bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–01–25
fifty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
  2. NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
  3. Recognition of small Tim chaperones by the mitochondrial Yme1 protease.
  4. Palmitic acid induces UCP1-independent mitochondrial depolarization specifcally in brown adipose tissue.
  5. Human mitochondrial helicase Twinkle has RNA binding, annealing, and strand-exchange activities.
  6. Neddylation Regulates Mitochondrial Dynamics and Turnover in the Adult Heart.
  7. Nuclear MBL-1 modulates mitochondrial morphology through carnitine palmitoyltransferase in Caenorhabditis elegans with toxic trinucleotide repeats.
  8. Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on TK2 Deficiency.
  9. Roles of DRP1 and the fission protein interactome as regulators of cellular stability and sarcopenia in skeletal muscle aging.
  10. NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.
  11. Case Report: Myoclonic and tremulous movements associated with COQ8A-related coenzyme Q10 deficiency type 4.
  12. Metabolic reprogramming during human neuron differentiation indicates glutaminase as a key determinant in Fragile X syndrome.
  13. Acetyl-CoA as a metabolic switch for selective mitophagy.
  14. Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.
  15. Mitochondrial acetyl-CoA reprogramming by the SIRT3-ACSS2-OPA1 axis confers resistance to ferroptosis in Parkinson's disease.
  16. TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
  17. Multiple Mitochondrial Dysfunction Syndrome Caused by IBA57 Gene Mutation: A Case Report and Literature Review.
  18. Leber Hereditary Optic Neuropathy-Associated Novel Mutation in MT-RNR2 Gene: A Case Report.
  19. Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.
  20. Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I Function.
  21. The Antiseizure Medication Stiripentol Inhibits Mitochondrial Complex I by Blocking Early-Stage Electron Transfer.
  22. Stuxnet balances mitochondria homeostasis by regulating uhg5 and parkin.
  23. Heterogeneous sympathetic control of brown adipose tissue.
  24. Upregulated GBP2 exacerbates Parkinson's disease pathogenesis by impairing NIX-dependent mitophagy.
  25. Protein-lipid interplay governs ion channel gating and bioenergetics in human mitochondrial VDAC3.
  26. ATF4 regulates mitochondrial dysfunction and mitophagy, contributing to corneal endothelial apoptosis.
  27. Impact of Toll/Interleukin-1 Receptor Domain Protein C on Mesenchymal Stem Cells Mitochondrial Protein Expression: A Proteomic Study.
  28. Identification of new human monogenic disorders and implementation of genomic medicine in sick newborn infants.
  29. The 2025 Sir David Cuthbertson Lecture: Energy metabolism: Beyond calories, feeding the mitochondria.
  30. Mitochondrial retrograde signal through GCN5L1 transition-mediated PPARγ stabilization promotes MASLD development.
  31. NMR-based urinary biomarkers in pediatric primary mitochondrial disorders and chronic kidney disease: shared mitochondrial dysfunction, diverging biosignatures.
  32. VPS13A Deficiency Leads to Impaired Lipid Distribution and Alteration of Mitochondrial Calcium Homeostasis in Fibroblasts of VPS13A Disease Patients.
  33. An hMAO-B-activatable mitochondrial binding fluorescent probe in live-cell via enzyme-anchored and charge-driven dual targeting.
  34. NLRP10 engages oxidized DNA through a Schiff-base mechanism and dissociates from NLRP3 upon inflammasome activation.
  35. Epigenetic insights of Olympic champions: nuclear and mitochondrial DNA methylation and regulators of aging.
  36. Mitochondrial DNA is an important signaling molecule in cardiovascular aging and pathophysiology.
  37. Emerging frontiers in the mitochondrial regulation of dendritic cell biology.
  38. Shikonin attenuates diabetic Parkinsonian neuronal injury by facilitating p53/SLC25A28-mediated iron shuttling.
  39. SLC25A45: a gatekeeper for methylated amino acid metabolism.
  40. Pregnancies in Women With Long-Chain Fatty Acid Oxidation Disorders: Results of a European and North American Survey.
  41. The emerging role of the paraventricular thalamic nucleus in bipolar disorder: Lessons from mitochondrial dysfunction.
  42. Inhibition of de novo ceramide synthesis mitigates alpha-synuclein pathology in a Parkinson's disease mouse model.
  43. Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.
  44. A Case Report of Unilateral OPA3-Related Dominant Optic Atrophy.
  45. A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.
  46. Modeling tissue-specific Drosophila metabolism identifies high sugar diet-induced metabolic dysregulation in muscle at reaction and pathway levels.
  47. Ethylmalonic encephalopathy caused by biallelic truncating variants in ETHE1: A case report.
  48. Astrocytic mitochondrial transfer: a new horizon for metabolic rescue and precision therapy in ischemic stroke.
  49. Charcot-Marie-Tooth disease and related neuropathies.
  50. Distinct sympathetic projections to brown fat regulate thermogenesis and glucose tolerance.
  51. Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.
  52. MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy.
  53. Past, present and future perspectives on the science of aging.
  54. 'Remote controlled' proteins illuminate living cells.
  55. Ultrasound-assisted gene therapy mitigates Leigh syndrome pathology.
  56. Mitochondrial dysfunction and Ca2+ dysregulation in human iPSC-derived neurons carrying presenilin-1 mutation arise under stress via an MCU-1-independent mechanism.
  1. Autophagy. 2026 Jan 22.
    C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
    Jianshuang Li, Wenjun Wang, Li He, Qinghua Zhou.
      Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in Drosophila and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.
    Keywords:  Homeostasis; MISO; SMEM; mitochondrial subdomains; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2621110
  2. JCI Insight. 2026 Jan 23. pii: e181812. [Epub ahead of print]11(2):
    NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
    Joy Richard, Giulia Lizzo, Noélie Rochat, Adrien Jouary, Pedro Tm Silva, Alice Parisi, Stefan Christen, Sofia Moco, Michael B Orger, Philipp Gut.
      Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2-/- zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2-/- zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.
    Keywords:  Cell biology; Genetic diseases; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.181812
  3. Protein Sci. 2026 Feb;35(2): e70445
    Recognition of small Tim chaperones by the mitochondrial Yme1 protease.
    Mariella Quispe-Carbajal, Lauren Todd, Steven E Glynn.
      Yme1 is a conserved ATP-dependent protease that maintains mitochondrial function by degrading proteins in the intermembrane space. However, how Yme1 selects substrates within the crowded mitochondrial environment is poorly understood. An established substrate of Yme1 in yeast is the Tim10 subunit of the small Tim9-Tim10 protein chaperone complex, which is degraded following disruption of the subunit's internal disulfide bonds. Here, we use biochemical and biophysical approaches to examine initial substrate binding and degradation of small Tim proteins by Yme1 and shed light on the molecular mechanism of substrate selection. We show that Yme1 preferentially binds Tim10 over other small Tim proteins by forming a strong interaction with the subunit irrespective of the presence of its disulfide bonds. This interaction is primarily mediated by Tim10's flexible N-terminal "tentacle," though substrate unfolding exposes additional contact sites that enhance engagement. Notably, the human ortholog TIMM13 is also recognized by yeast Yme1, suggesting conservation of recognition strategy across species. Yme1 also binds to the assembled Tim9-Tim10 chaperone but independently of the Tim10 N-terminal tentacle. These findings suggest that Yme1 interacts with both the functional chaperone complex and the disassembled Tim10 monomers but only commits to degradation after disruption of its disulfide bonds.
    Keywords:  AAA+ proteases; intermembrane space; i‐AAA; mitochondrial proteostasis
    DOI:  https://doi.org/10.1002/pro.70445
  4. J Biol Chem. 2026 Jan 20. pii: S0021-9258(26)00047-5. [Epub ahead of print] 111177
    Palmitic acid induces UCP1-independent mitochondrial depolarization specifcally in brown adipose tissue.
    Yuto Ishikawa, Isshin Shiiba, Eisho Kozakura, Haruto Yabu, Shun Hirose, Hijiri Oshio, Ken-Ichi Yamada, Yuko Okamatsu-Ogura, Ryoko Inatome, Shigeru Yanagi.
      Brown adipose tissue (BAT) is a major site of non-shivering thermogenesis, where mitochondria generate heat instead of adenosine triphosphate (ATP). The thermogenesis occurs through the activity of uncoupling protein 1 (UCP1) which specifically resides in the mitochondrial inner membrane and dissipates the mitochondrial proton gradient upon activation by long-chain free fatty acids (FFA). Although UCP1-independent proton leak has been reported, the mechanism underlying UCP1-independent mitochondrial membrane depolarization remains largely unknown. Here, using primary brown adipocytes, we found that cold-mimicking stimulation induces mitochondrial membrane depolarization even under UCP1 knockout and knockdown conditions. Furthermore, during cold-mimicking stimulation, palmitic acid shows the most prominent increase in a lipolysis-dependent manner. Notably, palmitic acid directly decreases mitochondrial membrane potential specifically in mitochondria isolated from BAT, but not in those isolated from liver or brain. These findings suggest that palmitic acid contributes to mitochondrial depolarization in BAT, thereby contributing to UCP1-independent depolarization.
    Keywords:  Brown adipose tissue; Mitochondria; Palmitic acid; UCP1-independent mitochondrial depolarization
    DOI:  https://doi.org/10.1016/j.jbc.2026.111177
  5. Nucleic Acids Res. 2026 Jan 14. pii: gkag008. [Epub ahead of print]54(2):
    Human mitochondrial helicase Twinkle has RNA binding, annealing, and strand-exchange activities.
    Anupam Singh, Laura C Johnson, Noe Baruch-Torres, Y Whitney Yin, Smita S Patel.
      Twinkle is the sole replicative helicase in human mitochondria, essential for mitochondrial DNA replication. Beyond its canonical unwinding activity, Twinkle has non-canonical activities, including DNA annealing and strand-exchange. Here, we show that these non-canonical activities extend to RNA. Twinkle binds RNA and catalyzes RNA:DNA hybrid formation through annealing, strand-exchange, and toehold-mediated strand displacement. Twinkle can unwind RNA:DNA forks when loaded onto the DNA tail but not the RNA tail. Although the physiological role of these RNA-related activities remains unclear, we show that Twinkle can strand-exchange an RNA downstream of a stalled replication fork to restart replication. The annealing/strand-exchange activity can be involved in DNA replication initiation and repair, but RNA:DNA hybrids can compromise genome integrity, emphasizing the need to balance unwinding and annealing activities. Interestingly, mitochondrial SSB inhibits the RNA:DNA annealing activity of Twinkle, thus regulating the non-canonical functions of Twinkle. A disease-associated W315L variant, which is defective in DNA replication, retains annealing and strand-exchange functions with both RNA and DNA, resulting in an imbalance between replication and annealing functions that may underlie its pathogenicity. Our findings of Twinkle's RNA-binding and strand-exchange activities may have a connection to its localization within mitochondrial RNA granules.
    DOI:  https://doi.org/10.1093/nar/gkag008
  6. bioRxiv. 2025 Dec 07. pii: 2025.12.03.692150. [Epub ahead of print]
    Neddylation Regulates Mitochondrial Dynamics and Turnover in the Adult Heart.
    Jianqiu Zou, Wenjuan Wang, Chen Qu, Lingxian Zhang, Josue Zambrano-Carrasco, Yilang Li, Yi Lu, Hongyi Zhou, Kunzhe Dong, Tohru Fukai, Masuko Ushio-Fukai, Dawn Bowles, Michelle Mendiola Pla, Ryan Gross, Weiqin Chen, Jiliang Zhou, Jie Li, Huabo Su.
       BACKGROUND: Disruption of mitochondrial homeostasis drives cardiomyopathy and heart failure, yet upstream regulatory mechanisms remain poorly defined. Neddylation, a reversible post-translational conjugation of the ubiquitin-like protein NEDD8 by E1/E2/E3 enzymes, is essential for cardiac morphogenesis, but its role in the adult heart is unknown.
