene therapy; Mitochondrial DNA mutation; Mitochondrial tyrosyl-tRNA synthetase; Optic neuropathy; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.jgg.2026.02.003
  5. Protein Sci. 2026 Mar;35(3): e70493
    In and out of the mitochondrial intermembrane space.
    Fara van der Schans, Kostas Tokatlidis, Daniela G Vitali.
      Mitochondria are essential organelles constituted by two membranes, the outer (OMM) and inner mitochondrial membrane (IMM), and two aqueous compartments, the intermembrane space (IMS) and the matrix. Although mitochondria contain their own genome, which encodes for 13 proteins in humans (8 in budding yeast), the vast majority (99%) of mitochondrial proteins are encoded by the nuclear DNA and imported into the organelle co- or post-translationally. The IMS lies between the cytosol and the matrix, making it a strategic hub for monitoring the mitochondrial proteome. All IMS-resident proteins are nuclear-encoded and play critical roles in cellular pathways, such as redox regulation, calcium signaling, apoptosis, and hypoxia response. Furthermore, most mitochondrial proteins pass through the IMS en route to their final destination within the organelle. During this transit, their targeting and folding states are carefully monitored: properly folded proteins are retained, while misfolded or potentially toxic polypeptides are retrotranslocated and degraded. In this review, we highlight the mechanisms by which proteins are sorted into the IMS and discuss its central role in regulating mitochondrial proteostasis and maintaining mitochondrial function.
    Keywords:  Mia40; intermembrane space; oxidative folding; proteostasis
    DOI:  https://doi.org/10.1002/pro.70493
  6. Mol Genet Metab. 2026 Feb 08. pii: S1096-7192(26)00050-8. [Epub ahead of print]147(3): 109767
    Rhabdomyolysis due to mtDNA pathogenic variants: Report of a subject with a novel MT-CO3 variant and review of the literature.
    Emanuele Barca, Nuri Jacoby, Ali Naini, Michael L Miller, Valentina Emmanuele, Christopher J Winfree, Saba Tadesse, Kurenai Tanji, Michio Hirano.
      Rhabdomyolysis can be due to mitochondrial myopathy, but mitochondrial DNA (mtDNA) pathogenic variants are often overlooked in standard genetic panels. We report a 41-year-old woman with recurrent rhabdomyolysis due to a novel MT-CO3 variant. Muscle biopsy showed cytochrome c oxidase-negative fibers that segregated with high heteroplasmic load on single-fiber. We additionally review previously reported mtDNA variants associated with rhabdomyolysis, highlighting the diagnostic relevance of mtDNA analysis and tissue-specific testing in unexplained rhabdomyolysis.
    Keywords:  COX stain; Mitochondrial DNA; Rhabdomyolysis; Single-fiber analysis; mtDNA pathogenic variant
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109767
  7. Science. 2026 Feb 12. 391(6786): 659-660
    The bottleneck of fat burning.
    Angela M Ramos-Lobo, Pierre Maechler.
      A mitochondrial transport protein promotes carnitine synthesis in mice when fat consumption is needed.
    DOI:  https://doi.org/10.1126/science.aef2173
  8. Int J Mol Sci. 2026 Jan 29. pii: 1375. [Epub ahead of print]27(3):
    Expanding the Phenotypic Spectrum of NDUFS6-Related Disease: From Neonatal Mitochondrial Encephalopathy to Childhood-Onset Axonal Neuropathy.
    Savas Baris, Rojan Ipek, Saniye Tugba Baris, Ibrahim Baris.
      Biallelic variants in NDUFS6, encoding an accessory subunit of mitochondrial complex I, were initially associated with lethal neonatal mitochondrial encephalopathy and Leigh syndrome. Recent studies have demonstrated that NDUFS6 variants can also cause childhood- or adolescent-onset axonal neuropathy and Charcot-Marie-Tooth (CMT)-like phenotypes, indicating marked clinical heterogeneity. Here, we report a patient with a novel homozygous truncating NDUFS6 variant presenting with a neuropathy-predominant phenotype accompanied by epilepsy, in the absence of neonatal metabolic decompensation. The patient presented with childhood-onset progressive gait abnormality, pes cavus deformity, distal weakness requiring Achilles tendon-release surgery, pyramidal signs, urinary incontinence, and focal epileptiform EEG findings. Brain MRI showed bilateral lenticular nucleus abnormalities. Whole-exome sequencing identified a novel homozygous NDUFS6 nonsense variant (c.130C>T, p.Gln44*). While neuropathy has previously been reported primarily in association with the recurrent splice-site variant c.309+5G>A, our findings demonstrate that truncating NDUFS6 mutations can also underlie a neuropathy-predominant phenotype. Together with previously published cases, our findings support a phenotypic heterogeneity ranging from lethal encephalopathy to neuropathy and reinforce the role of NDUFS6 as a disease-causing gene for inherited peripheral neuropathy. These data support inclusion of NDUFS6 among established neuropathy and Charcot-Marie-Tooth genes.
    Keywords:  CMT; NDUFS6; epilepsy; neuropathy
    DOI:  https://doi.org/10.3390/ijms27031375
  9. Nat Rev Mol Cell Biol. 2026 Feb 13.
    Mechanisms and disease relevance of mitochondrial translation in humans.
    Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach.
      Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41580-026-00948-2
  10. Autophagy. 2026 Feb 12. 1-3
    Mitophagy bridges glucose metabolism, inflammation and neuroprotection in astrocytes.
    Hanna Hakansson, Jack H Howden, Josef T Kittler.
      Mitochondria regulate ATP production, calcium buffering, and apoptotic signaling, and clearing dysfunctional mitochondria by mitophagy is essential for cellular homeostasis. While PINK1-dependent mitophagy is well-characterized in neurons, its function in glial cells such as astrocytes is less understood. Our study demonstrates that PINK1-mitophagy in astrocytes occurs faster and with less spatial restriction compared to neurons. This pathway was specifically regulated in astrocytes by the glycolytic enzyme, HK2 (hexokinase 2), which forms a glucose-dependent complex with PINK1 following mitochondrial damage. Inflammation also induces HK2-PINK1 mitophagy, and its activation in astrocytes protects against cytokine-induced neuronal death. Our findings characterize a novel HK2-PINK1 pathway in astrocytes that bridges mitophagy, metabolism, and immune signaling.Abbreviation: HK2: hexokinase 2; PD: Parkinson disease; PINK1: PTEN induced kinase 1; S65: serine 65.
    Keywords:  Astrocyte; HK1; PINK1; mitochondria; mitophagy; neurodegeneration; parkin
    DOI:  https://doi.org/10.1080/15548627.2026.2623987
  11. Quant Biol. 2026 Mar;14(1): e70018
    Single-cell mitochondrial lineage tracing: Opportunities and challenges.
    Siqi Li, Kun Wang, Xin Wang, Zheng Hu.
      Lineage tracing using endogenous mitochondrial DNA (mtDNA) variants holds great promise for reconstructing the lineage histories of individual cells, with broad applications in oncology, developmental biology, and regenerative medicine. Unlike synthetic DNA barcoding techniques, mitochondrial lineage tracing does not require genetic engineering of exogenous genetic markers, and thus is particularly suitable for human clinical samples. Various experimental and computational methods have been developed to profile mtDNA variants from single-cell genomic, transcriptomic, and epigenomic sequencing data. Despite the technical advances, several challenges still limit the robustness of single-cell mitochondrial lineage tracing, such as random genetic drift, genetic bottlenecks, informative variant identification, and low mtDNA coverage. In this review, we systematically examine current experimental and computational approaches for analyzing mtDNA variants in single cells and discuss current challenges and future technical developments aimed at enhancing the robustness and applicability of single-cell mitochondrial lineage tracing.
    Keywords:  lineage tracing; mtDNA variants; phylogenetic reconstruction; single‐cell genomics
    DOI:  https://doi.org/10.1002/qub2.70018
  12. Aging Cell. 2026 Feb;25(2): e70402
    p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control.
    Shan Sun, Jiaqi Xin, Yingping Zhang, Bojun Yang, Dan Su, Rui Ni, Qilian Ma, Ningning Li, Guoqiang Ma, Qiang Peng, Siqian Chen, Jochen H M Prehn, Kin Yip Tam, Hongfeng Wang, Zheng Ying.
      Mitochondrial quality control is tightly associated with aging-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Previous studies reported that ALS/FTD-associated protein p62 drives "mitochondrial clustering" (perinuclear clustering of fragmented and swollen mitochondria) during PINK1/Parkin-mediated mitophagy, but the underlying molecular mechanism, especially the precise role of p62 in mitochondrial clustering during mitophagy and the potential relationship between the mitochondrial quality control mediated by p62 and disease pathogenesis of ALS/FTD, remains unclear. Here, using cell biology in combination with an optogenetic tool, we show that the phase separation (condensation) of p62 mediates the clustering of damaged mitochondria to form "grape-like" clusters during PINK1/Parkin-mediated mitophagy, which is tightly associated with aging-related neurodegenerative diseases. In addition, our data suggest this mitochondrial clustering process is an arrest mechanism driven by p62 condensation (beyond the function of other autophagy receptors in mitophagy), which acts as a "brake" to reduce the surface area of dysfunctional mitochondria within cytoplasm for minimizing mitochondrial turnover in cells. Moreover, ALS/FTD-related pathological mutations perturb p62 condensation, thereby inhibiting mitochondrial clustering and destroying the "brake" machinery of mitochondrial quality control. Together, our data highlight how p62 condensation modulates organelle quality control in cell biology, and the important role of p62 condensation in both physiology and pathology.
    DOI:  https://doi.org/10.1111/acel.70402
  13. Transl Neurodegener. 2026 Feb 13. 15(1): 5
    Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.
    Abhishek Jauhari, Tanisha Singh, Diane L Carlisle, Robert M Friedlander.
      Mitochondrial DNA (mtDNA) plays a pivotal role in the regulation of neuroinflammation, acting as a potent trigger of innate immune responses when released into the cytoplasm or extracellular space. mtDNA is structurally similar to bacterial DNA, containing unmethylated CpG motifs that are readily recognized by immune sensors. Under conditions of cellular stress, injury, or mitochondrial dysfunction, mtDNA can escape into the cytoplasm, where it activates the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway, or it can be detected extracellularly by Toll-like receptors on immune cells. These signaling events lead to the production of pro-inflammatory cytokines and type I interferons, amplifying neuroinflammatory responses. In the central nervous system, this process contributes to the pathogenesis of various neurodegenerative and inflammatory conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), etc.. The dual role of mtDNA as both a damage-associated molecular pattern and a signaling molecule underscores its importance as a therapeutic target for modulating neuroinflammation and protecting against progressive neuronal damage. In this review, we will discuss the implications of mtDNA-mediated neuroinflammation in neurodegenerative diseases, including AD, PD, and HD, highlighting its potential as a diagnostic biomarker and therapeutic target.
    Keywords:  Mitochondria; Mitochondrial DNA; Neurodegeneration; Neuroinflammation
    DOI:  https://doi.org/10.1186/s40035-026-00540-w
  14. Mitochondrion. 2026 Feb 10. pii: S1567-7249(26)00021-8. [Epub ahead of print]88 102131
    Short telomeres in mitochondrial DNA depletion disorders.
    Yumi Dille, Emmanouil Rampakakis, Geraldine Aubert, Christelle Dassi, William Mannherz, Saoussen Berrahmoune, Myriam Srour, Daniela Buhas, Suneet Agarwal, Kenneth A Myers.