    METHODS: We assessed the relevance of neddylation to human cardiac disease by gene set enrichment analysis of ischemic (ICM) and non-ischemic cardiomyopathy (NICM) datasets and by immunoblotting and qPCR of ventricular tissue from patients with ICM or dilated cardiomyopathy (DCM). In adult mice, we induced cardiomyocyte-restricted deletion of the NEDD8-activating enzyme 1 (NAE1) by tamoxifen injection and monitored cardiac function at baseline and after transverse aortic constriction (TAC). Bulk RNA-seq 4 weeks post-tamoxifen was combined with bioenergetic, biochemical, and ultrastructural analyses. To assess mitochondrial dynamics, we generated NAE1/MFN2 and NAE1/DRP1 double-knockout mice. Cullin activity, mitochondrial ubiquitination, and mitophagy were measured in hearts and cultured cardiomyocytes.
    RESULTS: Neddylation pathways were dysregulated in human ICM and NICM datasets and in failing ICM/DCM myocardium. Cardiomyocyte-specific NAE1 deletion caused systolic dysfunction and heart failure by 10 weeks post-tamoxifen, culminating in premature death and exacerbating TAC-induced pressure-overload heart failure. At 4 weeks, NAE1 loss repressed metabolic and mitochondrial bioenergetic programs, reduced ATP production, and impaired respiration. Electron microscopy revealed elongated mitochondria and accumulated mitophagic vesicles, with dysregulation of DRP1, MFN2, PINK1, LC3-II, and p62. DRP1/NAE1 co-deletion accelerated systolic failure relative to either single knockout, whereas MFN2/NAE1 co-deletion did not alter early disease progression, implicating pathogenic mitochondrial hyperfusion. Genetic NAE1 depletion in vivo and pharmacologic NAE1 inhibition in vitro impaired mitophagic vesicle formation and flux, inactivated cullin scaffold proteins, reduced mitochondrial ubiquitination, and blunted mitophagic clearance.
    CONCLUSIONS: Cardiac neddylation preserves adult heart function by coordinating mitochondrial fusion-fission dynamics and sustaining cullin-dependent ubiquitination and turnover of damaged mitochondria. These findings identify neddylation as a key regulator of mitochondrial quality control and link its disruption to human cardiomyopathy. Therapeutically, targeting the neddylation-cullin axis may limit mitochondrial dysfunction, enhance mitophagy, and improve energetic reserve in failing hearts, while neddylation signatures in patient myocardium may help guide stratification and precision therapy for cardiomyopathy.
    Clinical Perspective: What Is New?: • Demonstrates for the first time that the NEDD8-activating enzyme (NAE1)driven neddylation pathway is indispensable for maintaining mitochondrial quality control in the adult heart.• Links loss of neddylation to mitochondrial hyperfusion, impaired mitophagy, and rapid progression to heart failure.• Reveals that neddylation promotes cullin-RING ligase-mediated ubiquitination of damaged mitochondria, coupling mitochondrial dynamics with turnover.What Are the Clinical Implications?: • Restoring or enhancing cardiac neddylation may represent a novel therapeutic avenue for cardiomyopathies characterized by mitochondrial dysfunction.• Pharmacologic agents that bolster DRP1-dependent fission or activate cullin neddylation could potentially normalize mitochondrial dynamics and improve myocardial energetics.• Conversely, systemic neddylation inhibitors now in oncology trials warrant careful cardiac monitoring, as they may precipitate mitochondrial injury and heart failure.• Circulating or tissue markers of neddylation might help stratify patients at heightened risk for mitochondrial-driven cardiac disease and guide precision therapy.
    DOI:  https://doi.org/10.64898/2025.12.03.692150
  7. Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2514994123
    Nuclear MBL-1 modulates mitochondrial morphology through carnitine palmitoyltransferase in Caenorhabditis elegans with toxic trinucleotide repeats.
    Joana Teixeira, Mikko J Frilander, Ove Eriksson, Susana M D A Garcia.
      Expansion of nucleotide repeat sequences is linked to a growing number of neuromuscular degenerative disorders. Metabolic changes, including disruptions in mitochondrial function and dynamics, characterize these disorders and are believed to contribute to organismal toxicity. To investigate how toxic RNA repeats affect mitochondria, we used a Caenorhabditis elegans model that expresses expanded CUG repeat RNAs in muscle cells and recapitulates muscle dysfunction. We found that the RNA-binding protein Muscleblind-like 1 (MBL-1) is essential for normal mitochondrial function and regulates organelle morphology. In animals expressing expanded CUG repeats, where MBL-1 function is impaired, we identified two distinct mechanisms of mitochondrial disruption: altered mitochondrial morphology regulated by MBL-1, and oxidative phosphorylation (OxPhos) dysfunction occurring independently of MBL-1. Our data further show that changes in mitochondrial morphology are specifically linked to nuclear MBL-1 dysfunction, which affects cpt-3 expression, a gene encoding carnitine palmitoyltransferase-an enzyme required for fatty acid transport into mitochondria. This mechanism is conserved, with similar disruptions observed in patients with Myotonic Dystrophy type 1. Importantly, our findings indicate that increased organelle fragmentation is not central to cellular pathogenesis. Instead, OxPhos dysfunction appears to be a primary contributor to organismal toxicity.
    Keywords:  Caenorhabditis elegans; RNA repeat toxicity; carnitine palmitoyl transferase; mitochondrial dysfunction; muscleblind-like
    DOI:  https://doi.org/10.1073/pnas.2514994123
  8. J Inherit Metab Dis. 2026 Jan;49(1): e70147
    Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on TK2 Deficiency.
    Paloma Martín-Jimenez, Laura Bermejo-Guerrero, Luz Edith Ochoa, María Navarro-Riquelme, Rocío Garrido-Moraga, Aurelio Hernández-Laín, Ana Hernández-Voth, Adrián González Quintana, Ana Bermejo-Moriñigo, Violeta González-Méndez, Cristina Martín-Arriscado Arroba, Dimitrii Smirnov, Nikita Konstantinovskiy, Joaquín Arenas, Miguel Ángel Martin, Alberto Blázquez, Cristina Domínguez-González.
      Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial myopathy with variable presentations, including late-onset forms beginning after age 12. Unlike early-onset disease, the natural history of late-onset TK2d remains poorly defined. We conducted a prospective, single-centre natural history study of 11 untreated patients with late-onset TK2d over 24 months. The median age at symptom onset was 27.2 years. Clinical phenotypes included progressive myopathy (n = 7), chronic progressive external ophthalmoplegia plus (n = 2), and exercise intolerance (n = 2). Most patients (72%) required non-invasive ventilation, and 70% showed axonal polyneuropathy. All patients carried biallelic pathogenic TK2 variants, with p.Lys202del being the most common (13/22 alleles). Muscle biopsies demonstrated mitochondrial DNA depletion and multiple deletions, and muscle MRI consistently showed selective involvement of the sartorius, gracilis and gluteus maximus, whose fat fraction correlated with motor impairment. Functional assessments revealed a mean forced vital capacity of 70.4%, an NSAA score of 25.9, a six-minute walk distance of 479.5 m, and a 100-m run time of 60.5 s. Serum GDF15 levels were elevated (median 2747.5 pg/mL) and significantly correlated with motor and respiratory function. Over 2 years, patients showed measurable clinical deterioration, with declines in NSAA (-2.65 points), FVC (-9.11%), and worsening 100-meter run times (+6 s). This study provides the first prospective longitudinal characterization of late-onset TK2d and identifies clinically relevant, quantifiable outcomes that may inform future therapeutic trials targeting this underrepresented patient population. Moreover, these results are also relevant for the design of clinical trials in other mitochondrial myopathies.
    Keywords:  GDF15; TK2 deficiency; biomarkers; late‐onset; mitochondrial myopathy; natural history
    DOI:  https://doi.org/10.1002/jimd.70147
  9. Aging Adv. 2025 Dec 18.
    Roles of DRP1 and the fission protein interactome as regulators of cellular stability and sarcopenia in skeletal muscle aging.
    C Nivedya, Prasanna Venkhatesh, Benjamin I Rodriguez, Han Le, Jeremiah Afolabi, Andrea Marshall, Kit Neikirk, Sepiso K Masenga, Muhammad Aftab, Leo Jake Kazma, Prasanna Katti, Antentor Hinton.
      Mitochondrial function is crucial in regulating cellular activity and determining cell fate. The replication and transcription of mitochondrial DNA are essential for maintaining mitochondrial integrity. These processes are governed by mitochondrial fission and fusion, which play a vital role in energy distribution, quality control, and metabolic regulation. Mitochondrial fission relies on the coordinated actions of mitochondria-endoplasmic reticulum contact sites, actin filaments, and dynamin-related protein 1, which collectively mediate mitochondrial constriction and fission. This interplay is fundamental to mitochondrial homeostasis and, critically, to the functionality of skeletal muscle. In this review, we explore the complex interactions among dynamin-related protein 1, mitochondria-endoplasmic reticulum contact sites, and actin and their significance for skeletal muscle function. Additionally, we discuss potential strategies to preserve these interactions, supporting optimal muscle performance in skeletal muscle aging. This review provides key insights and outlines future research directions to advance our understanding of this essential yet widely studied relationship.
    Keywords:  dynamin-related protein 1 (DRP1); exercise interventions; fission and fusion; mitochondria quality control; mitochondrial dynamics; mitochondria–endoplasmic reticulum contact sites (MERCs); mitophagy; posttranslational modifications; sarcopenia; skeletal muscle aging
    DOI:  https://doi.org/10.4103/agingadv.agingadv-d-25-00013
  10. Front Immunol. 2025 ;16 1734203
    NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.
    Oded Shamriz, Zahala Bar-On, Omri Yosef, Leonor Cohen-Daniel, Ayelet Sheer, Or Reuven, Wajeeh Salaymeh, Amijai Saragovi, Raz Somech, Atar Lev, Hagar Mor-Shaked, Yuval Tal, Aviva Fattal-Valevski, Simon Edvardson, Michael Berger.
       Introduction: Mitochondrial metabolism is essential for T-cell function, but the roles of individual electron transport chain (ETC) components are unclear. Here, we aimed to explore the role of mitochondrial complex I (CI) subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (NDUFS4) in T-cell metabolic fitness and immunity.
    Methods: We used a T cell-specific Ndufs4 knockout mouse model to find that NDUFS4 deficiency disrupts CI function, leading to metabolic and redox imbalances. Additionally, T cells from a patient with Leigh syndrome induced by NDUFS4 loss-of-function were analyzed.
    Results: Ndufs4-deficient T cells exhibit impaired OXPHOS, reduced respiratory capacity, and increased glycolysis, accompanied by reactive oxygen species (ROS) accumulation and defective TCR-driven activation, including reduced proliferation and cytokine production. In vivo, Ndufs4(-/-) mice show T-cell lymphopenia and impaired humoral and cytotoxic immunity. Importantly, T cells from a single Leigh syndrome patient with an NDUFS4 loss-of-function variant showed similar defects, including impaired activation and proliferation.
    Discussion: These findings highlight the importance of NDUFS4 for human immunity and establish a mechanistic link between complex I dysfunction and T-cell immunodeficiency. Our results identify NDUFS4 as a key regulator connecting mitochondrial integrity to adaptive immune function.
    Keywords:  NDUFS4; NDUFS4 knockout mice; T cells; leigh syndrome (LS); mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2025.1734203
  11. Front Genet. 2025 ;16 1682085
    Case Report: Myoclonic and tremulous movements associated with COQ8A-related coenzyme Q10 deficiency type 4.
    Di Wang, Guojian Zhang, Xiaojing Fang, Fang Liu, Li Wang.
       Background: Primary coenzyme Q10 (CoQ10) deficiency is a rare, treatable mitochondrial disorder often caused by biallelic pathogenic variants in COQ8A gene (also known as ADCK3). It typically manifests as childhood-onset cerebellar ataxia with variable multisystem involvement. Early recognition is critical, as CoQ10 supplementation has potential to significantly alleviate clinical manifestations and modify natural progression of the disease. Here, we provide a rare phenotype of paroxysmal dyskinesias caused by compound heterozygous variants of COQ8A gene.
    Case: A 21-year-old man presented with myoclonic tremor, mild dysarthria, ataxia and emotional instability. The brain MRI showed cerebellar atrophy. Biochemical workup revealed low plasma CoQ10 levels. Whole-exome sequencing identified compound heterozygous COQ8A variants: two novel missense substitutions [NM_020247.5:c.641T>A (p.Leu214Gln), NM_020247.5:c.1621T>C (p.Ser541Pro)], each inherited from an asymptomatic parent. The patient was initiated on oral CoQ10 at a dose of 200 mg twice daily, accompanied by supportive interventions targeting emotional regulation. A marked improvement in tremor symptoms was observed shortly after treatment initiation; however, intermittent muscle tremors persisted during periods of emotional agitation. At 1-year follow-up, the patient remained on CoQ10 at 300 mg twice daily and levetiracetam at 500 mg twice daily, with sustained symptom control.
    Conclusion: This case highlights that COQ8A-related CoQ10 deficiency can present with serious neurological crises among young people and underscores the importance of rapid genetic diagnosis in such scenarios. Early and aggressive CoQ10 supplementation led to clinical stabilization in our patient, reinforcing that primary CoQ10 deficiency is a reversible cause of neurodegenerative disease. We emphasize genotype-phenotype diversity in COQ8A disease and the crucial need for early detection and treatment to improve prognosis. We propose that clinicians maintain a high index of suspicion for primary CoQ10 deficiency in patients presenting with unexplained dystonia or ataxia, as timely intervention may significantly improve clinical outcomes.
    Keywords:  COQ8A gene; mitochondrial disorders (MIDs); movement disorder; myoclonic tremor; primary coenzyme Q10 deficiency
    DOI:  https://doi.org/10.3389/fgene.2025.1682085
  12. Cell Rep. 2026 Jan 19. pii: S2211-1247(25)01629-8. [Epub ahead of print]45(1): 116857
    Metabolic reprogramming during human neuron differentiation indicates glutaminase as a key determinant in Fragile X syndrome.
    Sneha Shah, Daniel Barnes, Botao Liu, Tenzin Tseyang, Thang Do, Jodi L Bubenik, Suna Jung, Mina N Anadolu, Maria P Ivshina, Verónica Martínez-Cerdeño, Elizabeth Berry-Kravis, Maurice S Swanson, Jessica B Spinelli, Joel D Richter.
      Metabolic homeostasis gone awry is a contributor to, if not an underlying cause of, several neurologic disorders. Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in FMR1 and consequent loss of the encoded protein FMRP, which results in downstream molecular, neurologic, and mitochondrial deficits that are linked to cognitive impairment. In the human postmortem brain, many metabolites and solute carrier proteins are coordinately dysregulated, which also occurs during the differentiation of human induced pluripotent stem cells (iPSCs) into excitatory neurons. Metabolic tracing in FXS neurons demonstrates a dearth of glutamine deamidation to glutamate, which reduces anaplerosis into the TCA cycle, potentially hindering the bioenergetic and biosynthetic functions of mitochondria. Mechanistically, aberrant expression of glutaminase isoforms in FXS is responsible for reduced glutaminolysis, thereby altering glutamate levels, which may contribute to FXS.
    Keywords:  CP: metabolism; CP: neuroscience; Fragile X syndrome; glutamate transporters; glutaminase; human neurons; iPSC; metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116857
  13. Autophagy. 2026 Feb;22(2): 235-237
    Acetyl-CoA as a metabolic switch for selective mitophagy.
    Daolin Tang, Rui Kang, Daniel J Klionsky.
      A recent study published in Nature by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.
    Keywords:  Acetyl-CoA; KRAS inhibitor; NLRX1; metabolic signaling; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2593032
  14. Cardiovasc Res. 2026 Jan 20. pii: cvag011. [Epub ahead of print]
    Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.
    Colleen S Stein, Xiaoming Zhang, Nathan H Witmer, Edward Ross Pennington, Scott Hahn, Adam C Straub, Saame Raza Shaikh, Ryan L Boudreau.
       AIMS: We and others discovered a highly conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca2+ retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress.
    METHODS AND RESULTS: We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally relevant role for Mtln in cardioprotection.
    CONCLUSION: Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.
    Keywords:  Cyb5r3; cardiolipin; cardioprotection; cristae; docosahexaenoic acid; ischemia-reperfusion; mitochondria; monolysocardiolipin; permeability transition; triglycerides
    DOI:  https://doi.org/10.1093/cvr/cvag011
  15. Redox Biol. 2026 Jan 13. pii: S2213-2317(26)00028-5. [Epub ahead of print]90 104030
    Mitochondrial acetyl-CoA reprogramming by the SIRT3-ACSS2-OPA1 axis confers resistance to ferroptosis in Parkinson's disease.
    Xv-Shen Ding, Bao Wang, Zheng Han, Chen-Xi Feng, Yang-Ni Li, Yu-Fei Wang, Jian-Cai Guru, Jie Cao, Rui-Li Zhang, Xue-Lian Wang, Qian Yang, Yan Qu, Li Gao.
      Mitochondrial dysfunction and ferroptosis have emerged as pivotal contributors to dopaminergic (DA) neuron degeneration in Parkinson's disease (PD). Here, a previously unrecognized SIRT3-ACSS2-OPA1 axis that couples mitochondrial acetyl-CoA (Ac-CoA) metabolism to ferroptosis resistance is identified. Analysis of public human substantia nigra datasets reveals marked reduction in SIRT3 expression, which is further confirmed in 6-OHDA-induced PD models. To establish translational significance, analyses of serum and peripheral blood mononuclear cells (PBMCs) from PD patient cohort demonstrates decreased SIRT3 protein levels and deacetylase activity. Moreover, SIRT3 overexpression inhibits ferroptosis and mitochondrial fragmentation in neurons. Mechanistically, SIRT3 deacetylates and activates acetyl-CoA synthetase 2 (ACSS2), thereby facilitating the redistribution of Ac-CoA from mitochondria to the nucleus, leading to Optic atrophy 1 (OPA1) deacetylation. Meanwhile, this Ac-CoA reprogramming enhances histone H3K27 acetylation at the OPA1 promoter, and thereby drives OPA1 transcriptional upregulation. OPA1 restores mitochondrial homeostasis, alleviates iron accumulation, reduces lipid peroxidation, and ultimately suppresses ferroptosis. In vivo, pharmacological activation of SIRT3 or AAV-mediated Opa1 overexpression mitigates ferroptosis, preserves DA neurons, and improves motor performance in PD mice. This study uncovers mitochondrial Ac-CoA reprogramming as a key defense mechanism against ferroptosis, positioning the SIRT3-ACSS2-OPA1 pathway as a promising therapeutic target for PD.
    Keywords:  Ferroptosis; Mitochondrial acetyl-CoA reprogramming; Mitochondrial dynamics; Parkinson's disease; SIRT3
    DOI:  https://doi.org/10.1016/j.redox.2026.104030
  16. FASEB J. 2026 Jan 31. 40(2): e71467
    TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
    Yuxuan Zhang, Ximeng Wang, Dachuan Li, Xiao Lu, Zhaoyang Gong, Zhidi Lin, Hanqiu Sun, Hongli Wang, Zian Lu, Xiaosheng Ma, Guangyu Xu, Jianyuan Jiang.
      The polarization state of microglia exerts an influence on neuroinflammation and neural tissue repair after injury. Modulating microglial polarization is emerging as a potential therapeutic strategy for various types of neural injuries and neurodegenerative diseases. However, the causal relationship between microglial polarization and mitochondrial dynamics, which include mitochondrial fusion and fission, remains to be fully clarified. Our study demonstrates that mitochondrial fusion promoter M1 promotes mitochondrial fusion in mouse microglial cells, leading to reduced glycolysis and increased fatty acid oxidation, and this metabolic reprogramming impacts microglial polarization. Additionally, in both cellular and animal experiments, it was observed that knocking down mitochondrial transcription factor A (TFAM) results in increased mitochondrial fission, decreased fatty acid β-oxidation, enhanced glycolysis, and promotes the polarization of microglia toward the pro-inflammatory M1 phenotype. In conclusion, our study has, for the first time, provided evidence that TFAM may play a role in the regulation of mitochondrial dynamics. Furthermore, we provide a detailed elucidation of the chronological sequence and underlying causal relationships among mitochondrial dynamics, mitochondrial metabolic reprogramming, and microglial polarization. These findings offer novel targets and strategies for the treatment of various neural injuries and neurodegenerative diseases.
    Keywords:  TFAM; cell polarization; fatty acid oxidation; glycolysis; metabolism; microglia; mitochondria
    DOI:  https://doi.org/10.1096/fj.202503182RR
  17. Mol Genet Genomic Med. 2026 Jan;14(1): e70200
    Multiple Mitochondrial Dysfunction Syndrome Caused by IBA57 Gene Mutation: A Case Report and Literature Review.
    Jia Xu, Xin Zhang, Ying Hua, Li Yang, Dongyu Shi, Shiyan Qiu.
       BACKGROUND: Pathogenic variants of IBA57 (OMIM ID: 615330) are usually associated with multiple mitochondrial dysfunction syndrome (MMDS) and hereditary spastic paraplegia type 74 (SPG74). Here, we present a novel compound heterozygous IBA57 mutation in a boy with severe global developmental delay, optic atrophy, spastic paraplegia, and focal epileptic seizures.
    METHODS: The clinical data of a child diagnosed with MMDS were retrospectively collected. Video electroencephalogram (VEEG), cranial magnetic resonance imaging (MRI), and family whole-exome sequencing (WES) were performed. Suspected mutation sites were further confirmed using Sanger sequencing. The activities of mitochondrial respiratory chain complexes I-IV were determined in peripheral blood mononuclear cells. The phylogenetic conservation of the affected residues was assessed by multiple sequence alignment of IBA57 gene orthologs. Furthermore, we conducted a review of the relevant literature.
    RESULTS: Whole-exome sequencing identified compound heterozygous variants in the IBA57 gene: c.395_400dup (p.V132_Q133dup) and c.832delC (p.R278Afs*23), inherited from his phenotypically normal father and mother, respectively. Biochemical assays demonstrated selective reduction of complexes I and II activities, with normal complexes III and IV, consistent with impaired 4Fe-4S cluster maturation. Phylogenetic alignment revealed strict conservation of residues V132-Q133 and R278 across vertebrates. These variants had not been previously reported in domestic or international databases. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the former was classified as a variant of uncertain significance (PM4 + PM2), while the latter was classified as likely pathogenic (PVS1 + PM2).
    CONCLUSION: Diseases associated with IBA57 gene variants are autosomal recessive disorders with a broad clinical phenotypic spectrum. Early genetic testing and family screening are beneficial for the diagnosis, treatment, and prognosis of the disease.
    Keywords:  IBA57 gene; MMDS; leukoencephalopathy; mitochondrial disease
    DOI:  https://doi.org/10.1002/mgg3.70200
  18. Case Rep Ophthalmol. 2026 Jan-Dec;17(1):17(1): 75-80
    Leber Hereditary Optic Neuropathy-Associated Novel Mutation in MT-RNR2 Gene: A Case Report.
    Sara KamaliZonouzi, Jonathan Micieli.