      Mitochondrial DNA (mtDNA) depletion disorders (MDDs) are rare, genetically diverse conditions marked by a significant reduction in mtDNA, primarily affecting energy-demanding tissues such as muscle, liver, and brain, sometimes leading to catastrophic multisystem failure. In a cohort of patients with MDDs, we measured telomere length in lymphocytes, granulocytes, T cells, and B cells, and compared to healthy controls. Telomere length was shorter overall in patients with MDDs, with the most significant differences observed in granulocytes. The observation that mtDNA depletion is associated with shorter telomeres may provide insight into MDD pathophysiology. Telomere length may have potential as a biomarker in mitochondrial disease, but further study is needed.
    Keywords:  C10orf2; DGUOK; Mitochondrial DNA depletion disorders; POLG; RRM2B; SUCLA2; SUCLG1; TK2; TYMP; Telomere length; Telomeres
    DOI:  https://doi.org/10.1016/j.mito.2026.102131
  15. Front Cell Dev Biol. 2025 ;13 1699206
    Altered senescence and mitochondrial transcriptome defines age-related changes in satellite cells.
    Fasih A Rahman, Joe Quadrilatero.
      Aging impairs the regenerative capacity of skeletal muscle in part through the functional decline of the resident stem cell population called satellite cells. With age, satellite cells exhibit a loss of quiescence, altered proliferation, and impaired differentiation, leading to incomplete myogenesis following injury. Mitochondria are central to stem cell function, providing ATP, regulating redox homeostasis, and integrating several signaling pathways during lineage progression. While mitochondrial remodeling and function is essential for supporting the metabolic demands of myogenesis, the extent to which these processes are altered in aged satellite cells across cell states remains unclear. To address this, we performed a comparative transcriptomic analysis of young and aged satellite cells in quiescent, proliferating, and early differentiating states using three publicly available microarray datasets. Our results reveal that aged satellite cells exhibit a dysregulated senescence profile, characterized by the simultaneous upregulation of both senescence-inducing and -inhibiting genes, suggestive of a metastable senescence state. These features persisted during early differentiation, where aged cells also displayed increased expression of senescence-associated secretory phenotype (SASP) components, potentially contributing to a pro-inflammatory niche. Mitochondrial gene expression was relatively stable in quiescent cells but showed marked remodeling upon activation, particularly in aged cells. While young satellite cells upregulated transcriptional programs related to mitochondrial function, aged cells exhibited broader and less coordinated responses enriched for stress, apoptotic, and metabolic pathways. Despite evidence of mitochondrial stress, mitophagy gene activation remained limited in aged cells, raising the possibility of impaired organelle quality control. Together, our findings highlight age-associated disruptions in both senescence and mitochondrial remodeling programs across the satellite cell lifecycle. These transcriptional changes likely underlie impaired regenerative responses in aging muscle and identify potential targets for rejuvenating muscle stem cell function.
    Keywords:  SASP; aging; mitochondrial remodeling; satellite cell; senescence; skeletal muscle; skeletal muscle regeneration
    DOI:  https://doi.org/10.3389/fcell.2025.1699206
  16. bioRxiv. 2026 Feb 05. pii: 2026.02.03.703549. [Epub ahead of print]
    Cognate amino acid therapies provide preclinical benefit in 19 C. elegans models of ARS2 deficiency.
    Cristina Remes, Kelsey Keith, Rui Xiao, Vernon E Anderson, Donna M Iadarola, Eiko Nakamaru-Ogiso, Neal D Mathew, Marni J Falk.
      Mitochondrial aminoacyl-tRNA synthetases (mt-ARS) are essential mitochondrial translation machinery components that catalyze mitochondrial transfer RNAs (tRNAs) charging with their cognate amino acid. Although mt-ARS have a common biochemical function, patients with mt-ARS pathogenic variants commonly develop neurological disorders with varying phenotypes, severity spectrum, and age of onset. Cognate amino acid supplementation has shown reported benefits in select cases of both mt-ARS ( ARS2 ) and cytosolic ( ARS1 ) deficiencies, although the safety and potential benefits of this candidate therapy approach across the full spectrum of mt-ARS disorders remain unclear. Here, C. elegans models were systematically generated for all 19 mitochondrial mt-ARS genes by feeding RNAi knockdown for one or two generations. mt-ARS deficient animals at baseline and upon cognate amino acid treatment were studied at the level of linear growth, neuromuscular activity, lifespan, mitochondrial physiology, and fertility. Results demonstrated that cognate amino acid treatment in a dose-dependent fashion consistently improved worm linear growth and neuromuscular activity, and reduced mitochondrial unfolded protein response stress, in all 19 knockdown models. It further rescued impaired fertility of hars-1 and fars-2 knockdown strains. Collectively, these preclinical studies provide compelling evidence to warrant future cognate amino acid treatment study in rigorous clinical trials spanning all human mt-ARS deficiencies.
    DOI:  https://doi.org/10.64898/2026.02.03.703549
  17. Int J Mol Sci. 2026 Jan 29. pii: 1357. [Epub ahead of print]27(3):
    Fusion Between Control Mesoangioblasts and mtDNA-Mutant Myotubes Preserves Myotube Morphology and Mitochondrial Network Organization.
    Somaieh Ahmadian, Patrick J Lindsey, Monique Ummelen, Anton Hopman, Marc A M J van Zandvoort, Hubert J M Smeets, Florence H J van Tienen.
      Mitochondria are the energy factories of a cell and mitochondrial morphology, quantity, membrane potential, and DNA copy number can change depending on metabolic requirements and/or genetic defects. Different mutations in mitochondrial DNA might affect mitochondrial morphology and membrane potential differently. In this study we investigated mitochondrial morphology and membrane potential in vitro in mesoangioblast-derived human myotubes harboring a pathogenic mtDNA mutation and analyzed mitochondrial behavior following fusion with healthy mesoangioblasts. Myotubes were differentiated in vitro from mesoangioblasts obtained from two mitochondrial myopathy patients, M02 (96% m.3271T>C) and M11 (73% m.3291T>C), and from a functionally healthy male control, M06 (3% m.3243A>G). On day 5 of differentiation, healthy male mesoangioblasts (mM06) were added to mutant myotube cultures to allow cell fusion. On day 11, mitochondrial morphology and membrane potential were assessed by three-dimensional live-cell imaging using spinning disk confocal microscopy with tetramethylrhodamine methyl ester (TMRM). Following live imaging, cells were fixed and subjected to Y-chromosome fluorescence in situ hybridization (FISH), enabling identification and retrospective analysis of hybrid (i.e., fused with male control mesoangioblasts) and non-hybrid (i.e., not fused with these control mesoangioblasts) myotubes within the same imaging fields. Quantitative image analysis at the level of individual myotubes revealed that, when normalized to sarcoplasmic volume, mitochondrial volume, object number, and membrane potential did not differ between mutant and control myotubes despite heteroplasmy levels exceeding 70%. Fusion of healthy mM06 mesoangioblasts did not impair myotube formation and resulted in redistribution of mitochondrial content without an increase in mitochondrial object number, consistent with integration of donor mitochondria into the existing mitochondrial network. Across conditions, mitochondrial parameters were strongly influenced by myotube size, underscoring the importance of accounting for biological variation when quantifying mitochondrial features. Together, these findings demonstrate that high mtDNA mutation loads do not necessarily alter mitochondrial morphology or membrane potential under standard in vitro differentiation conditions and provide mechanistic insight into mitochondrial behavior following mesoangioblast fusion in human myotubes. Fusion of healthy mesoangioblasts supports integration of donor mitochondria into the existing network without compromising myogenesis, consistent with mitochondrial mixing rather than replacement.
    Keywords:  mesoangioblasts; mitochondrial mass; mitochondrial membrane potential; mtDNA mutation
    DOI:  https://doi.org/10.3390/ijms27031357
  18. J Biol Chem. 2026 Feb 06. pii: S0021-9258(26)00134-1. [Epub ahead of print] 111264
    Molecular mechanisms of mitochondrial AAA+ proteases.
    S Quinn W Currie, Monica M Goncalves, Aaron D Schimmer, Siavash Vahidi.
      Mitochondrial AAA+ proteases, LONP1, ClpXP, YME1L (i-AAA), and the m-AAA complex, maintain protein quality and shape organelle function. Growing interest in these enzymes stems from their association with neurodegeneration, cardiomyopathy, metabolic disease, and cancer. Recent structural and biophysical work clarifies how ATP-driven conformational cycles enable substrate recognition, unfolding, translocation, and proteolysis, and how assembly state, subunit composition, and regulatory inputs tune activity. These insights help interpret patient variants and guide experiments that connect mechanism to phenotype. Here we review shared mechanistic principles across the four proteases, contrast their architectures and regulatory features, and relate these properties to substrate selection and disease mechanisms, with emphasis on evidence from structural, biochemical, and cellular studies. We also survey strategies to modulate function. Small molecules, exemplified by Dordaviprone (ONC201) which activate human ClpP, provide proof of concept, and emerging modalities such as engineered macromolecules, may offer the selectivity and localization required to correct disease mechanisms or exploit disease dependencies. By integrating mechanism, disease links, and modulation strategies, this review provides a framework for translating basic insight on mitochondrial AAA+ proteases into new tools and, ultimately, therapies.
    Keywords:  ClpXP; LONP1; YME1L; i-AAA; m-AAA; mitochondrial proteostasis
    DOI:  https://doi.org/10.1016/j.jbc.2026.111264
  19. EMBO J. 2026 Feb 11.
    STIM1-containing contact sites promote direct calcium flux from the endoplasmic reticulum to mitochondria.
    Yolanda Orantos-Aguilera, Irene Sanchez-Lopez, Carlos Pascual-Caro, Patricia Gómez-Suaga, Estela Area-Gomez, Eulalia Pozo-Guisado, Jorge Montesinos, Francisco Javier Martin-Romero.
      STIM1 is a transmembrane protein localized in the endoplasmic reticulum (ER), where it acts as a calcium ion sensor, activating store-operated Ca2+ entry upon ER Ca2+ depletion. Via cellular calcium influx, STIM1 is thought to indirectly affect mitochondrial calcium content. Here we show that STIM1 also interacts with mitochondrial proteins such as PTPIP51 and GRP75, suggesting its presence in mitochondria-associated ER membranes (MAMs), which are specialized ER regions that facilitate ER-mitochondria communication. Lowering STIM1 expression disrupts ER-to-mitochondria Ca2+ transfer, reduces basal mitochondrial Ca2+ levels, impairs maximal mitochondrial respiration, and reduces ATP production. The STIM1-GRP75 interaction depends on STIM1's Ca2+-sensing ability. ER Ca2+ depletion or the constitutive-open R429C mutation both reduce STIM1 binding to GRP75, suggesting that conformational changes in STIM1 play a role in this interaction. Deletion analysis revealed that the STIM1 (551-611) segment is crucial for GRP75 binding, as the peptide STIM1(551-611) binds GRP75, while STIM1(Δ551-611) shows reduced binding. These findings reveal a previously unrecognized role of STIM1 in direct inter-organelle communication.
    Keywords:  Calcium; GRP75; MAM; Mitochondria; STIM1
    DOI:  https://doi.org/10.1038/s44318-026-00700-8
  20. bioRxiv. 2026 Feb 02. pii: 2026.01.30.702552. [Epub ahead of print]
    Divergent mitochondrial and metabolic adaptations shape selective vulnerability in ALS.
    Bianca A Cotto, Lizi Zhang, Benjamin Fait, Chris Peralta, Ece Kilic, Henrik Molina, Nathaniel Heintz, Eric F Schmidt.
      Neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) exhibit striking cell-type selectivity, yet the basis for this vulnerability remains elusive. Here, we uncover that even closely related neurons can harbor distinct mitochondrial properties that shape their response to disease. Using TOM-Tag, a circuit-based AAV-based strategy for cell type-specific mitochondrial immunopurification from projection neurons, we performed integrative proteomic, metabolomic, transcriptomic, and functional analyses of mitochondria from ALS-vulnerable corticospinal projection neurons (CSPNs) and resilient corticothalamic projection neurons (CTPNs) in vivo. We discovered that CSPNs and CTPNs exhibit divergent mitochondrial profiles at baseline, despite sharing cortical layer and developmental origin. CTPNs were primed for antioxidant buffering and fatty acid metabolism, whereas CSPNs were enriched for oxidative phosphorylation components. In ALS, CTPNs employed mitochondrial flexibility and redox defense, whereas CSPNs exhibited respiratory failure and metabolic stress. These findings reveal that intrinsic mitochondrial programs vary even between similar neurons, and that this hidden layer of diversity may critically shape susceptibility to neurodegeneration. By enabling high-resolution access to mitochondria in defined neuronal circuits, TOM-Tag offers a powerful new lens for dissecting disease mechanisms and identifying cell-specific therapeutic targets.
    DOI:  https://doi.org/10.64898/2026.01.30.702552
  21. ArXiv. 2026 Feb 03. pii: arXiv:2602.04058v1. [Epub ahead of print]
    RareCollab -- An Agentic System Diagnosing Mendelian Disorders with Integrated Phenotypic and Molecular Evidence.
    Guantong Qi, Jiasheng Wang, Mei Ling Chong, Zahid Shaik, Shenglan Li, Shinya Yamamoto, Undiagnosed Diseases Network, Pengfei Liu, Hu Chen, Zhandong Liu.
      Millions of children worldwide are affected by severe rare Mendelian disorders, yet exome and genome sequencing still fail to provide a definitive molecular diagnosis for a large fraction of patients, prolonging the diagnostic odyssey. Bridging this gap increasingly requires transitioning from DNA-only interpretation to multi-modal diagnostic reasoning that combines genomic data, transcriptomic sequencing (RNA-seq), and phenotype information; however, computational frameworks that coherently integrate these signals remain limited. Here we present RareCollab, an agentic diagnostic framework that pairs a stable quantitative Diagnostic Engine with Large Language Model (LLM)-based specialist modules that produce high-resolution, interpretable assessments from transcriptomic signals, phenotypes, variant databases, and the literature to prioritize potential diagnostic variants. In a rigorously curated benchmark of Undiagnosed Diseases Network (UDN) patients with paired genomic and transcriptomic data, RareCollab achieved 77% top-5 diagnostic accuracy and improved top-1 to top-5 accuracy by ~20% over widely used variant-prioritization approaches. RareCollab illustrates how modular artificial intelligence (AI) can operationalize multi-modal evidence for accurate, scalable rare disease diagnosis, offering a promising path toward reducing the diagnostic odyssey for affected families.
  22. Adv Sci (Weinh). 2026 Feb 12. e23462
    Illuminating Mitochondrial RNA G-Quadruplexes as Structural Brakes on RNA Granule Assembly and OXPHOS.
    Gui-Xue Tang, Jia-Tong Yan, Mao-Lin Li, Cui Zhou, Jian Wang, Shuo-Bin Chen, Zhi-Shu Huang, Jia-Heng Tan.
      G-quadruplexes (G4s) have been extensively investigated in cells, with established methods available for studying nuclear DNA G4s, cytoplasmic RNA G4s, and even mitochondrial DNA G4s. However, mitochondrial RNA (mtRNA) G4s have remained largely unexplored in cells due to the lack of suitable tools, leaving their biological functions poorly understood. Here, through rational molecular design, we developed MitoQUMA, a fluorescent probe that allows the visualization of mtRNA G4 dynamics in live cells. Using this probe, we observed that, unlike cytoplasmic RNA G4s, which generally promote phase separation to form RNA granules, excessive formation of mtRNA G4s correlates with reduced assembly of mitochondrial RNA granules (MRGs). A MitoQUMA-based chemical genetic screen revealed that the Wnt/β-catenin pathway regulates this mitochondrial event by modulating GRSF1 expression, thereby affecting mtRNA G4 abundance and processing. When RNA processing is compromised, mtRNA maturation is impaired, and MRG becomes unstable and undergoes disassembly, ultimately disrupting mitochondrial gene expression and energy metabolism. Collectively, our study introduces a tool for real-time monitoring of mtRNA G4s in cells and identifies the Wnt/β-catenin-GRSF1-mtRNA G4 axis as a previously unrecognized pathway coordinating MRG assembly and energy metabolism, providing new insights into phase separation within mitochondria.
    Keywords:  GRSF1; Wnt/β‐catenin pathway; mitochondrial RNA G‐quadruplex; mitochondrial RNA granule; molecular probe
    DOI:  https://doi.org/10.1002/advs.202523462
  23. BMC Neurol. 2026 Feb 13.
    Neuronal intranuclear inclusion disease: a diagnostic pitfall for MELAS.
    Xu Liu, Zhe-Sheng Zhang, Qing-Qing Tao.
      
    Keywords:  Cognitive impairment; Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; Muscle biopsy; Neurodegenerative disease; Neuronal intranuclear inclusion disease
    DOI:  https://doi.org/10.1186/s12883-026-04705-y
  24. J Transl Med. 2026 Feb 07.
    The importance of mitochondria and mitochondrial calcium signaling in health and disease: an updated outlook on inflammation.
    Giampaolo Morciano, Giulia Pellielo, Esther Densu Agyapong, Cristina Pellegrino, Simone Patergnani, Davide Franceschini, Konstantinos Koutsikos, Leonardo Rigon, Paolo Pinton, Alessandro Rimessi.
      
    Keywords:  Aging; Cancer; Cardiovascular diseases; IBD; Inflammation; Mitochondria; Mitochondria targeted-therapy; Neurodegenerative diseases; ROS; Respiratory diseases; mtDNA
    DOI:  https://doi.org/10.1186/s12967-026-07783-1
  25. Commun Biol. 2026 Feb 09. 9(1): 195
    Proximity labeling unveils potential roles of the Miro2-CISD1 network in mitochondrial dynamics and neuronal differentiation.
    Im Kyeung Kang, Sunwoo Lee, Tae Kwon Moon, A Reum Han, Dae Bong Yu, Minkyo Jung, Chulhwan Kwak, Jeong Kon Seo, Hyun-Woo Rhee, Seong Who Kim, Ha-Na Woo, Ji Young Mun, Heuiran Lee.
      Adult hippocampal neurogenesis, crucial for maintaining neural homeostasis, is integral to neurodegeneration. We previously identified Miro2 as a key regulator of mitochondrial dynamics and survival in hippocampal neural stem cells with potential relevance to Alzheimer's disease. Here, using TurboID-based proximity labeling, we explore Miro2's interaction networks and identify sixty-six unique interactors specific to hippocampal neural stem cells. Functional enrichment analysis reveals that these proteins are crucial for mitochondrial organization, transport, and neurodegeneration. CISD1 emerges as a significant interaction partner. Knockdown of Miro2 and CISD1 impairs mitochondrial trafficking in adult hippocampal stem cells, disrupted stem cell differentiation with increased cytotoxicity. Rescue experiments partially reverse cell death, and both Miro2 and CISD1 show increased expression and interaction during differentiation. These findings suggest the Miro2-CISD1 axis as a critical regulator of mitochondrial remodeling and neurogenesis, providing a framework for future studies on how mitochondrial dynamics contribute to neurodegenerative disease mechanisms.
    DOI:  https://doi.org/10.1038/s42003-025-08990-0
  26. J Biol Chem. 2026 Feb 06. pii: S0021-9258(26)00125-0. [Epub ahead of print] 111255
    HuR-Driven Reversible Mitochondrial Shuttling Buffers Cytosolic miRNA Levels in Hepatic Cells.
    Saikat Banerjee, Sourav Hom Choudhury, Susanta Chatterjee, Guoku Hu, Kamalika Mukherjee, Suvendra N Bhattacharyya.
      Subcellular compartmentalization may be an effective way of controlling the abundance and activity of miRNAs in mammalian cells. Exploring the regulatory processes that control miRNA activity, we found that specific miRNAs are reversibly localized to the mitochondrial matrix in a context-dependent manner. Our data suggest a de novo role of mitochondria as miRNA storage site in mammalian cells. miR-122 is a key hepatic miRNA regulating metabolic processes in the mammalian liver. In this study, we observed increased mitochondrial targeting of miR-122 in amino acid-starved hepatic cells. Interestingly, when cells are refed with amino acids, mitochondrial miR-122 is relocalized to the cytosol and reused for translational repression. Moreover, this phenomenon is not limited to miR-122, as other mitochondrial miRNAs (mito-miRs) follow similar transient storage inside mitochondria in stressed cells. Bioinformatic analysis revealed that mitochondria-localized mito-miRs preferentially target mRNAs encoding crucial mitochondrial components related to apoptosis. Hence, hepatic cells regulate apoptosis pathways during the starvation-refeeding cycle by shuttling a specific set of miRNAs to and from mitochondria, thereby balancing cytosolic miRNA content. Stress response miRNA binder ELAVL1 or HuR protein was found to be both necessary and sufficient for transporting the mito-miRs to the mitochondrial matrix - a process also controlled by the interaction between mitochondria and the endoplasmic reticulum.
    Keywords:  Ago2; HuR; miRNA; miRNA import to mitochondria; mito-miRs; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2026.111255
  27. Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00036-7. [Epub ahead of print]45(2): 116958
    A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
    Ying Wang, Xinwan Su, Yu Chen, Yijian Chen, Chengyu Shi, Fangzhou Liu, Yuqi Ye, Panyi Sun, Manman Tan, Meng Yu, Ya Wang, Shanshan Xie, Jian Liu, Qingfeng Yan, Qiming Sun, Dante Neculai, Wei Liu, Jianzhong Shao, Yang Liu, Weiqiang Lin, Aifu Lin.
      Mitochondrial genetic diseases arise from mitochondrial DNA (mtDNA) defects, which gene therapy tools may rectify. However, delivering single-guide RNAs (sgRNAs) into mitochondria remains a challenge limiting CRISPR-mediated mtDNA therapy. Here, through network analysis of mitochondrion-localized long noncoding RNAs (lncRNAs) and RNA-binding proteins (RBPs), we found that lncRNA RP11-46H11.3 translocates into mitochondria via binding mitochondria-associated RBPs using its key RNA recognition motifs (RRMs); its derived 30 nt ST2-RNA mitochondrial targeting sequence (RMTS) showed the highest mitochondrial localization efficiency. We engineered the RMTS-CRISPR tool by fusing ST2-RMTS to sgRNA, verifying its ability to target and cleave mtDNA. Strikingly, our results demonstrated that RMTS-CRISPR could achieve heteroplasmic mtDNA shifting efficiencies of up to 26.37% in m.3243A>G mutant cell models and 26.79% in vivo, offering a technological approach for the correction of heterogeneous mtDNA mutations. Taken together, our findings reveal a CRISPR-based mitochondrial gene intervention strategy that may have applications in mitochondrial disorders.
    Keywords:  CP: genomics; CRISPR-Cas system; RNA recognition motif; mitochondrial DNA; mitochondrial disorder; organelle-associated RNA
    DOI:  https://doi.org/10.1016/j.celrep.2026.116958
  28. Nat Metab. 2026 Feb 11.
    Mitochondrial Ca2+ efflux controls neuronal metabolism and long-term memory across species.
    Anjali Amrapali Vishwanath, Typhaine Comyn, Rodrigo G Mira, Claire Brossier, Carlos Pascual-Caro, Maya Faour, Kahina Boumendil, Chaitanya Chintaluri, Carla Ramon-Duaso, Ruolin Fan, Kishalay Ghosh, Helen Farrants, Jean-Paul Berwick, Riya Sivakumar, Mario Lopez-Manzaneda, Eric R Schreiter, Thomas Preat, Tim P Vogels, Vidhya Rangaraju, Arnau Busquets-Garcia, Pierre-Yves Plaçais, Alice Pavlowsky, Jaime de Juan-Sanz.