       Introduction: Leber hereditary optic neuropathy (LHON) is a hereditary optic neuropathy mainly caused by mutations at 1,178, 14,484, and 3,460 in mitochondrial DNA. Patients with LHON have a higher risk of developing multiple sclerosis (MS), a coexistence also known as Harding's syndrome. A growing body of evidence shows that other mitochondrial and non-mitochondrial mutations can lead to LHON and Harding's syndrome. Herein, we report a novel mutation in MT-RNR2 resulting in LHON.
    Case Presentation: A 35-year-old woman with bilateral painless optic neuropathy presented to neuro-ophthalmology clinic. Her blood work-up did not reveal any nutritional deficiencies, and she did not respond to steroid therapy. Genetic test revealed a m.1737A>G mutation in MT-RNR2 gene with 99.9% penetrance; therefore, she was diagnosed with LHON.
    Conclusion: MT-RNR2 gene mutation was the possible cause for LHON in this patient. Herein, we describe a novel mutation and associated clinical features. This case report also underscores the importance of considering LHON as a differential diagnosis for optic neuritis, even in a patient with an established MS.
    Keywords:  Case report; Hereditary optic neuropathy; Leber hereditary optic neuropathy; RNR2; m.1737A>G
    DOI:  https://doi.org/10.1159/000550116
  19. Adv Sci (Weinh). 2026 Jan 22. e23368
    Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.
    Parmeshar Singh, Amir Tahavvori, Cyrus E Kuschner, Blanca B Espin, Jacob Kazmi, Sofhia V Ramos, Tai Yin, Kei Hayashida, Kanako Ito-Hagiwara, Yusuke Endo, Keitaro Yoshioka, Jun Hagiwara, Avijot Sohi, Alisha Oropallo, Ghania Haddad, Timmy Li, Lance B Becker, Junhwan Kim.
      Mitochondria are essential organelles responsible for cellular energy production and diverse metabolic processes. Mitochondrial dysfunction is implicated in a wide range of diseases. Specifically, genetic mitochondrial diseases, arising from mutations in mitochondrial or nuclear DNA, lead to significant mitochondrial deficits, which result in debilitating and often life-threatening symptoms. Conventional treatments frequently fail to address these underlying mitochondrial defects, leaving few therapeutic options. Mitochondrial transplantation (MTx), an emerging therapeutic approach involving the delivery of healthy exogenous mitochondria to target cells, has demonstrated beneficial effects in various mitochondria-mediated diseases in both preclinical and early clinical studies. However, its application to inherited mitochondrial disorders remains largely unexplored and raises important questions about the need for repeated or continuous administration to sustain therapeutic effects. This review systematically examines the potential of MTx for inherited mitochondrial disorders by classifying these diseases by mitochondrial and nuclear DNA origin, critically assessing MTx evidence and mechanisms, and identifying unique translational requirements for chronic inherited disorders. While significant challenges remain, MTx represents a promising approach to directly address mitochondrial dysfunction in these life-threatening conditions with limited therapeutic alternatives.
    Keywords:  chronic diseases; genetic diseases; mitochondrial transplantation; therapeutics
    DOI:  https://doi.org/10.1002/advs.202523368
  20. Aging Cell. 2026 Feb;25(2): e70378
    Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I Function.
    Meiling Wang, Yumin Chang, Aojie He, Jing Yang, Ang Li, Hongqin Wang, Kah-Leong Lim, Xing Guo, Chengwu Zhang, Li Lu.
      Age-related memory decline is a hallmark of brain aging and a primary risk factor for neurodegenerative disorders. Microglia play a crucial role in preserving memory function by maintaining brain homeostasis through phagocytosis, yet the specific mechanisms governing this protective function remain elusive. In the present study, we identified a population of Secreted Phosphoprotein 1 (Spp1)-positive microglia in both aged mouse and human brains. To investigate the role of microglial Spp1 in aging, we generated microglia-specific Spp1 knockout (Spp1-cKO) mice. We demonstrate that Spp1 deficiency selectively precipitates memory deficits in aged mice, without affecting memory function in young mice, indicating an age-dependent reliance on Spp1 signaling. Microglial phagocytic capacity positively correlates with Spp1 levels and is diminished by Spp1 deficiency. Mechanistically, Spp1 deficiency leads to the downregulation of the AKT/mitochondrial complex I pathway, thereby compromising microglial oxidative phosphorylation and function. Notably, microglia-specific overexpression of Spp1 partially ameliorates the age-related phenotypes induced by Spp1 deficiency. In conclusion, this study is the first to reveal the crucial role of microglial Spp1 in brain aging and to uncover its underlying mechanism, providing novel insights into age-related memory decline.
    Keywords:  ATP; Spp1; age‐related memory decline; microglia; mitochondrial complex I
    DOI:  https://doi.org/10.1111/acel.70378
  21. J Biol Chem. 2026 Jan 20. pii: S0021-9258(26)00049-9. [Epub ahead of print] 111179
    The Antiseizure Medication Stiripentol Inhibits Mitochondrial Complex I by Blocking Early-Stage Electron Transfer.
    Cyrielle L Bouchez, Thibaut Molinié, Guillaume Duranthon, Sebastian Lillo, Corinne Pellon, Nadia El Mammeri, Benjamin Dartigues, Philippe Pasdois, Benoit Pinson, Macha Nikolski, Anne Devin, Arnaud Mourier, Roland T Ullrich, Thomas Daubon.
      The oxidation of NADH is essential for maintaining cellular redox balance and supporting cell metabolism. Mitochondrial complex I (NADH:ubiquinone oxidoreductase) plays a central role in this process by coupling NADH oxidation to electron transfer and proton translocation across the inner mitochondrial membrane. We previously reported that the antiseizure medication stiripentol decreases lactate production and mitochondrial respiration, suggesting an impact on NADH turnover beyond its known inhibition of lactate dehydrogenase. In this study, we identify complex I as a target of stiripentol across multiple species and cell types. Biochemical and spectroscopic analyses demonstrate that stiripentol inhibits NADH oxidation and electron transfer through a mechanism distinct from that of classical ubiquinone pocket inhibitors such as rotenone or piericidin A. Remarkably, stiripentol acts upstream of the ubiquinone reduction site, representing the first example of a complex I inhibitor with a binding site within the N-module. These findings uncover a previously unrecognized mode of complex I inhibition and link stiripentol's metabolic effects to direct modulation of mitochondrial NADH oxidation. This work broadens the understanding of stiripentol's mechanism of action and highlights its potential to modulate redox metabolism in cancer cells.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111179
  22. Cell Rep. 2026 Jan 17. pii: S2211-1247(25)01627-4. [Epub ahead of print]45(1): 116855
    Stuxnet balances mitochondria homeostasis by regulating uhg5 and parkin.
    Xianguo Zhao, Xingzhuo Yang, Yuansheng Huang, Yifan Zhang, Xiangzhou Cui, Junzheng Zhang, Juan Du.
      Emerging evidence implicates the Stuxnet (Stx) protein in human disease, extending beyond its known role in proteasome-independent degradation. Exploring this further, our investigation into stx downstream targets in Drosophila reveals that loss of the U snoRNA host gene 5 (Uhg5) gene disrupts sleep. This sleep phenotype is linked to inefficient translation of mitochondrial genes, as Uhg5 produces small nucleolar RNAs (snoRNAs) that directly regulate mitochondrial transcripts. Using GoldCLIP technology, we discover that Stx interacts with both Uhg5 and parkin mRNAs. parkin is a key regulator of mitochondrial quality control. Genetic tests confirm functional relationships between stx, Uhg5, and parkin. This study establishes that Uhg5-derived snoRNAs regulate sleep by controlling mitochondrial gene translation. Crucially, our findings propose a model in which Stx coordinates mitochondrial biogenesis (via Uhg5) with mitophagy (via parkin). This provides a molecular link for Stx's potential role in Parkinson's disease pathogenesis.
    Keywords:  CP: molecular biology; CP: neuroscience; Drosophila; RNA binding protein; Uhg5; midnolin; mitochondria; mitochondrial gene translation; parkin; sleep; snoRNA host genes; stuxnet
    DOI:  https://doi.org/10.1016/j.celrep.2025.116855
  23. Nat Metab. 2026 Jan 20.
    Heterogeneous sympathetic control of brown adipose tissue.
    Xun Huang, Li Ye.
      
    DOI:  https://doi.org/10.1038/s42255-025-01435-2
  24. Redox Biol. 2026 Jan 17. pii: S2213-2317(26)00027-3. [Epub ahead of print]90 104029
    Upregulated GBP2 exacerbates Parkinson's disease pathogenesis by impairing NIX-dependent mitophagy.
    Wenqi Cui, Tianlu Wang, Juan Feng.
      Parkinson's disease (PD), characterized by dopaminergic neuron loss, still lacks disease-modifying therapies due to incompletely understood mechanisms. Guanylate-binding proteins (GBPs) are well-known immune regulators, but their roles in PD are largely unknown. In this study, we identify GBP2 as a critical driver of PD pathogenesis by impairing mitophagy. We found that GBP2 was significantly upregulated in the substantia nigra of PD patients, and in both MPTP-induced and A53T transgenic mouse models, as well as in MPP+-treated or A53T α-synuclein-overexpressing SH-SY5Y cells. Both in vivo and in vitro, genetic knockdown of GBP2 robustly alleviated the MPTP/MPP+-induced motor deficits, dopaminergic neuron loss, and apoptosis. Mechanistically, PD-related stress promotes GBP2 geranylgeranylation, driving its mitochondrial accumulation. At mitochondria, GBP2 directly binds the mitophagy receptor NIX via its large GTPase domain and targets it for ubiquitin-proteasomal degradation, thereby suppressing NIX-mediated mitophagy. Accordingly, GBP2 knockdown enhanced mitophagy, improved mitochondrial homeostasis, and protected against neuronal apoptosis. The neuroprotective effects of GBP2 knockdown were abolished by either pharmacological inhibition of mitophagy or genetic knockdown of NIX, indicating a linear pathway. Importantly, therapeutically targeting geranylgeranylation with GGTI298 significantly attenuated MPTP-induced neurotoxicity. Our study unveils a novel, druggable axis in PD pathogenesis where GBP2 disrupts mitochondrial quality control. Targeting GBP2 geranylgeranylation with GGTI298 presents a promising therapeutic strategy.
    Keywords:  GBP2; Geranylgeranylation; Mitochondrial dysfunction; Mitophagy; NIX; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.redox.2026.104029
  25. Protein Sci. 2026 Feb;35(2): e70486
    Protein-lipid interplay governs ion channel gating and bioenergetics in human mitochondrial VDAC3.
    Aadish Rawat, Radhakrishnan Mahalakshmi.
      The interaction between transmembrane proteins and their lipid environment is central to protein stability and function. Yet, the molecular factors guiding specificity of protein-lipid interactions remain poorly defined. Here, using the human voltage-dependent anion channel 3 (hVDAC3), a member of the essential outer mitochondrial membrane β-barrel VDAC family, as a model, we show that lipid headgroups, and hydrocarbon chain length and saturation, critically shape ion channel behavior. Physiological lipids effectively mitigate the functional deficiency of hVDAC3. Surprisingly, cardiolipin uniquely disrupts hVDAC3 gating by preferentially retaining the channel in an "open-like" conductive state. Single-channel electrophysiology and all-atom molecular dynamics simulations together reveal that lipid composition selectively modulates hVDAC3 structure and its N-terminal helix dynamics, without altering the global β-barrel fold and stability. We conclude that anionic headgroups, negative protein-bilayer mismatch, and increased membrane viscosity favor optimal channel stability and function. We find the specific functional outcome of cardiolipin-hVDAC3 cross-talk a potential regulator of the onset of mitochondria-mediated apoptosis. These findings offer fundamental insights into the unexpected sensitivity of mitochondrial channels to the physicochemical diversity of their lipid environment.
    Keywords:  human VDAC; lipid‐regulated function; lipid–protein interaction; mitochondrial β‐barrel; voltage gating
    DOI:  https://doi.org/10.1002/pro.70486
  26. Sci Rep. 2026 Jan 21.
    ATF4 regulates mitochondrial dysfunction and mitophagy, contributing to corneal endothelial apoptosis.
    Saba Qureshi, Stefan Y Kim, Stephanie Lee, Lukas Ritzer, William Steidl, Gayle Joliet Krest, Anisha Kasi, Varun Kumar.
      
    Keywords:  ATF4; Cell survival; ER stress; Mitochondrial stress; Mitophagy
    DOI:  https://doi.org/10.1038/s41598-026-36453-x
  27. Curr Mol Med. 2026 Jan 13.
    Impact of Toll/Interleukin-1 Receptor Domain Protein C on Mesenchymal Stem Cells Mitochondrial Protein Expression: A Proteomic Study.
    Yameng Wang, Jiaqi Fang, Dongyang Guo, Liang Xia.
       INTRODUCTION: Stem cells play a pivotal role in immunomodulation and tissue repair, and their functions can be influenced by TLR signaling. The Toll/interleukin-1 receptor domain-containing protein C (TcpC), secreted by Uropathogenic Escherichia coli, can inhibit host immunity by interfering with TLR pathways. As mitochondria are crucial for stem cell function, there may be links between TcpC and mitochondrial homeostasis.
    METHODS: We isolated MSC mitochondria using magnetic beads coated with a monoclonal antibody against the outer mitochondrial membrane protein OMP25 and conducted a proteomic study to examine the MSC mitochondrial proteome with or without TcpC. Bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and proteinprotein interaction (PPI) network analysis, were employed.
    RESULTS: A total of 33 proteins with significant changes in abundance were identified: 4 increased in abundance, including glycolytic enzymes (Pkm [FC=1.6599, p=0.0217]) and stress response proteins (Ywhaq [FC=1.4666, p=0.04502]); and 29 decreased, mainly related to mitochondrial oxidative phosphorylation (e.g., Atp5f1e [FC=0.001, p=0.00120], Ndufa11 [FC=0.001, p=0.00674]) and protein quality control (e.g., Grpel1 [FC=0.46663, p=0.02083], Hspa9 [FC=0.48089, p=0.0435], Pitrm1 [FC=0.12764, p=0.01388]).
    DISCUSSION: The possible effects of TcpC on the MSC mitochondrial proteome are reported here for the first time. This information provides a clearer understanding of MSCs in the context of infectious disease and offers a scientific basis for future stem cell therapy research.
    CONCLUSION: TCP-C intervention leads to a series of differentially expressed proteins in MSC mitochondria, which are involved in several functional clusters, including oxidative phosphorylation, respiratory electron transport, the tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism, branched-chain amino acid catabolism, and cristae formation.
    Keywords:  Mesenchymal stem cells; Mitochondria; TCPC; oxidative phosphorylation; protein quality control.; proteomics
    DOI:  https://doi.org/10.2174/0115665240411988251128121911
  28. Pediatr Int. 2026 Jan-Dec;68(1):68(1): e70327
    Identification of new human monogenic disorders and implementation of genomic medicine in sick newborn infants.
    Toshiki Takenouchi.
      Over the past few decades, advances in genomic analysis techniques and bioinformatics have enabled the identification of many new human monogenic diseases. In 2015, the Japan Agency for Medical Research and Development launched a national project for undiagnosed diseases called the Initiative on Rare and Undiagnosed Diseases (IRUD). Through this project, we identified Takenouchi-Kosaki syndrome (OMIM#616737), which is caused by specific pathogenic variants in CDC42, a critical regulator of diverse cellular functions, and is clinically characterized by intellectual disability and macrothrombocytopenia. In addition to the identification of disease-causing genes and new human monogenic disorders, significant progress has also been made in the clinical implementation of genomic medicine. In 2019, we launched a national project called Precise and Rapid Genetic Diagnosis and Treatability for Infants (Priority-i) to provide rapid genetic diagnosis for sick newborns in neonatal intensive care units. It is our mission to apply the benefits of the latest advances in genomic medicine to the clinical care of newborns and children.
    Keywords:  CDC42; Takenouchi‐Kosaki syndrome; exome sequencing; initiative on rare and undiagnosed diseases; precise and rapid genetic diagnosis and treatability for infants
    DOI:  https://doi.org/10.1111/ped.70327
  29. Clin Nutr. 2026 Jan 09. pii: S0261-5614(26)00002-6. [Epub ahead of print]57 106575
    The 2025 Sir David Cuthbertson Lecture: Energy metabolism: Beyond calories, feeding the mitochondria.
    Eric Fontaine.
      In this article, I explore how energy metabolism depends on proper mitochondrial function. Adenosine triphosphate (ATP), the main source of energy for cells, is mainly produced in the mitochondria as a result of the fusion of hydrogen produced by the breakdown of nutrients with oxygen. This reaction allows protons to be pumped across the inner mitochondrial membrane, creating a gradient that powers ATP synthesis. However, ATP production is not perfectly efficient. Some oxygen is consumed without generating ATP due to proton leaks or other processes that utilize the gradient. Diet, hormones, and cellular signals can alter mitochondrial efficiency: for example, hyperthyroidism and polyunsaturated fatty acid deficiency cause uncoupling, while hypothyroidism and nitric oxide increase coupling but reduce maximum ATP production. I also point out that the use of ATP depends on its thermodynamic value, which is reflected in the Adenosine triphosphate/Adenosine diphosphate ratio ([ATP]/[ADP] ratio). A decrease in this ratio can selectively reduce certain ATP-consuming processes, as shown in studies on metformin and imeglimin. In cases of stress or nutritional deficiency, cells can consume ATP without performing useful work, leading to inefficiency or even cell death when the [ATP]/[ADP] ratio collapses. Knowing that these concepts are quite complex, I have simplified them to make clear that mitochondria are more than just passive "powerhouses of cells".
    Keywords:  Efficiency; Energy metabolism; Flux–force relationship; Kinetics; Mitochondria; Thermodynamics
    DOI:  https://doi.org/10.1016/j.clnu.2026.106575
  30. JCI Insight. 2026 Jan 23. pii: e196695. [Epub ahead of print]11(2):
    Mitochondrial retrograde signal through GCN5L1 transition-mediated PPARγ stabilization promotes MASLD development.
    Jiaqi Zhang, Danni Wang, Qiqi Tang, Yaoshu Yue, Xin Lu, Xiuya Hu, Yitong Han, Jiarun Chen, Zihan Wang, Xue Bai, Kai Zhang, Yongsheng Chang, Longhao Sun, Lu Zhu, Lingdi Wang.
      Mitochondrial retrograde signaling plays crucial roles in maintaining metabolic homeostasis via regulating genome modification and oxidative responsive gene expression. In this study, we identified GCN5L1, a protein localized in both mitochondria and cytoplasm, and demonstrated its specific translocation from mitochondria to cytoplasm during lipid overload and high-fat diet feeding. Using transcriptome and proteome analyses, we identified that cytoplasmic GCN5L1 binds to and promotes the acetylation of PPARγ at lysine 289 (K289). This acetylation protected PPARγ from ubiquitination-mediated degradation by proteasome. GCN5L1 translocation enhanced protein stability of PPARγ and subsequently promoted lipid accumulation in both cultured cells and murine models. Our study further reveals that PPARγ-K289 mutation reduces the ubiquitination of PPARγ and exacerbates liver steatosis in mice. These findings unveil a mitochondrial retrograde signaling during lipid overload, which regulates the crucial lipogenic transcriptional factor. This discovery elucidates an unrecognized mitochondrial function and mechanism underlying hepatic lipid synthesis.
    Keywords:  Cell biology; Hepatology; Mitochondria; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.196695
  31. Metabolomics. 2026 Jan 19. 22(1): 17
    NMR-based urinary biomarkers in pediatric primary mitochondrial disorders and chronic kidney disease: shared mitochondrial dysfunction, diverging biosignatures.
    Margarida Paiva Coelho, João E Rodrigues, Teresa Costa, Aureliano Dias, Inês C R Graça, Hugo Rocha, Laura Vilarinho, Esmeralda Martins, Ana M Gil.
       BACKGROUND: Renal involvement is a recognized feature of primary mitochondrial disorders (PMD), either at presentation or during the disease course. Simultaneously, the metabolomic fingerprint of chronic kidney disease (CKD) is often associated with underlying mitochondrial dysfunction. This study aimed to characterize urinary metabolic signatures in genetically confirmed paediatric PMD without chronic kidney disease, comparing them to healthy controls, suspected (unconfirmed) mitochondrial disease (SMD), and non-mitochondrial CKD.
    METHODS: We performed untargeted 1H NMR metabolomic profiling of 76 urine samples from 51 paediatric patients and 10 healthy controls. PMD patients in acute decompensation or known CKD and statistical outlier samples were excluded. Final comparisons included genetically confirmed PMD without CKD (n = 13), SMD (n = 10), non-mitochondrial CKD (n = 28; 17 at stages 1-2 and 9 at stages 3-5), and healthy controls (n = 10). Spectral data were analyzed using multivariate statistical approaches-including principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA)-as well as univariate methods with Mann-Whitney U for pairwise group metabolite comparison.
    RESULTS: Urinary metabolic profiles of PMD patients differed from healthy controls and CKD patients. Multivariate analysis revealed a strong discriminative ability between PMD and controls (Q² = 0.53) and advanced CKD (Q2 = 0.78). Compared to controls, PMD patients had increased levels of Krebs cycle intermediates (cis-aconitate, fumarate and succinate), creatine, tryptophan, homovanillate (HVA) and hypoxanthine, as well as decreased histidine. All, except fumarate and histidine, remained discriminative when comparing PMD to CKD. CKD patients showed a diverging metabolomic fingerprint with 1-methylnicotinamide (MNA) and 2-hydroxyisobutyrate emerging as potential CKD-specific biomarkers, effectively discriminating between CKD stage 3-5 from earlier stages and controls. A five-metabolite panel comprising cis-aconitate, fumarate, HVA, tryptophan and histidine achieved high diagnostic performance for identifying PMD, with an area under the curve (AUC) of 0.836 (PMD vs. controls) and AUC = 0.783 across all groups. This biosignature integrates metabolites involved in distinct functional domains including energy metabolism, neurotransmitter turnover and amino acid metabolism and renal handling.
    CONCLUSION: Urinary metabolomic profiling by NMR revealed a distinct biosignature in pediatric PMD patients without renal involvement, characterized by elevated levels of tryptophan, HVA, and Krebs cycle intermediates, and diminished histidine. The divergent changes in tryptophan, histidine and HVA, suggest a mitochondria-specific metabolic phenotype in PMD. These findings support the use of urinary NMR metabolomics as a non-invasive tool for biomarker discovery in PMD and highlight the potential of integrated, multiparametric metabolic fingerprints for diagnostic refinement and patient stratification.
    Keywords:  Biomarkers; Metabolomics; NMR; Pediatric CKD; Primary mitochondrial disorders; Urine
    DOI:  https://doi.org/10.1007/s11306-025-02363-8
  32. Mov Disord. 2026 Jan 19.
    VPS13A Deficiency Leads to Impaired Lipid Distribution and Alteration of Mitochondrial Calcium Homeostasis in Fibroblasts of VPS13A Disease Patients.
    Dajana Grossmann, Adrian Spranger, Emily Fischer, Johanna W Schubarth, Jenny Leopold, Hannes Glaß, Sebastian Klicker, My Uyen Dang Thi, Anna Elisabeth Bartalis, Andreas Hermann, Kevin Peikert.