      From insects to mammals, essential brain functions, such as forming long-term memories (LTMs), increase metabolic activity in stimulated neurons to meet the energetic demand associated with brain activation. However, while impairing neuronal metabolism limits brain performance, whether expanding the metabolic capacity of neurons boosts brain function remains poorly understood. Here, we show that LTM formation of flies and mice can be enhanced by increasing mitochondrial metabolism in central memory circuits. By knocking down the mitochondrial Ca2+ exporter Letm1, we favour Ca2+ retention in the mitochondrial matrix of neurons due to reduction of mitochondrial H+/Ca2+ exchange. The resulting increase in mitochondrial Ca2+ over-activates mitochondrial metabolism in neurons of central memory circuits, leading to improved LTM storage in training paradigms in which wild-type counterparts of both species fail to remember. Our findings unveil an evolutionarily conserved mechanism that controls mitochondrial metabolism in neurons and indicate its involvement in shaping higher brain functions, such as LTM.
    DOI:  https://doi.org/10.1038/s42255-026-01451-w
  29. Mol Biol Evol. 2026 Feb 10. pii: msag035. [Epub ahead of print]
    Mammalian Mitochondrial DNA Accumulates Insertions and Deletions with Age in Energetically Demanding Tissues.
    Edmundo Torres-González, Barbara Arbeithuber, Nick Stoler, Marzia A Cremona, Omar Shebl, Thomas Ebner, Irene Tiemann-Boege, Francisco Diaz, Francesca Chiaromonte, Kateryna D Makova.
      Mitochondrial function can be affected by mutations in mitochondrial DNA (mtDNA). However, detecting de novo mutations in mtDNA has been challenging due to its high copy number, particularly in germline cells, and the low accuracy of conventional next-generation sequencing technologies. Using highly accurate duplex sequencing, we study the frequency of de novo insertion and deletion (indel) mtDNA mutations across multiple age groups in somatic and germline tissues of three mammalian species-mouse, macaque, and human. We demonstrate that, similar to de novo nucleotide substitutions, indels accumulate rapidly with age in somatic tissues with high energetic demand (brain and skeletal muscle) or high proliferation (liver). However, in oocytes, indels accumulate slower with age than nucleotide substitutions (or do not accumulate at all). The increases in indel frequency with age are driven mostly by deletions. Short tandem repeats are highly enriched for indels, implicating DNA replication slippage as a major driver of indel formation in mtDNA. For some species and tissues, indels are depleted at protein-coding sequences, however, indels that are multiples of 3 bp are not overrepresented. omfOurs is the most detailed study of de novo small indels in mtDNA to date. It provides parameters for models of mtDNA evolution, informs molecular mechanisms for a multitude of human genetic diseases, and illuminates the accumulation of indel mutations with age. Such accumulation may have functional consequences, as it affects reproduction later in life and drives the decline of mitochondrial function during aging.
    DOI:  https://doi.org/10.1093/molbev/msag035
  30. Kidney Med. 2026 Mar;8(3): 101233
    Mitochondrial DNA Analysis Should Be Considered in the Genetic Assessment of Focal Segmental Glomerulosclerosis or Unexplained Chronic Kidney Disease: A Case Report.
    Chloe Borden, Iman Chaudhry, Rhyan Maditz, Sarah Mazzola, Ronit Salomon Kent, Kristen Tomaszewski, Xiangling Wang.
      Genetic testing is increasingly used to assist the precise diagnosis and clinical management of suspected genetic kidney diseases; however, mitochondrial DNA (mtDNA) analysis remains underutilized. Here we report a 61-year-old man who presented with chronic kidney disease (CKD), microscopic hematuria since childhood, bilateral sensorineural hearing loss (SNHL), and peripheral polyneuropathy. Laboratory reports showed serum creatinine 1.5 mg/dL with an estimated glomerular filtration rate of 55 mL/min/1.73m2, no proteinuria, and a negative serological workup. Kidney biopsy demonstrated focal segmental glomerulosclerosis (FSGS) with segmental thinning of glomerular basement membrane and dysmorphic mitochondria. A 401 renal disease gene panel was negative, including type IV collagen genes. mtDNA analysis identified a pathogenic variant in the MT-TV gene (m.1642 G>A; NC_012920.1) with 2% heteroplasmy in leukocyte-derived DNA, confirmed in urine-derived DNA at 5% heteroplasmy. Genetic counseling was offered along with systemic evaluation revealing left ventricular hypertrophy on echocardiogram. The patient was started on levocarnitine and coenzyme Q10 with multidisciplinary care. This is the first reported case of FSGS with dysmorphic mitochondria and a pathogenic MT-TV variant confirmed via both leukocyte-derived and urine-derived DNA. It supports the role of mitochondrial dysfunction in CKD and highlights the importance of mtDNA analysis in the evaluation of FSGS and unexplained CKD.
    Keywords:  Mitochondrial disorders; case report; chronic kidney disease (CKD); focal segmental glomerulosclerosis (FSGS); genetic testing
    DOI:  https://doi.org/10.1016/j.xkme.2025.101233
  31. Free Radic Biol Med. 2026 Feb 09. pii: S0891-5849(26)00107-3. [Epub ahead of print]
    Zinc protects against neuroinflammation after spinal cord injury by regulating mitophagy-dependent mtDNA-cGAS-STING signaling.
    Feng Jin, Zengtao Song, Yu Deng, Hongkai Yang, Yajiang Yuan, Zhanpeng Guo, Haosen Zhao, Xifan Mei.
      Spinal cord injury (SCI) induces secondary damage characterized by mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and chronic neuroinflammation. Cytosolic release of mitochondrial DNA (mtDNA) acts as a potent damage-associated molecular pattern (DAMP) that activates the cGAS-STING pathway and amplifies inflammation. However, the precise mechanisms by which mtDNA-driven innate immune signaling contributes to SCI pathology and how this pathway can be therapeutically modulated remain incompletely understood. In this study, we identify zinc as a dual-function regulator that preserves mitochondrial integrity and attenuates mtDNA-triggered innate immune activation after SCI. In both in vivo and in vitro models, zinc enhanced PINK1-Parkin dependent mitophagy, promoted the removal of damaged mitochondria, and stabilized mitochondrial membranes through the regulation of BAX, BAK, and VDAC1. These actions collectively reduced mtDNA leakage, thereby suppressing cGAS-STING signaling. Zinc further promoted anti-inflammatory microglial polarization and improved locomotor recovery in SCI mice. These findings uncover a previously unrecognized role of mtDNA-cGAS-STING signaling in SCI and identify zinc as a potential therapeutic candidate that restores mitochondrial-immune homeostasis to achieve neuroprotection.
    Keywords:  cGAS-STING pathway; mitophagy; mtDNA; neuroinflammation; spinal cord injury; zinc
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.010
  32. Forensic Sci Int Genet. 2026 Feb 03. pii: S1872-4973(26)00025-6. [Epub ahead of print]83 103444
    Statistical interpretation of mtDNA matches in two uncommon types of forensic cases.
    Gloria Dimick, Mitchell M Holland, Walther Parson, Michael Krawczak.
      Mitochondrial DNA (mtDNA) analysis is a frequently used tool for determining the potential origin of biological traces found at crime scenes. The method typically involves comparing the genetic profile of the trace with that of a suspect. While a mismatch between the two profiles usually leads to the exclusion of the suspect, the evidential value of a match is sometimes difficult to grasp. This is particularly true in cases that are more complex than a simple trace-suspect comparison. We considered two such scenarios and developed means for appropriate statistical interpretation of the respective mtDNA results. One scenario requires the evaluation of a composite hypothesis about trace donorship in multiple cases involving an mtDNA profile match with one and the same suspect. The other scenario calls for the consideration of a second mtDNA profile found at the crime scene that matches a matrilineally unrelated contact person of the suspect. For both scenarios, we propose formally linked mathematical methods for interpreting the mtDNA data which, under certain assumptions, allow valid quantification of the evidential value of the latter for or against the suspect. Furthermore, we illustrate the application of both methods with example calculations under realistic assumptions about the required parameters.
    Keywords:  Evidential value; Likelihood ratio; Match probability; Mitochondrial DNA; Trace donorship
    DOI:  https://doi.org/10.1016/j.fsigen.2026.103444
  33. Orphanet J Rare Dis. 2026 Feb 12.
    Myopathy and ataxia related to impaired mitochondrial function in mevalonate kinase deficiency.
    Alessia Pugliese, Christina von Landenberg, Romina Gallizzi, Alba Migliorato, Sabata Pierno, Carmelo Rodolico, Cornelia Kornblum, Ignazio Giuseppe Arena, Wolfram S Kunz, Jens Reimann, Antonio Toscano, Olimpia Musumeci.
      
    Keywords:  Ataxia; Coenzyme Q10; Metabolic myopathy; Mevalonate kinase deficiency; Mevalonic aciduria; Mitochondrial dysfunction; hyperCKemia
    DOI:  https://doi.org/10.1186/s13023-026-04248-y
  34. Res Sq. 2026 Feb 02. pii: rs.3.rs-8735353. [Epub ahead of print]
    Structural and biochemical basis of ROC-dependent activation of LRRK2.
    Quyen Hoang, Yangshin Park, Chunxiang Wu, Kayla Tennessen, Li Wan, Neo Hoang, Cardea Hoang, Jingling Liao.
      Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease, yet the molecular mechanism governing LRRK2 activation remains incompletely understood. LRRK2 is a large multidomain enzyme whose kinase activity is regulated by intramolecular interactions and by its Ras of complex proteins (ROC) GTPase domain. Here, we combine cryo-electron microscopy, X-ray crystallography, and structure-guided biochemical perturbations to define how ROC conformational switching regulates LRRK2 activation. Cryo-EM reconstructions reveal that monomeric full-length LRRK2 samples three distinct conformational states-autoinhibited, intermediate, and activated-indicating that large-scale activation-associated rearrangements can occur through an intrinsic intramolecular pathway, independently of Rab29 binding, higher-order oligomerization, or membrane association. A 1.6 Å crystal structure of an extended ROC construct reveals intrinsic conformational plasticity within the GTPase switch regions that likely underlies these transitions. Structure-guided disulfide engineering identifies a functional coupling between residue R1441 and Switch II that directly modulates GTPase activity in both isolated ROC and full-length LRRK2. Disruption of this coupling phenocopies the disease-associated R1441H mutation. Together, these findings establish ROC as a dynamic conformational engine that drives a multistep intramolecular activation mechanism in LRRK2, providing mechanistic insight into how pathogenic mutations promote aberrant kinase activation.
    DOI:  https://doi.org/10.21203/rs.3.rs-8735353/v1
  35. medRxiv. 2026 Jan 25. pii: 2026.01.23.26344724. [Epub ahead of print]
    ASSOCIATION ANALYSIS OF MITOCHONDRIAL HETEROPLASMIC VARIANTS AND CARDIOMETABOLIC TRAITS.
    TOPMed mtDNA working group
      Mitochondrial heteroplasmic variant has been increasingly recognized as a potential contributor to common complex diseases, yet its relationship with cardiometabolic disorders (CMDs) remains poorly understood. Leveraging deep whole-genome sequencing data from 16,882 participants across six multi-ancestry TOPMed cohorts, we systematically evaluated the associations between rare heteroplasmic variants and eight CMD traits, including body mass index (BMI), obesity, blood pressure, hypertension, blood glucose, diabetes, low-density lipoprotein (LDL), and hyperlipidemia. Using a previously developed statistical framework, we identified heteroplasmic variants according to three coding definitions and performed gene-based burden, SKAT, SKAT-O and ACAT-O tests within sixteen mitochondrial DNA (mtDNA) genes. We identified twelve significant gene-trait associations after Bonferroni correction, with consistent effect directions across coding definitions. The strongest association was observed between hyperlipidemia and heteroplasmic variants in CO1 gene (OR=0.28, 95% CI=(0.17, 0.46), p=3.4E-7) among EA (European Americans). Additional associations were detected for BMI, adjusted SBP (systolic blood pressure), BG (blood glucose), diabetes, and adjusted LDL. These findings highlight the contribution of heteroplasmic variation within mtDNA to cardiometabolic phenotypes and provide new insight into mitochondrial involvement in CMD pathophysiology.