       BACKGROUND: Membrane contact sites are crucial for the exchange of ions or lipids and thus are critical for the function and maintenance of organelles. VPS13A is a membrane-residing, bridge-like protein connecting two membranes to enable bulk lipid transfer. Loss-of-function mutations in the VPS13A gene cause VPS13A disease. Previous studies showed alterations of lipid transfer and impaired calcium homeostasis.
    OBJECTIVE: Although membrane contact sites are becoming increasingly important in neurodegenerative disease research, their contribution to cellular homeostasis is still unclear. We attempted to investigate the consequences of loss of VPS13A function on membrane contact sites and related mechanisms in the context of VPS13A disease.
    METHODS: VPS13A-deficient patient-derived fibroblasts were compared with fibroblasts from healthy donors. Specific dyes, labeled fatty acids, and a specific marker for mitochondrial-endoplasmic reticulum contact sites were used to investigate lipid transfer and distribution in involved organelles. Mitochondrial calcium handling was investigated using the calcium indicator Rhod-2, AM. Images were obtained by super-resolution microscopy using Airyscan2 technology.
    RESULTS: We observed a general disturbance of membrane contact sites in VPS13A disease, accompanied by a reduction in lipid droplet formation, diminished lipid transfer into mitochondria, and unusual mitochondrial calcium uptake behavior in VPS13A disease fibroblasts.
    CONCLUSIONS: Loss of VPS13A causes alterations beyond an impairment of lipid shuttling, which includes a dysregulation of membrane contact sites as well as impaired mitochondrial calcium handling. Accordingly, our findings contribute significantly to the understanding of mechanisms directly or indirectly linked to the function of VPS13A. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  Bridge‐like lipid‐transport proteins (BLTPs); MERCS; VPS13A; calcium; lipids; mitochondria
    DOI:  https://doi.org/10.1002/mds.70177
  33. Spectrochim Acta A Mol Biomol Spectrosc. 2026 Jan 14. pii: S1386-1425(26)00035-1. [Epub ahead of print]351 127464
    An hMAO-B-activatable mitochondrial binding fluorescent probe in live-cell via enzyme-anchored and charge-driven dual targeting.
    Siqi Li, Lin Ma, Rong Lin, Xiongwang Li, Xinyi Yao, Yufei Hu, Jia-Jia Lang, Zhonghua Yuan, Pengbing Mi.
      Enzyme-responsive (ER) probes trageting human monoamine oxidase B (hMAO-B) represent pivotal tools for investigating a variety of diseases, including neurodegenerative pathologies, liver diseases, heart failure, metabolic disorders and cancers. Herein, we report THT-MTP-a thiochromone-based fluorescent probe exhibiting highly sensitivity and specificity for hMAO-B that undergoes hMAO-B-catalyzed oxidative conversion of its MTP moiety to MPy+, along with >100-fold fluorescence enhancement. Its activation mechanism was validated through safinamide-inhibition assays in both enzyme and cellular models. The hMAO-B-activatable imaging capability demonstrates intensity proportionality to enzyme levels across cell lines with differential MAO-B expression (HepG2 > SH-SY5Y ≫ NIH-3T3). THT-MTP exhibited excellent mitochondrial accumulation via enzyme-anchored and charge-driven dual targeting. This work establishes a design paradigm for hMAO-B-selectvie probes combining high-precision subcellular targeting, activatable imaging capability and wash-free operation, offering a robust molecular tool for investigating hMAO-B-associated diseases.
    Keywords:  Enzyme-responsive; Fluorescent probe; Human monoamine oxidase B; Mitochondria; Thiochromone
    DOI:  https://doi.org/10.1016/j.saa.2026.127464
  34. Commun Biol. 2026 Jan 22. 9(1): 72
    NLRP10 engages oxidized DNA through a Schiff-base mechanism and dissociates from NLRP3 upon inflammasome activation.
    Julia Elise Cabral, Angela Lackner, Wenjin Jiang, Sophia Lin, Haitian Zhou, Anna Wu, Courtney Demos, Minh Anh Pham, Reginald McNulty.
      Mitochondrial DNA release into the cytosol is a critical event in innate immune activation, often acting as a damage-associated molecular pattern (DAMP) that triggers inflammasome assembly. Here, we demonstrate that NLRP3 is involved in the release of D-loop mtDNA into the cytosol. We further show that NLRP3 interacts with NLRP10. NLRP10-mediated oxidized DNA cleavage involves a Schiff base intermediate and is inhibited by small molecules known to inhibit glycosylases. These findings support a model where NLRP10 interaction with oxidized DNA may contribute to long-term senescence secretory phenotype and modulate inflammasome activation. Our study highlights a novel mechanism by which NLRP10 can respond to mitochondrial stress signals to influence innate immunity and suggests therapeutic potential for targeting these interactions in inflammatory diseases.
    DOI:  https://doi.org/10.1038/s42003-025-09501-x
  35. Geroscience. 2026 Jan 17.
    Epigenetic insights of Olympic champions: nuclear and mitochondrial DNA methylation and regulators of aging.
    Timea Teglas, Ferenc Torma, Zoltan Bori, Dora Aczel, Gergely Babszky, Takuji Kawamura, Mitsuru Higuchi, Gu Yaodong, Muhammad Lee, Steve Horvath, Zsolt Radak.
      The interaction between nuclear (nDNA) and mitochondrial DNA (mtDNA) methylation is not well known in the healthy population. The D-loop methylation level of the Olympic champions (N = 58) was significantly lower than that of non-champions (N = 32) (~ 36% unadjusted mean difference p = 0.016, sex and age adjusted p = 0.017). Interestingly, the robust linear analysis revealed that biological sex is a significant factor in mtDNA D-loop methylation (estimate = 1.521, p = 0.033). On the other hand, we cannot find relationships between the methylation levels of mtDNA and nuclear DNA, suggesting distinct regulation of the methylation/demethylation process of mtDNA and nuclear DNA. DNA methylation-based aging clocks showed a significant relationship with the levels of Klotho, irisin, and its receptor (irisin receptor integrin alpha-V), as well as with epigenetic regulators such as ten-eleven translocation enzyme 2, which were measured using enzyme-linked immunosorbent assay. Therefore, the data suggest a complex regulatory process of epigenetic aging and raise the possibility that D-loop methylation may have functional relevance in health, which remains to be explored.
    Keywords:  Aging; Methylation; Mitochondrial DNA; Olympic champions
    DOI:  https://doi.org/10.1007/s11357-025-02092-9
  36. Am J Physiol Heart Circ Physiol. 2026 Jan 22.
    Mitochondrial DNA is an important signaling molecule in cardiovascular aging and pathophysiology.
    Yutao Hua, Yuxin Chu, Sarah Fu, Armaan Verma, Jianhua Zhang, Palaniappan Sethu, Timmy Lee, Min Xie.
      Mitochondrial DNA (mtDNA) has emerged as a key signaling molecule, extending beyond its primary role in supporting energy production. Its replication, release, and degradation are tightly regulated, and their dysregulation can activate immune pathways, including TLR9, cGAS-STING, and inflammasomes. In this review, we summarize recent advances in understanding mtDNA biology, including mechanisms of replication and release, recognition by pattern recognition receptors, and its impact on disease. We highlight evidence linking mtDNA to cardiovascular disease, as well as the aging-related chronic kidney disease, lung disorders, and neurodegeneration, and discuss the utility of circulating mtDNA copy number as a biomarker. Finally, we outline therapeutic strategies to reduce mtDNA release, block its sensing, and enhance clearance via autophagy/mitophagy. These findings underscore mtDNA as both a driver of pathology and a promising target for diagnosis and therapy across multiple organ systems.
    Keywords:  aging; cardiovacular diseases; inflammation; mitochondrial DNA
    DOI:  https://doi.org/10.1152/ajpheart.00686.2025
  37. Redox Biol. 2026 Jan 14. pii: S2213-2317(26)00030-3. [Epub ahead of print]90 104032
    Emerging frontiers in the mitochondrial regulation of dendritic cell biology.
    B Chen, J U Mayer.
      Dendritic Cells are central players of our immune system, linking innate sensing to adaptive immunity through antigen presentation and T cell priming. Beyond transcriptional and cytokine-based regulation, mitochondria are emerging as potential regulators of Dendritic Cell biology. While still in its infancy, evidence is accumulating that mitochondrial pathways affect Dendritic Cell differentiation; that mitochondrial remodeling and bioenergetic rewiring underpin Dendritic Cell maturation and activation in response to pathogenic and inflammatory stimuli and that shifts in mitochondrial and redox dynamics, reactive oxygen species production and mitochondrial DNA release coincide with Dendritic Cell activation and co-stimulatory molecule expression. Mitochondria are furthermore involved in regulating Dendritic Cell migration by influencing cellular metabolism and cytoskeletal dynamics and support the antigen processing and presentation machinery, thereby dictating the quality of the initiated T cell response. Importantly, mitochondrial checkpoints also regulate Dendritic Cell survival, balancing immune activation with timely cell death to preserve immune homeostasis. While the exact pathways of mitochondrial regulation are just beginning to be understood, disruptions in these programs can be far reaching. During aging, progressive mitochondrial dysfunction has been associated with impaired Dendritic Cell differentiation, diminished antigen presentation and impaired T cell responses. Similar defects have been observed in chronic diseases and cancer, leading us to hypothesize that genetic disorders linked to mitochondrial dysfunction also lead to defects in Dendritic Cell biology, impacting clinical symptoms such as immune dysregulation, heightened infection risk and inappropriate chronic inflammation. Therefore, in this review we have summarized the emerging roles of mitochondrial regulation in Dendritic Cell biology and discuss therapeutic opportunities to restore immune competence by targeting mitochondrial and redox pathways in settings of Dendritic Cell dysfunction. These insights aim to encourage further research into these topics and propose targeted metabolic reprogramming as a new therapeutic strategy for healthy ageing and chronic disease management.
    Keywords:  Dendritic cell; Mitochondria; Mitochondrial diseases; Mitochondrial dynamics; Redox biology
    DOI:  https://doi.org/10.1016/j.redox.2026.104032
  38. Biochem Pharmacol. 2026 Jan 20. pii: S0006-2952(26)00062-6. [Epub ahead of print] 117731
    Shikonin attenuates diabetic Parkinsonian neuronal injury by facilitating p53/SLC25A28-mediated iron shuttling.
    Yanwei Wang, Ziwei Han, Shanshan Pan, Minsong Guo, Meihong Wu, Xuesong Liu, Yuan Zhou, Jiahui Zhao, Yong Chen, Tengfei Xu.
      Diabetes significantly increases the risk of Parkinson's disease (PD), and mitochondrial dysfunction is considered a shared pathological mechanism between diabetes and PD. Although our previous research indicated that shikonin ameliorates hyperglycemia-driven PD progression through dual regulation of glycolysis (via inhibition of pyruvate kinase muscle isozyme 2) and mitochondrial function, its mitochondrial repair mechanism remains unclear. Here, we demonstrate that shikonin repairs neuronal damage induced by high glucose and 6-hydroxydopamine via a PKM2-independent, p53/Solute Carrier Family 25 Member 28 (SLC25A28)-dependent mitochondrial iron shuttle. Proteomic analysis revealed that shikonin activates the SLC25A28-cytochrome c axis, maintaining mitochondrial Fe2+ homeostasis. Molecular validation confirmed that shikonin directly binds to p53 (isothermal titration calorimetry KD = 6.3 μM), promotes mitochondrial translocation of p53, and subsequently activates SLC25A28. This process facilitates Fe2+-dependent assembly of the cytochrome c/cytochrome c oxidase subunit 4 complex, restoring oxidative phosphorylation. Our work uncovers the p53/SLC25A28 axis as a target for shikonin-mediated mitochondrial iron homeostasis, providing a therapeutic strategy for diabetes-associated PD.
    Keywords:  Chemical proteomics; Iron homeostasis; P53; SLC25A28; Shikonin
    DOI:  https://doi.org/10.1016/j.bcp.2026.117731
  39. Trends Endocrinol Metab. 2026 Jan 22. pii: S1043-2760(25)00283-8. [Epub ahead of print]
    SLC25A45: a gatekeeper for methylated amino acid metabolism.
    Yue Zhang, Yan Tian, Xianghui Fu.
      The metabolite substrates of numerous transporters remain largely elusive. Two recent studies by Khan et al. and Dias et al. identify SLC25A45 as a mitochondrial transporter of methylated amino acids that supports de novo carnitine synthesis, providing a valuable strategy for deorphanizing transporters and novel insights into cytoplasm-mitochondria communication and metabolic coordination.
    Keywords:  carnitine biosynthesis; fasting; machine learning; mitochondria; trimethyllysine
    DOI:  https://doi.org/10.1016/j.tem.2025.12.005
  40. J Inherit Metab Dis. 2026 Jan;49(1): e70140
    Pregnancies in Women With Long-Chain Fatty Acid Oxidation Disorders: Results of a European and North American Survey.
    Sarah C Grünert, Mirjam Langeveld, Lisa Rudolph, Ute Spiekerkoetter, Allan M Lund, Annalisa Sechi, Halil Tuna Akar, Karolina M Stepien, Hanım Aghakishili, Amelie S Lotz-Havla, Klaus G Parhofer, Saadet Mercimek-Andrews, Havva Yazıcı, Sema Kalkan Uçar, Thomas Scherer, Margreet Wagenmakers, Nur Arslan, Irene Chang, Allie LaTray, Vladimir Bzduch, Ivo Barić, Corina Weigel, Sonja L van Ockenburg, Alexander Rennings, Terry G J Derks, Alessandro Rossi, David Cassiman, Elaine Murphy.
      Long-chain fatty acid oxidation disorders (lcFAODs) are genetic disorders of energy metabolism that are associated with a risk of metabolic decompensation, especially during catabolic episodes. With improvement in diagnostics and treatment, more women with lcFAODs now reach child-bearing age. So far, little is known about the risk and outcome of pregnancies, particularly in women with more severe forms of lcFAODs. We performed an international web-based survey among health care professionals involved in the care of individuals with lcFAODs and collected data on 89 pregnancies in 39 women (mild VLCAD deficiency n = 8, severe VLCAD deficiency n = 10, LCHAD deficiency n = 4, CPT2 deficiency n = 14, CPT1 deficiency n = 3). There were 72 live births, 12 spontaneous miscarriages, and one stillbirth at 41 weeks of gestation. Four women were still pregnant at the time of the survey. In 25 women, the diagnosis was known before the first pregnancy, whereas 14 had at least one pregnancy before diagnosis. Most women remained metabolically stable during pregnancy, although 19% of women had at least one metabolic decompensation during pregnancy. Forty-one percent of babies were delivered by spontaneous vaginal delivery, 33% after induced labor, and 19% by an elective Caesarean section. Most deliveries were uncomplicated, with preventive i.v. glucose infusions given in 50%. However, 21% of mothers developed a metabolic decompensation in the postpartum period. No maternal deaths were reported. In conclusion, our data show that the outcome of pregnancies in lcFAOD patients is generally favorable, despite a significant risk of metabolic decompensation during the postpartum period.
    Keywords:  carnitine palmitoyltranferase 2 deficiency; fatty acid oxidation defects; long chain fatty acid oxidation disorders; peripartum management; pregnancy; very long chain acyl‐CoA dehydrogenase deficiency
    DOI:  https://doi.org/10.1002/jimd.70140
  41. Psychiatry Clin Neurosci. 2026 Jan 19.
    The emerging role of the paraventricular thalamic nucleus in bipolar disorder: Lessons from mitochondrial dysfunction.
    Tadafumi Kato, Mie Kubota-Sakashita, Yasuyuki Shima, Masaki Nishioka.
      Bipolar disorder is a psychiatric disorder marked by recurrent mood episodes and a strong genetic component. Despite widespread use of mood stabilizers and atypical antipsychotics, effective treatments remain limited, highlighting the need for mechanistic insights. Early studies revealed decreased phosphocreatine and increased mitochondrial DNA (mtDNA) deletions in the brains of bipolar disorder patients, leading to the mitochondrial dysfunction hypothesis. This framework proposes that mtDNA mutations impair Ca2+ buffering, producing neuronal dysfunction and mood instability. Supporting evidence spans neuroimaging, postmortem, genetic, and cellular studies, as well as therapeutic responses to mitochondrial modulators. Large-scale genomic analyses implicate both rare and common variants affecting Ca2+ signaling and mitochondrial-endoplasmic reticulum function, while somatic mtDNA mutations further link mitochondrial pathology to bipolar disorder. Animal and induced pluripotent stem cell models converge on neuronal hyperexcitability as a downstream effect of impaired Ca2+ regulation. Recent work highlights the paraventricular thalamic nucleus (PVT) as a critical site of pathology. The PVT integrates serotonergic and limbic circuits, regulates salience, and exhibits the highest burden of mtDNA deletions in mutant Polg (mtDNA polymerase) mice. In humans, single-nucleus RNA sequencing reveals a ~50% reduction of PVT neurons in bipolar disorder, with marked transcriptional dysregulation enriched for bipolar disorder risk loci in PVT, with additional changes in microglia. Neuropathological studies further suggest neurodegenerative changes in PVT, particularly in late-onset bipolar disorder. Collectively, these findings position PVT pathology at the core of bipolar disorder pathophysiology, offering a framework that integrates genetic risk, neuronal hyperexcitability, and circuit-level dysregulation and guiding future therapeutic strategies.
    Keywords:  bipolar disorder; intracellular calcium signaling; microglia; paraventricular nucleus of the thalamus; serotonin
    DOI:  https://doi.org/10.1111/pcn.70015
  42. NPJ Parkinsons Dis. 2026 Jan 21.
    Inhibition of de novo ceramide synthesis mitigates alpha-synuclein pathology in a Parkinson's disease mouse model.
    Eunkyung Lee, Moon-Young Park, Minkuk Park, Na-Yeong Kim, Shibo Wei, Nahee Hwang, Dongryeol Ryu, Hoon Ryu, Dohyun Park, Gakyung Lee, Chang-Myung Oh.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of α-synuclein aggregates. Ceramide metabolism is increasingly implicated in protein aggregation and mitochondrial dysfunction, both of which are prevalent in neurodegenerative disorders. While prior studies using cell lines have hinted at ceramide's role in PD, the in vivo relevance and therapeutic efficacy of inhibiting its synthesis remained largely unexplored. We aimed to evaluate the therapeutic potential of inhibiting ceramide synthesis in various models of PD, including the A53T α-synuclein transgenic mouse model, primary neurons from patients with PD, and patient-derived midbrain organoids. We found that inhibiting de novo ceramide biosynthesis decreases α-synuclein aggregation and improves motor and cognitive function in A53T α-synuclein transgenic mice. Treatment with myriocin, a serine palmitoyltransferase inhibitor, restored mitochondrial morphology, enhanced mitophagy, and reduced neuroinflammation. Single-nucleus transcriptomic analysis revealed that myriocin normalized gene networks related to synaptic transmission, mitochondrial homeostasis, and inflammation. Additionally, human midbrain organoids derived from PD patient-induced pluripotent stem cells exhibited reduced α-synuclein aggregation and preserved dopaminergic neurons following myriocin treatment. Together, these results suggest that targeting ceramide synthesis is a promising strategy for addressing protein aggregation and neuronal death in PD.
    DOI:  https://doi.org/10.1038/s41531-026-01263-5
  43. Sci Rep. 2026 Jan 17.
    Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.
    Olivier Reynaud, Marie-Belle Ayoub, Jean-Philippe Leduc-Gaudet, Marina Cefis, Marc P Lussier, Sabah Na Hussain, Gilles Gouspillou.
      Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular disorder. Mitochondrial dysfunctions are key disease features of the disease, and strategies that improve mitochondrial health have emerged as promising to slow disease progression. Emerging evidence indicates that impaired/insufficient mitophagy may contribute to the accumulation of mitochondrial dysfunction seen in patients and animal models of DMD. We therefore hypothesized that overexpressing Parkin, a key mitophagy regulator, may improve mitochondrial and muscle health in a mouse model of DMD. To this end, Parkin was overexpressed using intramuscular injections of adeno-associated viruses performed in 5-week-old and 18-week-old D2.B10-Dmdmdx/J mice (D2.mdx), a widely used mouse model of DMD. Four and 16 weeks of Parkin overexpression initiated in 5-week-old and 18-week-old D2.mdx, respectively, resulted in muscle hypertrophy, as indicated by an increase in muscle mass and fiber cross-sectional area. While Parkin overexpression did not impact maximal mitochondrial respiration or mitochondrial content, it increased the Acceptor Control Ratio, an index of mitochondrial bioenergetic efficiency. Parkin overexpression also decreased mitochondrial H2O2 emission, a surrogate for mitochondrial ROS production. However, Parkin overexpression failed to reduce the proportion of fibers with central nuclei and markers of muscle damage and/or necrosis. Taken all together, our results indicate that Parkin overexpression can attenuate muscle atrophy, improve mitochondrial bioenergetics and lower mitochondrial ROS production in a mouse model of DMD. These findings showcase the partial beneficial effects of overexpressing Parkin in ameliorating some, but not all, pathological features observed in a mouse model of DMD.
    DOI:  https://doi.org/10.1038/s41598-025-34223-9
  44. Case Rep Ophthalmol. 2026 Jan-Dec;17(1):17(1): 81-86
    A Case Report of Unilateral OPA3-Related Dominant Optic Atrophy.
    Matthaeus Antony Ware, Haoran Charles Li, Jonathan Micieli.
       Introduction: Autosomal dominant optic atrophy (DOA) is an inherited optic neuropathy characterized by progressive bilateral vision loss, cecocentral visual field (VF) defects, and retinal ganglion cell degeneration. Most cases are associated with OPA1 mutations, while OPA3-related DOA is rare and typically involves both eyes. To date, unilateral disease has not been reported.
    Case Presentation: A 33-year-old man presented with progressive, painless vision loss in the left eye. Best corrected visual acuity was 20/20 in the right eye and 20/30 in the left, with a left relative afferent pupillary defect and optic disc pallor. Optical coherence tomography revealed normal retinal nerve fiber layer thickness in the right eye and diffuse thinning in the left; VF testing showed a central scotoma in the left eye. MRI excluded compressive or inflammatory causes. Genetic testing identified a novel heterozygous OPA3 missense variant, c.199G>C, p.Val67Leu, not previously reported in population databases. Four years later, vision in the left eye had declined to 20/100 with persistent unilateral atrophy, while the right eye remained normal.
    Conclusion: This represents the first documented case of unilateral OPA3-related DOA, challenging the long-held view that DOA is inherently bilateral. Recognition of such atypical presentations may expand the clinical spectrum of OPA3-related disease and inform diagnostic and genetic counseling approaches for patients with unilateral optic neuropathy.
    Keywords:  Dominant optic atrophy; Mitochondrial dysfunction; OPA3:c.199G>C, p.Val67Leu; Retinal ganglion cells; Unilateral optic neuropathy
    DOI:  https://doi.org/10.1159/000550003
  45. Nat Commun. 2026 Jan 17.
    A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.