    DOI:  https://doi.org/10.64898/2026.01.23.26344724
  36. Endocrinol Metab (Seoul). 2026 Feb 12.
    Sarcopenia and Muscle Aging: Updated Insights into Molecular Mechanisms and Translational Therapeutics.
    Thanh T Nguyen, Tam Dao, Ha Thu Nguyen, Jun-Hyeon Park, Seung-Jun Jeong, Sei Kim, Yunju Jo, Nhung T H Thieu, Jiangqi Zhao, Fuan Ding, Ying Yu, Vu Chi Dung, Karim Gariani, Beom-Jun Kim, Dongryeol Ryu.
      Sarcopenia is a progressive, age-related condition characterized by the loss of skeletal muscle mass, strength, and function, which increases the risk of falls, frailty, and loss of independence. Despite growing recognition and its incorporation into geriatric assessments, there is still no approved pharmacological treatment. This review provides an updated overview of sarcopenia, encompassing diagnostic criteria, biological mechanisms, and emerging therapeutic strategies. Key molecular features include mitochondrial dysfunction, nicotinamide adenine dinucleotide (NAD⁺) decline, fiber-type alterations, and dysregulation of myokines. Recent singlecell and multi-omics studies have revealed the heterogeneity of muscle tissue and distinct cell-type-specific aging patterns. Therapeutic efforts are evolving beyond lifestyle interventions toward targeted approaches, including myostatin inhibitors, NAD⁺ boosters, senolytics, and microbiome modulators. However, clinical translation remains constrained by heterogeneity in trial design and the absence of standardized outcome measures. Future sarcopenia care will likely involve precision medicine guided by biomarkers and supported by digital monitoring tools. Progressing from molecular discovery to clinical application will be essential for preserving muscle health and function in aging populations.
    Keywords:  Aging; Mitochondria; Muscle weakness; Myokines; Protein metabolism; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.3803/EnM.2025.2656
  37. Anal Chem. 2026 Feb 11.
    Dissecting Mitochondrial Sulfur Dioxide Generation Mechanism in Rheumatoid Arthritis with a NIR Luminogenic Iridium(III)-Based Probe.
    Yameng Wang, Guantong Shen, Daniel Shiu-Hin Chan, Lei Wu, Chun-Yuen Wong, Jing Wang, Chung-Hang Leung, Wanhe Wang.
      Sulfur dioxide (SO2), a gaseous signaling molecule that can be produced endogenously in mitochondria, is an important antioxidant for maintaining redox homeostasis. Abnormal levels of mitochondrial SO2 are associated with the pathogenesis and progression of rheumatoid arthritis (RA). Therefore, it is crucial to develop a luminescence probe that can detect subcellular SO2 levels for unmasking the pathological changes and diagnosis of RA. However, current luminescence probes for SO2 in RA suffer from low photostability, weak response, short emission wavelengths below 650 nm, and/or poor mitochondria targetability. In this work, we developed a near-infrared (NIR) iridium(III) complex-based probe based on the Michael addition mechanism for rapid, real-time, and accurate detection of mitochondrial SO2. The probe not only achieved sensitive detection of SO2 in aqueous solution with a detection limit of 2.12 μM but also imaged endogenous mitochondrial SO2 levels in a cellular RA model. Furthermore, it visualized aspartate aminotransferase 1 (AAT1)-mediated SO2 generation, offering insight into the mechanism of SO2 generation in RA. Finally, it also exhibits an excellent penetration capability within 3D tumor spheroids (approximately 103 μm). Overall, this probe offers a powerful tool for effectively imaging subcellular SO2 in RA, thereby enhancing our understanding of the pathological mechanisms of RA and accelerating the development of diagnostic tools for RA.
    DOI:  https://doi.org/10.1021/acs.analchem.5c06894
  38. Neuromuscul Disord. 2026 Jan 30. pii: S0960-8966(26)00032-5. [Epub ahead of print]60 106364
    MSTO1-related mitochondrial myopathy and ataxia syndrome: Case series and literature review.
    Rishi Sharma, Lisa A Schimmenti, Benn Smith, Filippo Pinto E Vairo, Duygu Selcen, Radhika Dhamija.
      We report clinical and genetic features in four patients from 3 independent families with an ultra-rare autosomal recessive myopathy associated with biallelic pathogenic or likely pathogenic variants in MSTO1. Exome or genome sequencing was used to identify genetic variants in patients with suspected hereditary myopathy who had negative results on targeted genetic panels. Age at diagnosis ranged from 13 to 30 years. All patients exhibited myopathy of variable severity. Two had congenital hypotonia and global developmental delay, while the remaining two developed muscle weakness at ages 2 and 5. Magnetic resonance imaging evidence of cerebellar atrophy was noted in Patient 3. The most common non-neurologic abnormality noted in our cases was skeletal abnormalities. MSTO1-related disease presents primarily as an early-onset myopathy, occasionally accompanied by cerebellar atrophy and skeletal abnormalities. As genome-wide sequencing is increasingly becoming a first line test for unexplained myopathy, further characterization of the phenotypic spectrum is likely.
    Keywords:  Exome sequencing; MSTO1; Mitochondrial myopathy; Myopathy
    DOI:  https://doi.org/10.1016/j.nmd.2026.106364
  39. J Mol Neurosci. 2026 Feb 12. 76(1): 28
    Expanding the Clinical Spectrum of SCN8A-Related Epileptic Encephalopathy: Additional Auditory Impairment, Atypical MRI Abnormalities and Putative Mitochondrial Involvement.
    Marwa Maalej, Lamia Sfaihi, Roeya Kolsi, Olfa Alila-Fersi, Marwa Ammar, Thouraya Kammoun, Abdelaziz Tlili, Faiza Fakhfakh.
      
    Keywords:   SCN8A ; Epileptic encephalopathy; Mitochondrial complex I deficiency
    DOI:  https://doi.org/10.1007/s12031-026-02481-5
  40. Mol Cell Endocrinol. 2026 Feb 10. pii: S0303-7207(26)00035-3. [Epub ahead of print]616 112758
    Growth hormone enhances mitochondria biogenesis and endows mitochondrial thermogenesis in murine adipocytes.
    Esha Sadiq, Yinghao Liu, Ni Li, Chen Zong, Xiaojie Li, Tianfu Yu, Zeqing Pu, Luqman Alameri, Zhuoxuan Li, Siying Li, Xiangdong Wang, Ruxing Zhao.
      Growth hormone (GH) can reduce the size of white adipocytes in vivo and in vitro. This catabolic effect was previously believed to be related to the breakdown of stored triglycerides into free fatty acids. However, little is known about its effects on mitochondria in adipose or adipocytes. We thus examined effects of GH on mitochondrial number change and metabolic changes in fat of diet induced obese mice as well as 3T3-L1 adipocytes. We first found in vitro GH increase the density of mitochondria in 3T3-L1 adipocytes. We figured out that GH enhanced the expression of mitochondria biogenesis related genes, such as peroxisome proliferative activated receptor gamma coactivator 1 alpha (Pgc1α), DNA polymerase gamma (Polg) and transcription factor A of mitochondria (Tfam) in vitro and in vivo. To explore the underlying mechanism, we further confirmed that the enhanced expression of these proteins was dependent on the three pathways of GH signaling transduction and that GH enhanced the promoter transactivation of Pgc1α or Polg. We also found that GH increased the cell death-inducing DNA fragmentation factor alpha subunit-like effector A (CIDEA) and uncoupling protein 1 (UCP1) expression by enhancing the promoter transactivation of Cidea. We further elucidated that GH induced UCP1 expression was dependent on CIDEA using CRISPR-Cas9 technique. We therefore conclude that GH has effects on reducing adipocyte size via promoting PGC1α and POLG mediated mitochondrial biogenesis, and also on increasing UCP1 expression via CIDEA. Making adipocytes browning by GH or its analogs may provide a therapeutic strategy for metabolic diseases.
    Keywords:  Adipose tissue browning; Cidea; GH; Mitochondria biogenesis; UCP1
    DOI:  https://doi.org/10.1016/j.mce.2026.112758
  41. Chem Sci. 2026 Jan 30.
    Catalytic relevance of a quinol anion in biological energy conversion by respiratory complex I.
    Oleksii Zdorevskyi, Johannes Laukkanen, Vivek Sharma.
      Redox chemistry of quinones is an essential component of life on Earth. In the mitochondrial electron transport chain, the ubiquinone molecule is reduced to ubiquinol by respiratory complex I to drive the synthesis of ATP. By performing both classical and hybrid QM/MM simulations on high-resolution cryo-EM structures, including quantitative free energy calculations, we show that the semiquinone species in complex I is anionic in nature and can be trapped in the active site chamber for its subsequent reduction. Two-electron reduction of ubiquinone yields a metastable ubiquinol anion, which is electrostatically pushed by 15-20 Å towards the exit of the ubiquinone binding chamber to drive the proton pump of complex I. As part of the two-electron reduction of ubiquinone, protonic rearrangements take place in the active site in which a highly conserved histidine converts from its one tautomeric state to another. The combined findings challenge the currently held views on quinone redox chemistry of respiratory complex I and provide a detailed and testable mechanistic picture of the proton-coupled electron transfer reaction at its active site under wild-type and mutant conditions.
    DOI:  https://doi.org/10.1039/d5sc07500a
  42. bioRxiv. 2026 Feb 01. pii: 2026.01.28.702368. [Epub ahead of print]
    Molecular mechanisms of mitochondrial Ca 2+ exchanger NCLX.
    Li Zhang, Yan Han, Weizhong Zeng, Jing Xue, Yan Wang, Youxing Jiang.
      Mitochondria serve as central hubs for Ca 2+ signaling, which is critical for metabolism, intercellular communication, and cell fate determination. Mitochondrial Ca 2+ homeostasis is maintained through tightly coordinated influx and efflux processes, with NCLX long recognized as the primary Ca 2+ extruder operating via Na + /Ca 2+ exchange. Despite its physiological significance, the molecular basis of NCLX function has remained unclear. Here, we report cryo-EM structures of rat NCLX in cytosolic-facing occluded and open states. The central transmembrane (TM) module of NCLX comprises 10 helices organized into two structurally similar halves with inverted orientations. Two characteristic α-repeats form a central ion-binding pocket, while peripheral TMs 1 and 6 are loosely associated with the core, likely mediating alternative access to the binding site. These structural features closely resemble those of NCXs, revealing a conserved mechanism underlying ion exchange. While NCLX retains the canonical Ca 2+ -binding site, it lacks several key Na + -binding residues found in NCXs, suggesting it functions as a non-selective cation/Ca 2+ exchanger. Consistent with this, cell-based Ca 2+ uptake assays show that NCLX mediates slower Ca 2+ exchange than NCX and can utilize Na + , K + , Li + , and potentially protons as counterions. Leveraging the structural symmetry of NCLX and its bidirectional exchange capability, we propose a model for the matrix-facing state and an alternating-access mechanism in which the sliding-door motions of TMs 1 and 6 enable ion access from cytosolic and matrix sides, analogous to NCX. These findings provide a structural and mechanistic framework for understanding mitochondrial NCLX function.
    DOI:  https://doi.org/10.64898/2026.01.28.702368
  43. Bone Res. 2026 Feb 09. 14(1): 20
    Sialin-STAT3 axis regulates bone homeostasis in mice.
    Xiaoyu Li, Lei Hu, Yifan Xu, Xue Wang, Zichen Cao, Ou Jiang, Jiawei Yao, Meijing Liu, Sihan Kong, Jinsong Wang, Xiaogang Wang, Songlin Wang.
      Mitochondrial regulation in mesenchymal stem cells (MSCs) serves as a critical determinant of bone formation and skeletal homeostasis. While dietary nitrate and its transporter Sialin are implicated in systemic homeostasis, their specific roles in MSCs' function remain unclear. Here, we demonstrate that Sialin deficiency impairs MSCs' function and disrupts bone homeostasis. Gain- and loss-of-function studies reveal that Sialin localizes to the mitochondrial membrane and promotes osteogenic differentiation by maintaining mitochondrial bioenergetic integrity. Mechanistically, Sialin recruits pSTAT3S727 to mitochondria, forming a functional complex that activates mitochondrial bioenergy and stabilizes bone remodeling. Notably, dietary nitrate restores Sialin expression in aged mice, thereby enhancing MSCs' function and preventing osteoporosis. Our findings identify a nutrient-responsive signaling axis-nitrate-Sialin-pSTAT3S727-that promotes osteogenic differentiation via mitochondrial homeostasis, offering a potential therapeutic strategy for age-related osteoporosis.
    DOI:  https://doi.org/10.1038/s41413-025-00504-2
  44. bioRxiv. 2026 Feb 03. pii: 2026.02.01.703106. [Epub ahead of print]
    Conformational Remodeling Underlies Activity Loss in Disease-Linked Asparagine Synthetase Variant.
    Lucciano A Pearce, Adriana Coricello, Alanya J Nardone, Giovanni Bottegoni, Yuichiro Takagi, Wen Zhu.
      Asparagine synthetase deficiency (ASNSD) is a devastating congenital disorder characterized by profound neurological impairment and early childhood mortality. It is associated with pathogenic mutations in the asparagine synthetase (ASNS) gene. Despite the critical role of ASNS in the amino acid cycle, the molecular basis by which ASNSD-linked missense mutations impair enzyme function remains poorly understood. Here, we present a comprehensive characterization of a recurrent ASNSD-linked variant, R48Q. Steady-state kinetic assays reveal severe reductions in L-glutamine-dependent catalysis and disrupted product stoichiometry, implicating impaired interdomain communication. Cryogenic electron microscopy (cryo-EM) and 3D variable analysis of the EM map uncovers altered loop conformations at the N-terminal active site and subtle conformational changes at the C-terminal domain. Consistent with the structural data, molecular dynamics simulations support that the local disruption propagates across the protein, thereby decoupling coordinated domain motions essential for catalysis. Additionally, we demonstrate that the flanking arginine and the affected loop are evolutionarily conserved across Class II glutamine amidotransferases, highlighting their shared mechanistic importance. These findings provide the molecular basis of an ASNSD variant and establish a framework for understanding how point mutations disrupt complex enzyme dynamics, with broad implications for precision medicine.
    Significance: Understanding how mutations affect multidomain enzymes is crucial for elucidating the molecular mechanisms underlying genetic disorders. Here, we examine the molecular consequences of the R48Q variant in human asparagine synthetase (ASNS), the sole enzyme responsible for de novo L-asparagine synthesis; mutations of this enzyme lead to a fatal neurometabolic disorder, asparagine synthetase deficiency (ASNSD). By combining biochemical, cryogenic electron microscopy, and molecular dynamics simulation, we show that a single N-terminal amino acid substitution disrupts both local and global coordination, impairing enzyme activity. Our work provides the first mechanistic blueprint of an ASNSD-linked variant. These findings not only deepen our understanding of ASNS but also offer a generalized framework for studying the dynamic regulation of multidomain enzymes in disease.
    DOI:  https://doi.org/10.64898/2026.02.01.703106
  45. Int J Mol Sci. 2026 Jan 31. pii: 1450. [Epub ahead of print]27(3):
    Unveiling Specificity, Redundancy, and Promiscuity of Five Saccharomyces cerevisiae Mitochondrial Carriers.
    Pawel Lojko, Lyubomir Dimitrov Stanchev, Felicia Cara Schulz, Christoph Crocoll, Carlos G Acevedo-Rocha, Irina Borodina.
      The transport of metabolites across biological membranes is vital for normal cellular functions, including nutrient uptake, homeostasis, and toxin efflux. In eukaryotes, mitochondrial transporters in the inner mitochondrial membrane (IMM) play a pivotal role in energy production, metabolism, and the biosynthesis of a wide range of compounds. While functional assignments exist for over half of the mitochondrial transporters, emerging high-throughput methodologies underscore the need for reassessment and expansion of the current knowledge, particularly as evidence suggesting functional redundancy and substrate promiscuity has emerged. In this study, we investigated the substrate specificity of five yeast mitochondrial transporters-Crc1 (YOR100c), Ctp1 (YBR291c), Oac1 (YKL120w), Pet9 (YBL030c), and Yhm2 (YMR241w)-via heterologous gene expression in Xenopus laevis oocytes and liquid chromatography-mass spectrometry (LC-MS)-based transport assays. We used two substrate mixtures: a 17-compound organic acid mix and a 13C-labeled yeast metabolite extract. Our results revealed broader substrate specificities than previously reported, as partially supported by substrate docking simulations. Pet9 transported several organic acids and amino acids, while Yhm2 showed uptake of nine amino acids and fumaric acid. Additional promiscuous transport activity was observed for Crc1, indicating that these proteins may have more extensive metabolic roles than previously known. This study advances the understanding of yeast mitochondrial transporter function, demonstrating redundancy and broad substrate specificity among mitochondrial carriers. It highlights the importance of utilizing in vivo heterologous systems and physiologically relevant substrate mixtures to elucidate transporter functionality.
    Keywords:  Saccharomyces cerevisiae; Xenopus laevis oocyte; amino acids; mitochondria; organic acids; transport proteins
    DOI:  https://doi.org/10.3390/ijms27031450
  46. Adv Sci (Weinh). 2026 Feb 08. e17141
    Mitochondrial CircRNA CircMT-RNR2 Safeguards Antioxidant Defense to Support Fibroblast Functions in Wound Repair.
    Guanglin Niu, Jennifer Geara, Yongjian Chen, Lihua Luo, Yanwei Xiao, Zhuang Liu, Margaux Gaborieau, Ling Pan, Edmund Loh, Dongqing Li, Pehr Sommar, Aoxue Wang, Xiaowei Zheng, Ning Xu Landén.
      Diabetic foot ulcers (DFUs) are a debilitating diabetes complication in which mitochondrial dysfunction and oxidative stress are prominent but mechanistically unresolved features. Here, we identify the mitochondria-encoded circular RNA (mecciRNA) circMT-RNR2 as a novel modulator of mitochondrial redox homeostasis in human skin wound healing. CircMT-RNR2 is reduced in DFU patient tissue and diabetic mouse wounds, enriched in dermal fibroblasts, and localized to mitochondria. Its loss impairs fibroblast proliferation, migration, extracellular matrix production, and contraction by destabilizing the mitochondrial antioxidant protein PRDX3, leading to elevated oxidative stress, mitochondrial damage, and mitophagy. In murine and human ex vivo wound models, circMT-RNR2 knockdown delays healing, whereas overexpression accelerates repair and boosts antioxidant defenses. These findings position circMT-RNR2 as a mitochondrial guardian of skin healing and a promising therapeutic target for DFU.
    Keywords:  DFU; circRNA; mitochondria; wound healing
    DOI:  https://doi.org/10.1002/advs.202517141
  47. Biology (Basel). 2026 Jan 26. pii: 228. [Epub ahead of print]15(3):
    New Insights on Mitochondria-Targeted Neurological Drugs.
    Silvia Lores-Arnaiz.
      Aging and neurodegenerative diseases are characterized by common features involving bioenergetics deficiencies, oxidative stress and alterations of calcium buffering. Mechanisms of mitochondrial-targeted drugs include the modulation of electron transport chain and oxidative phosphorylation, the binding to mitochondrial lipids, free-radical scavenging, calcium signaling, and possible effects on mitochondrial biogenesis and dynamics and on the regulation of mitophagic pathways. One of the main sites of action of mitochondria-targeted drugs is the interaction with respiratory chain components. Mitochondrial-targeted compounds such as Mito-Q, and Mito-apocynin have been developed by conjugating triphenylphosphonium (TPP+) lipophilic cation group with natural molecules, therefore obtaining promising drugs for reestablishing the correct functioning of the mitochondrial respiratory chain. Stabilization of cardiolipin at the inner mitochondrial membrane by elamipretide or SkQ1 and mitochondria-targeted ROS scavengers can also offer a therapeutic approach to prevent bioenergetic impairment associated with several diseases. In addition, the modulation of calcium signaling can be achieved using both MCU agonists and antagonists representing another mitochondrial target for drug therapies development. Finally, potential strategies for treating neurodegenerative diseases based on the modulation of mitochondrial biogenesis, dynamics and/or mitophagic pathways are discussed.
    Keywords:  ETC modulation; ROS scavenging; mitochondria-targeted drugs; mitochondrial function
    DOI:  https://doi.org/10.3390/biology15030228
  48. Biol Reprod. 2026 Feb 09. pii: ioag035. [Epub ahead of print]
    DRP1 in Reproduction and Reproductive Aging.
    Cheng-Rung Huang, Yin-Hua Cheng, Yung-Chiao Chang, Pei-Ling Weng, Kuo-Chung Lan.
      Dynamin-related protein 1 (DRP1) is a central regulator of mitochondrial fission and plays a critical role in maintaining mitochondrial function, distribution, and turnover in reproductive cells. Mitochondrial integrity is essential for oocyte quality, folliculogenesis, fertilization, embryonic development, and ultimately, female reproductive longevity. In this review, we synthesize evidence from mammalian and invertebrate models to illustrate the essential roles of DRP1 in reproductive physiology and aging. Genetic deletion or pharmacologic inhibition of DRP1 results in mitochondrial clustering, energy failure, increased reactive oxygen species (ROS) production, meiotic arrest, and embryo fragmentation. Furthermore, DRP1 dysfunction has been increasingly implicated in age-associated reproductive decline due to impaired mitophagy and defective organelle crosstalk. Model systems such as mice, pigs, and C. elegans have demonstrated that DRP1 activity is modulated by metabolic and epigenetic pathways, including NAD+/sirtuin signaling and GTP metabolism. Therapeutic interventions aimed at restoring DRP1 function-including nicotinamide mononucleotide (NMN), coenzyme Q10 (CoQ10), and dietary modulation-have shown promising effects in delaying reproductive aging and improving oocyte or embryo competence in animal models. Despite the current absence of human interventional efficacy data, DRP1 is a plausible and testable target in reproductive biology, with preclinical findings indicating potential relevance to infertility treatment and reproductive aging. This review highlights DRP1 as a key target in reproductive biology, emphasizing its translational potential for treating infertility and mitigating age-related oocyte deterioration.
    Keywords:  Aging; DRP1; Fertility; Mitochondria; Oocyte; Reproduction
    DOI:  https://doi.org/10.1093/biolre/ioag035
  49. Mitochondrion. 2026 Feb 11. pii: S1567-7249(26)00024-3. [Epub ahead of print] 102134
    URMD-Seq: A high-throughput method for scalable detection of ultra-rare mutations in the human mitochondrial genome.
    Zeshuo E S Li, Rachel Dunn, Loïc C Caloren, Adam S Ziada, Hailey Chapman, Izabelle Gadawska, Hélène C F Côté.
      The study of mitochondrial genetics has long been limited to polymorphisms and high frequency mutations owing in part to technical and technological limitations in reliably detecting and quantifying rare somatic mutations. Over the past decade or so, the study of rare somatic mitochondrial DNA (mtDNA) variants has expanded and continues to garner increasing interest in a wide range of research fields. Here, we describe Ultra-Rare Mutation Detection-Sequencing (URMD-Seq), a high-throughput method that combines unique molecular identifier (UMI)-based library preparation and Next Generation Sequencing (NGS) for the accurate and scalable detection of ultra-rare mutations in the mtDNA control region. Our method exploits degenerate primers to label individual mtDNA molecules. This is followed by several purification, quantification and amplification steps, to obtain high quality amplicons for sequencing on the Illumina MiSeq platform. Our approach enables the use of total genomic DNA extract as starting point for the assay, overcoming the need for organelle isolation and/or mtDNA enrichment, hence broadening the type of specimen that can be studied, while offering cost and time benefits. The assay described herein has been demonstrated to reliably measure variants present at on average 0.09%, but as low as 0.03%, variant allele frequency in a variety of tissues, including fresh and frozen biobanked specimens. Using this protocol, library preparation of 300 specimens can be completed by a single individual with general nucleic acid handling experience in approximately 20 days. Given its flexibility and scalability, URMD-Seq is particularly well suited for epidemiological studies using a large number of specimens.
    Keywords:  Ultra-rare mutations; mitochondrial DNA (mtDNA); next-generation sequencing (NGS); unique molecular identifiers (UMIs)
    DOI:  https://doi.org/10.1016/j.mito.2026.102134
  50. Invest Ophthalmol Vis Sci. 2026 Feb 02. 67(2): 25
    Semaglutide Protects Retinal Ganglion Cells Against Rotenone-Induced Degeneration via Improved Glucose Metabolism.
    Zaynab A Mouhammad, James R Tribble, Alan Nicol, Evgenia Andreopoulou, Mariana Y García-Bermúdez, Blanca I Aldana, Rupali Vohra, Miriam Kolko, Pete A Williams.
       Purpose: Glaucoma is a multifactorial disease, where metabolic and mitochondrial dysfunction may play a major role in the progressive loss of retinal ganglion cells that characterize the disease. Currently, treatment strategies consist of IOP-lowering approaches with no available neuroprotective agent. In epidemiological studies and models of glaucoma, GLP-1 receptor agonists (GLP-1RAs) reduce the risk of glaucoma and provide protection against the loss of retinal ganglion cells.
    Methods: In this study, we explored the potential of semaglutide (SEM), a known GLP-1RA, to protect retinal ganglion cells from rotenone-induced metabolic dysfunction. We pretreated C57BL/6 mice subcutaneously with either SEM (5 mg/kg) or saline solution for one week. After one week, the mice received intravitreal injections of rotenone (10 mM) or dimethylsulfoxide (1%) and were euthanized 24 hours later.
    Results: We demonstrated that rotenone caused a significant loss of retinal ganglion cells, which was prevented by SEM pretreatment. Metabolic analyses revealed that SEM enhanced glucose metabolism, which suggested the enhancement of glucose homeostasis/alternative pathways possibly supporting metabolic flexibility of retinal ganglion cells.
    Conclusions: SEM may help preserve retinal ganglion cells under conditions of mitochondrial Complex I inhibition, suggesting a potential therapeutic role in glaucoma management; however, further studies are required to confirm metabolic changes observed in this study.
    DOI:  https://doi.org/10.1167/iovs.67.2.25
  51. J Clin Med. 2026 Jan 30. pii: 1109. [Epub ahead of print]15(3):
    MELAS Syndrome Presenting with Hypertrophic Cardiomyopathy and Advanced Heart Failure: A Multisystem Diagnostic Challenge.
    Jozef Dodulík, Marie Lazárová, Eva Kapsová, Jan Václavík.
      Background: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare multisystem disorder caused by mitochondrial DNA mutations, most commonly the m.3243A>G variant in the MT-TL1 gene. Although neurological manifestations predominate, cardiac involvement, including hypertrophic cardiomyopathy (HCM), heart failure (HF), and arrhythmias, may be the initial or dominant presentation and often remains underrecognized. Case Presentation: We report a 43-year-old man with chronic kidney disease (CKD) and long-standing bilateral sensorineural hearing loss who presented with progressive dyspnea and acute decompensated HF. Transthoracic echocardiography revealed severe left ventricular (LV) systolic dysfunction with diffuse hypertrophy. Cardiac magnetic resonance showed non-ischemic cardiomyopathy with diffuse late gadolinium enhancement and increased LV wall thickness. Coronary angiography excluded obstructive disease. Initial endomyocardial biopsy performed at a referring center showed nonspecific hypertrophy and fibrosis without diagnostic features. Given the multisystem involvement, a metabolic or genetic etiology was suspected. Whole-exome sequencing identified the pathogenic m.3243A>G MT-TL1 mutation, confirming MELAS syndrome. The patient was managed with guideline-directed HF therapy, received an implantable cardioverter-defibrillator for primary prevention, and was subsequently evaluated for heart transplantation. Conclusions: This case highlights the importance of considering mitochondrial disorders in the differential diagnosis of unexplained cardiomyopathy, particularly when cardiac dysfunction coexists with renal impairment and auditory deficits. Comprehensive multimodality evaluation and genetic testing are essential to establishing a unifying diagnosis and optimizing management.
    Keywords:  MELAS syndrome; genetic testing; heart failure (HF); hypertrophic cardiomyopathy (HCM); mitochondrial disease
    DOI:  https://doi.org/10.3390/jcm15031109
  52. Am J Physiol Endocrinol Metab. 2026 Feb 01. 330(2): E265-E266
    Missing the rhythm in skeletal muscle mitochondrial respiration.
    Jan-Frieder Harmsen, Andries Kalsbeek.
      
    Keywords:  circadian; diabetes; energy metabolism; exercise; sex differences
    DOI:  https://doi.org/10.1152/ajpendo.00469.2025
  53. J Hepatol. 2026 Feb 06. pii: S0168-8278(26)00062-0. [Epub ahead of print]
    Distinct effects of ketogenic and non-ketogenic weight-loss diets on hepatic steatosis and mitochondrial metabolism in MASLD.
    Sami F Qadri, Kimmo Porthan, Sylvie Dufour, Tiina E Lehtimäki, Kitt Falk Petersen, Gerald I Shulman, Hannele Yki-Järvinen, Panu K Luukkonen.
       BACKGROUND & AIMS: Weight loss is the cornerstone therapy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal dietary approach for reducing intrahepatic triglycerides (IHTG) and the mechanisms underlying steatosis resolution remain poorly defined. We investigated whether weight loss via a ketogenic diet (KD) differentially affects IHTG content, hepatic mitochondrial metabolism, and the circulating metabolome compared with a non-ketogenic diet (ND).
    METHODS: Individuals with varying IHTG content underwent short-term hypocaloric KD and ND in a crossover design. Before and after each diet, IHTG was quantified by proton magnetic resonance spectroscopy and liver stiffness by magnetic resonance elastography. We used state-of-the-art isotope tracer methodology to compare KD and ND effects on in vivo rates of hepatic mitochondrial tricarboxylic acid (TCA) cycle oxidation, endogenous glucose production, and β-hydroxybutyrate production (ketogenesis). Targeted plasma metabolomics by NMR and LC-MS evaluated systemic metabolic responses.
    RESULTS: Despite similar energy deficits and body fat loss, IHTG decreased 45% more with KD than ND (-29% vs. -20%), accompanied by a threefold greater improvement in hepatic insulin sensitivity (59% vs. 21%). KD, but not ND, markedly reduced serum insulin concentrations (-54%), thereby promoting lipolysis and intrahepatic fatty acid partitioning toward mitochondrial β-oxidation, increasing hepatic mitochondrial [NADH]/[NAD+] (redox state) (+51%), and decreasing rates of hepatic mitochondrial TCA cycle oxidation (-34%). KD, but not ND, increased plasma concentrations of branched-chain amino acids, acylcarnitines, and tricarboxylic acid cycle intermediates.
    CONCLUSIONS: Both diets ameliorated MASLD, but KD produced a greater reduction in IHTG owing to a starvation-like metabolic state. However, the benefits of KD were accompanied by increased hepatic mitochondrial redox state and suppression of TCA cycle oxidation, which are features previously linked to progressive liver injury.
    IMPACT AND IMPLICATIONS: This study provides mechanistic justification for considering dietary composition, in addition to caloric restriction, as a key determinant of steatosis resolution in MASLD. The findings highlight a potential trade-off between greater short-term reductions in liver fat and the emergence of metabolic features previously associated with increased susceptibility to liver injury. While a ketogenic diet may facilitate rapid liver fat reduction in selected clinical contexts, its use should be approached cautiously, particularly in individuals with advanced MASLD. These results underscore the need for systematic evaluation of dietary composition as a determinant of both efficacy and safety of nutritional interventions for MASLD.
    CLINICAL TRIAL NUMBER: NCT03737071.
    Keywords:  caloric restriction; citric acid cycle; cross-over study; energy metabolism; fatty liver; humans; insulin resistance; ketogenic diet; metabolome; redox state; weight loss
    DOI:  https://doi.org/10.1016/j.jhep.2026.02.001
  54. Cell Death Differ. 2026 Feb 13.
    M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress.
    Camilla Reiter Elbæk, Sophie Gradinaru, Anna M Dahlström, Alexander Frueh, Akhee S Jahan, Joyceline Cuenco, Anna L Aalto, John Rizk, Simon A Hawley, Sarah N J Franks, Michael Stumpe, Srinivasa Prasad Kolapalli, Chris Kedong Wang, Cara J Ellison, Ximena Hildebrandt, Klara Nielsen, Dominik Priesmann, Julian Koch, Mathilde Deichmann, Josef Gullmets, Lien Verboom, Geert van Loo, Nieves Peltzer, Lisa B Frankel, Paul R Elliott, Mads Gyrd-Hansen, Jörn Dengjel, Brent J Ryan, D Grahame Hardie, Annika Meinander, Kei Sakamoto, Rune Busk Damgaard.
      Methionine-1 (M1)-linked ubiquitin chains, assembled by the linear ubiquitin chain assembly complex (LUBAC) and disassembled by the deubiquitinase OTULIN, are critical regulators of inflammation and immune homoeostasis. Genetic loss or mutation of the LUBAC subunits HOIP and HOIL-1 or of OTULIN causes autoinflammatory syndromes accompanied by metabolic defects, including amylopectinosis, lipodystrophy, and fatty liver disease. Yet, it remains unclear how LUBAC and OTULIN control metabolic signalling. Here, we demonstrate that LUBAC and OTULIN dynamically regulate the energy-sensing kinase AMPK, a central sensor and switch for cellular and organismal energy balance. LUBAC's activity through the catalytic subunit HOIP is required for full AMPK activation in response to energetic stress, whereas OTULIN antagonises this response. LUBAC and OTULIN form a complex with AMPK, and LUBAC can directly ubiquitinate AMPKα and β subunits in cells and in vitro, establishing AMPK as a bona fide M1-linked ubiquitin substrate. Loss of LUBAC blunts AMPK activation, reduces bioenergetic adaptability, impairs autophagy, and sensitises cells to starvation-induced death, while Drosophila lacking Lubel - the fly orthologue of LUBAC - exhibit defective AMPK activation and reduced survival during starvation. Our findings identify M1-linked ubiquitination as a previously unrecognised regulatory layer controlling AMPK activation, metabolic adaptability, and the cellular response to energetic stress.
    DOI:  https://doi.org/10.1038/s41418-026-01675-z
  55. Nat Commun. 2026 Feb 12. 17(1): 1493
    Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation.
    Sathish Babu Vasamsetti, Samreen Sadaf, Mohammad A Uddin, Jixing Shen, Ebin Johny, Awishi Mondal, Jonathan Florentin, Liqun Lei, Aleef Mannan, Krithika Sudhakar Rao, John Sembrat, Mauricio Rojas, Ian Sipula, Jake Kastroll, Michael J Jurczak, Sruti Shiva, Robert M O'Doherty, Vijay Yechoor, Partha Dutta.
      How cellular metabolism facilitates tissue-resident macrophage maintenance remains elusive. Here we show that visceral adipose tissue (VAT)-resident macrophages, unlike monocyte-derived macrophages, are enriched with mitochondrial-specific antioxidant enzymes restraining inflammation and promoting VAT homeostasis and insulin sensitivity. Additionally, VAT resident macrophages express high levels of plasminogen activator inhibitor type 2, encoded by SerpinB2, which is involved in the blood coagulation cascade. SerpinB2 promotes adipose resident macrophage survival by regulating mitochondrial oxidative phosphorylation and preventing the release of pro-apoptotic cytochrome c from the mitochondria into the cytoplasm via antioxidant glutathione production. Chronic inflammation, such as obesity, diminishes SerpinB2 expression in VAT macrophages in patients and mice, leading to the decline of this macrophage subset. Mechanistically, interferon-γ elevation in diabetes induces Ikaros, a transcriptional suppressor, which binds to the SerpinB2 promoter and decreases SerpinB2 expression. Congruently, selective depletion of the IFN-γ receptor in myeloid cells or supplementation of macrophage-specific SerpinB2 deficient mice with N-acetylcysteine, a glutathione precursor, restores VAT resident macrophage survival, decreases adipocyte size, and improves glucose tolerance and insulin sensitivity. Our data thus reveal an unexpected function of SerpinB2 in the regulation of mitochondrial function and survival of tissue-resident macrophages.
    DOI:  https://doi.org/10.1038/s41467-026-69196-4
  56. bioRxiv. 2026 Feb 04. pii: 2026.02.02.703364. [Epub ahead of print]
    Sympathetic innervation regulates metabolic flexibility of skeletal muscle.
    Jordan Owyoung, HaoMin Sima, Junwon Heo, Tess Klugherz, Tina Tian, Brittney Ward, Nikki Boon, Garrett W Cooper, Andrew L Hong, Jarrod Call, Patricia J Ward.
      The sympathetic nervous system (SNS) is recognized for its role in the physiological regulation of organs, such as heart, vasculature and lungs, and has emerged as a potential player in skeletal muscle metabolic and neuromuscular junction (NMJ) health. However, the mechanism through which SNS signaling influences skeletal muscle function and adaptation to exercise remains unclear. Using molecular, electrophysiological, immunohistochemical, and high-resolution respirometry techniques, we tested the role of sympathetic innervation to skeletal muscle in response to exercise. Our findings reveal that sympathetic denervation disrupts the NMJ, reducing motor and sympathetic receptor expression, with concomitant deficits in skeletal muscle function. Mechanistically, these deficits are linked to diminished CPT1 enzyme activity, which impairs long-chain fatty acid-mediated oxidation in skeletal muscle mitochondria. These findings reveal a key role for sympathetic innervation in maintaining mitochondrial metabolic function and by extension, skeletal muscle performance, offering novel insight into the interplay between the SNS, exercise, and muscle mitochondria.
    DOI:  https://doi.org/10.64898/2026.02.02.703364
  57. Epigenomics. 2026 Feb 11. 1-8
    Mitochondrial D-loop region methylation differentiates Parkinson's disease from atypical parkinsonism and Parkinson's disease dementia.
    Bilge Karacicek, Bilgesu Ozturk, Ozgur Oztop Cakmak, Fatos Sibel Ertan, Pembe Keskinoglu, Sermin Genc.
       BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and α-synuclein aggregation. Epigenetic mechanisms, including mitochondrial DNA (mtDNA) methylation, have been implicated in PD pathogenesis. Methylation of the mitochondrial displacement loop (D-loop) region may play a role in neurodegenerative processes.
    RESEARCH DESIGN AND METHODS: This case study assessed D-loop methylation levels in peripheral blood samples from 37 patients with PD, 18 patients with Parkinson's disease dementia (PD-D), 26 patients with atypical parkinsonism (APS), and 26 healthy controls (HC). Associations with clinical parameters, sex, and L-dopa treatment were analyzed.
    RESULTS: D-loop methylation levels were significantly reduced in patients with PD-D and APS compared to PD patients and HC. Methylation levels were not associated with disease duration, clinical variables, sex, or L-dopa treatment.
    CONCLUSIONS: Decreased mitochondrial D-loop methylation in PD-D and APS may reflect disease-specific epigenetic mechanisms rather than clinical characteristics or treatment effects.
    Keywords:  D-loop; Parkinson disease; Parkinson’s disease dementia; atypical parkinsonism; mtDNA methylation
    DOI:  https://doi.org/10.1080/17501911.2026.2627263
  58. Mitochondrial Commun. 2025 ;3 109-115
    A chemical-genetic approach to target voltage-sensitive fluorophores to mitochondria.
    Julia G Martin, Tong Zhan, Deshka L Neill, Ke Xu, Evan W Miller.
      Mitochondria play central roles in the physiology of eukaryotic cells. Mitochondrial membrane potential, in turn, is a key driver of mitochondrial physiology. We previously developed a system to localize voltage-sensitive fluorophores to mitochondria based on the hydrolysis of labile acetoxymethyl (AM) esters. One potential problem with this system is the premature hydrolysis of the labile AM ester prior to accumulation in the mitochondria. A possible solution is to replace the AM ester with a bulky cyclopropylmethylacetoxy (CPM) ester, which resists uncatalyzed hydrolysis but can be removed by certain esterases. When paired with exogenous expression of mitochondrially-targeted esterases like porcine liver esterase (PLE), this chemical-genetic hybrid approach can improve localization to mitochondria. In this manuscript, we use superresolution microscopy to show that a variety of proteins, including esterases from pig and bacteria can be effectively localized to mitochondria. Further, we establish that a CPM-modified rhodamine voltage reporter (RhoVR-CPM) shows improved localization to mitochondria in cells expressing mitochondrially-targeted esterases. Finally, RhoVR-CPM can be paired with fluorescence lifetime imaging microscopy (FLIM) to map changes in mitochondrial membrane potential.
    DOI:  https://doi.org/10.1016/j.mitoco.2025.12.002
  59. Int J Mol Sci. 2026 Feb 02. pii: 1469. [Epub ahead of print]27(3):
    Carbon Dots and Mitochondria-Advances in Targeting, Imaging, and Therapeutics.
    Aasia Bibi, Daniela De Benedictis, Giuseppe Capitanio, Alessandra Gabriele, Amer Ahmed, Mariapompea Cutroneo, Lorenzo Torrisi, Daniela Manno, Antonio Serra, Domenico De Rasmo, Anna Signorile.
      Carbon dots (CDs), a class of fluorescent nanomaterials, have emerged as powerful tools for biological applications, particularly in the targeting, imaging, and therapeutic modulation of mitochondria. Due to their small size, simplicity of synthesis, biocompatibility, and tunable optical properties, CDs can be engineered to selectively accumulate in mitochondria, enabling real-time imaging of mitochondrial function and dynamics in live cells. Moreover, their ability to carry therapeutic agents, such as antioxidants, drugs, and gene delivery vectors, offers potential in treating mitochondrial dysfunction, which is central to various diseases, including neurodegenerative disorders, cancer, and metabolic diseases. Recent advancements in surface functionalization have enhanced mitochondrial targeting and specificity, while ongoing research aims to optimize the safety, efficiency, and clinical translation of CDs for therapeutic applications. This review highlights the latest developments in the use of carbon dots for mitochondrial imaging, therapeutic delivery, and disease intervention, offering promising avenues for future research and clinical applications.
    Keywords:  CDs (carbon dots); imaging; mitochondria; therapeutics
    DOI:  https://doi.org/10.3390/ijms27031469
  60. Int J Mol Sci. 2026 Jan 24. pii: 1191. [Epub ahead of print]27(3):
    MitoTex (Mitochondria Texture Analysis User Interface): Open-Source Framework for Textural Characterization and Classification of Mitochondrial Structures.
    Amulya Kaianathbhatta, Malak Al Daraawi, Natasha N Kunchur, Rayhane Mejlaoui, Zoya Versey, Edana Cassol, Leila B Mostaço-Guidolin.
      Mitochondria are essential organelles involved in metabolism, energy production, and cell signaling. Assessing mitochondrial morphology is key to tracking cell metabolic activity and function. Quantifying these structural changes may also provide critical insights into disease pathogenesis and therapeutic responses. This work details the development and validation of a novel, quantitative image analysis pipeline for the characterization and classification of dynamic mitochondrial morphologies. Utilizing high-resolution confocal microscopy, the pipeline integrates first-order statistics (FOS) and a comprehensive suite of gray-level texture analyses, including gray level co-occurrence matrix (GLCM), gray level run length matrix (GLRLM), gray level dependence matrix (GLDM), gray level size zone matrix (GLSZM), and neighboring gray tone difference matrix (NGTDM) with machine learning approaches. The method's efficacy in objectively differentiating key mitochondrial structures-fibers, puncta, and rods-which are critical indicators of cellular metabolic and activation states is demonstrated. Our open-source pipeline provides robust quantitative metrics for characterizing mitochondrial variation.
    Keywords:  machine learning; microscopy; mitochondria; texture analysis
    DOI:  https://doi.org/10.3390/ijms27031191
  61. Sleep Breath. 2026 Feb 13. 30(1): 45
    Sleep in MELAS syndrome.
    Alejandro Herrero San Martin, Eva María Arias, Cristina Dominguez Gonzalez, Montserrat Morales Conejo, Trinidad Diaz Cambriles.
      
    Keywords:  MELAS syndrome; Mitochondrial diseases; REM sleep behavior; Sleep; Sleep apnea
    DOI:  https://doi.org/10.1007/s11325-026-03611-4
  62. Biochem Biophys Res Commun. 2026 Feb 06. pii: S0006-291X(26)00169-5. [Epub ahead of print]806 153405
    Optimised measurement of mitochondrial respiratory capacity in frozen rat liver and heart.
    Alice E Knapton, Katie A O'Brien, Alice P Sowton, Jenna L Armstrong, Vashti Davies, Catherine M Kirk, Ben D McNally, Benjamin D Thackray, Lorenz Mw Holzner, Andrew J Murray.
      High-resolution respirometry is widely used to assess mitochondrial respiratory capacity and oxidative phosphorylation coupling in preparations of fresh tissues, but is significantly limited in freeze-thawed preparations owing to mitochondrial membrane disruption. Reconstitution of the electron transfer system (ETS) by adding exogenous cytochrome c and using NADH as a complex I electron donor can partially circumvent these limitations, allowing assessment of ETS capacity uncoupled from ADP phosphorylation. We sought to optimise this approach for rat liver and heart homogenates but found that use of NADH resulted in high residual O2 consumption, independent of canonical electron flow to complex IV. This could be minimised in liver homogenates through the inclusion of superoxide dismutase (SOD) and catalase to reconstitute O2 from superoxide formed, and in heart homogenates by the further inclusion of S1QEL1.1, an IQ site-specific inhibitor of superoxide formation at complex I. We validated this modified approach by measuring ETS capacities in frozen liver and heart samples from rats exposed to inhalation hypoxia, replicating findings in fresh preparations from the same rats.
    Keywords:  Bioenergetics; Heart; Liver; Mitochondria; Respiration; Respirometry
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153405
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