    Wenjing Yan, Daniel C Talley, Antara Syam, Carina Danchik, Yongwang Zhong, Xianzheng Zhang, Xiaoying Liu, Bolormaa Baljinnyam, Stephen C Kales, Matthew G Cyr, Yuhong Fang, Alexey V Zakharov, Xin Hu, Taylor Niehoff, Tuan Xu, Yanyan Qu, Allison Yang, Valentine V Courouble, Qin Yao, Anton Simeonov, Ruili Huang, Tatiana K Rostovtseva, Sergey M Bezrukov, Christopher A LeClair, Josephine M Egan, Hua Wang, Dingyin Tao, Ganesha Rai, Mark J Henderson, Shengyun Fang.
      Endoplasmic reticulum-associated degradation (ERAD) is a critical protein quality control mechanism that also regulates lipid metabolism and calcium homeostasis. Dysregulation of ERAD and unfolded protein response underlies diseases including cancer, neurodegenerative disorders, and metabolic syndromes. Small molecule modulators of ERAD could enable mechanistic discovery and therapeutic intervention, but few have been identified. Using a high-content screening, we discovered several ERAD-modulating compounds, including NCATS-SM0225, an ERAD inhibitor that unexpectedly binds all three isoforms of VDAC, outer mitochondrial membrane proteins enriched at mitochondria-associated membranes. This led us to discover an essential role for VDACs in ERAD and ER-phagy. NCATS-SM0225 elevates cytosolic, ER, and mitochondrial calcium through calcium influx and IP3R-MCU activity. This calcium imbalance strengthens VDAC1-IP3R coupling and activates PERK, which phosphorylates STIM1 and drives degradation of key ERAD regulators. Loss of these components amplifies PERK signaling and selectively kills cancer cells while sparing normal cells. These findings uncover a cancer-specific role of VDACs in ERAD regulation and calcium signaling, highlighting a therapeutically actionable vulnerability.
    DOI:  https://doi.org/10.1038/s41467-025-67816-z
  46. Nat Commun. 2026 Jan 19.
    Modeling tissue-specific Drosophila metabolism identifies high sugar diet-induced metabolic dysregulation in muscle at reaction and pathway levels.
    Sun Jin Moon, Yanhui Hu, Monika Dzieciatkowska, Ah-Ram Kim, John M Asara, Angelo D'Alessandro, Norbert Perrimon.
      Individual tissues perform highly specialized metabolic functions to maintain whole-body metabolic homeostasis. Although Drosophila serves as a powerful model for studying human metabolic diseases, modeling tissue-specific metabolism has been limited in this organism. To address this gap, we reconstruct 32 tissue-specific genome-scale metabolic models (GEMs) by integrating a curated Drosophila metabolic network with pseudo-bulk single-nuclei transcriptomics data, revealing distinct metabolic network structures and subsystem coverage across tissues. We validate enriched pathways identified through tissue-specific GEMs, particularly in muscle and fat body, using metabolomics and pathway analysis. Moreover, to demonstrate the utility in disease modeling, we apply muscle-GEM to investigate high sugar diet (HSD)-induced metabolic dysregulation. Constraint-based semi-quantitative flux and sensitivity analyses identify altered NAD(H)-dependent reactions and distributed control of glycolytic flux, including GAPDH. This prediction is further validated through in vivo 13C-glucose isotope tracing study. Notably, decreased glycolytic flux, including GAPDH, is linked to increased redox modifications. Finally, our pathway-level flux analyses identify dysregulation in fructose metabolism. Together, this work establishes a quantitative framework for tissue-specific metabolic modeling in Drosophila, demonstrating its utility for identifying dysregulated reactions and pathways in muscle in response to HSD.
    DOI:  https://doi.org/10.1038/s41467-026-68395-3
  47. SAGE Open Med Case Rep. 2026 ;14 2050313X251412221
    Ethylmalonic encephalopathy caused by biallelic truncating variants in ETHE1: A case report.
    Delmer-Alejandro Ruiz-Martinez, Emilio-Rodrigo Vega-Peniche, Yazmin Quiñonez-Pacheco, Hugo Laviada-Molina, Carlos-Alejandro Medina-Campos, Felix-Julian Campos-Garcia.
      Ethylmalonic encephalopathy is a rare autosomal recessive mitochondrial disorder caused by biallelic pathogenic variants in ETHE1, the gene encoding mitochondrial persulfide dioxygenase, an enzyme crucial for hydrogen sulfide (H2S) detoxification. Loss of this enzyme results in H2S accumulation, cytochrome c oxidase inhibition, oxidative stress, and disrupted energy metabolism. Clinically, ethylmalonic encephalopathy manifests during early infancy with developmental delay, hypotonia, progressive encephalopathy, seizures, chronic diarrhea, and microvascular abnormalities such as petechiae and acrocyanosis. Fewer than 100 cases have been reported globally, mostly among Mediterranean and Arab populations, with scarce data from Latin America. We report the first documented case of ethylmalonic encephalopathy in a Mexican patient. The affected male infant, born to healthy nonconsanguineous parents of indigenous Maya origin from Yucatán, presented at 2 weeks of age with persistent hemorrhagic diarrhea, followed by metabolic acidosis, hyperammonemia, hyperlactatemia, elevated C4-acylcarnitine, and increased urinary ethylmalonic acid. Neurological findings included developmental delay, hypotonia, and myoclonic epilepsy. Whole-exome sequencing revealed a homozygous frameshift pathogenic variant in ETHE1 (NM_014297.5):c.19_20dup (p.Val8Glyfs*7), predicted to introduce a premature stop codon and abolish protein function. Despite targeted interventions-antiepileptic therapy, ammonia-lowering treatment, and metabolic support-the patient's condition progressively worsened, culminating in death at 15 months after metabolic decompensation and brain death. This case broadens the known mutational spectrum of ETHE1 by identifying a previously unreported pathogenic variant and underscores the need to include ethylmalonic encephalopathy in the differential diagnosis of infants presenting with chronic diarrhea, vascular lesions, and neurological deterioration, even in regions where the condition is not typically observed.
    Keywords:  ETHE1; ethylmalonic encephalopathy; mitochondrial disease
    DOI:  https://doi.org/10.1177/2050313X251412221
  48. J Transl Med. 2026 Jan 19.
    Astrocytic mitochondrial transfer: a new horizon for metabolic rescue and precision therapy in ischemic stroke.
    Xin Lan, Chuxin Zhang, Zilin Ren, Jialin Cheng, Congai Chen, Yuxiao Zheng, Jinhua Han, Yang Zhao, Jiaming Li, Fafeng Cheng, Xueqian Wang, Qingguo Wang, Changxiang Li.
      Ischemic stroke (IS) remains a leading cause of global mortality and neurological disability, with neuronal mitochondrial dysfunction as a central pathological mechanism. Astrocytes, the metabolic custodians of the central nervous system, exert neuroprotection by transferring functional mitochondria to compromised neurons via tunneling nanotubes (TNTs), extracellular vesicles (EVs), connexin 43 (Cx43) mediated gap junctions, and membrane fusion. These transfers replenish neuronal energy reserves, mitigate oxidative stress, and enhance synaptic plasticity. This review systematically delineates the molecular mechanisms of astrocyte-mediated mitochondrial transfer, its regulatory roles in oxidative stress, calcium dyshomeostasis, and ferroptosis, and its therapeutic potential in IS. Experimental models demonstrate that pharmacological enhancement of mitochondrial transfer or exogenous transplantation significantly reduces infarct volume and improves neuronal survival. However, clinical translation faces challenges including low mitochondrial viability, immune rejection, and inefficient delivery. Future research should integrate gene-editing tools, nanocarrier systems, and organoid models to optimize mitochondrial dynamics and develop precision therapies. By bridging mechanistic insights with translational innovations, astrocytic mitochondrial transfer emerges as a groundbreaking strategy for ischemic stroke treatment.
    Keywords:  Astrocyte; Ischemic stroke; Mitochondrial transfer; Neuron; Neuroprotection
    DOI:  https://doi.org/10.1186/s12967-025-07290-9
  49. Nat Rev Dis Primers. 2026 Jan 22. 12(1): 3
    Charcot-Marie-Tooth disease and related neuropathies.
    Joshua Burns, Vincent Timmerman, Matilde Laurá, Eppie M Yiu, Maurizio D'Antonio, Bipasha Mukherjee-Clavin, Jonathan De Winter, Steven S Scherer.
      Charcot-Marie-Tooth disease (CMT) subsumes many different inherited neuropathies. CMT and related neuropathies are among the most common inherited neurological disorders, affecting ~1 in 2,500 people globally and including both sexes. Mutations in genes that cause demyelinating forms of CMT often affect the proteins of the myelin sheath, the unfolded protein response, endosomal signalling and recycling, or key transcription factors. Mutations in genes that cause axonal forms often affect mitochondrial biology, aminoacyl-tRNA synthetases, molecular chaperones or the axonal cytoskeleton. All forms of CMT result in length-dependent, progressive axonal loss that correlates with clinical impairments such as distal upper and lower limb weakness, musculoskeletal deformity, absent deep tendon reflexes and distal sensory deficits. Compared with the general population, children and adults with CMT have reduced quality of life across physical, emotional and social domains, with the physical domain being the most disabling. Disease-modifying therapies are not yet available for any form of CMT. Management includes rehabilitative approaches such as muscle strength training and orthotic devices, surgical interventions, symptom relief and anticipatory monitoring of associated complications. The investigation of genetically authentic cellular, organoid and animal models will enable the development of rational therapies. Natural history studies and biomarkers will enable potential therapies to be critically evaluated.
    DOI:  https://doi.org/10.1038/s41572-025-00679-2
  50. Nat Metab. 2026 Jan 20.
    Distinct sympathetic projections to brown fat regulate thermogenesis and glucose tolerance.
    Daniele Neri, Seoeun Lee, Alexis M Fohn, Xinhong Chen, Dominique Bozec, Alexandre J Lafond, Natalie R Lopatinsky, Lucas Castro E Souza, Gawri Mohanan Nair, Angela M Ramos-Lobo, Markus Heine, Anna Worthmann, Joerg Heeren, Vidhu V Thaker, Viviana Gradinaru, Lori M Zeltser.
      Brown adipose tissue (BAT) contributes to thermoregulation and glucose metabolism, but how these functions are coordinated remains unclear. While thermogenesis in the activated BAT typically coincides with increased blood flow and glucose uptake1-5, several pathophysiological and nutritional states dissociate these processes6,7, suggesting they are governed by distinct sympathetic circuits. Here we identify subpopulations of sympathetic neurons in the stellate ganglion that mediate distinct functions of intrascapular BAT (iBAT) in mice. Two main types of sympathetic neurons project to iBAT: those that innervate the organ parenchyma and those that innervate the large blood vessels feeding the depot8-12. Here we develop a toolkit to parse the functions of these neuronal subclasses through targeted chemogenetic activation of projections to iBAT, while sparing other organs, and single-cell transcriptomics coupled to retrograde tracing from iBAT to the stellate ganglion. We find that stimulation of the parenchymal projections increases blood flow and thermogenesis in iBAT, without affecting circulating glucose levels. Conversely, stimulation of the vascular projections improves glucose tolerance but does not alter blood flow or thermogenesis in iBAT. These data provide a mechanistic explanation for the dissociation between the thermogenic and glycaemic effects of BAT activation13-16.
    DOI:  https://doi.org/10.1038/s42255-025-01429-0
  51. J Nutr. 2026 Jan 20. pii: S0022-3166(26)00016-7. [Epub ahead of print] 101367
    Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.
    Luisa F Castillo, Katarina E Heyden, Abigail R Williamson, Wenxia Ma, Olga V Malysheva, Nathaniel M Vacanti, Anna E Thalacker-Mercer, Martha S Field.
       BACKGROUND: Vitamin B12 is a cofactor in folate-mediated one-carbon metabolism (FOCM), which generates nucleotides (thymidylate (dTMP) and purines) and methionine. Depressed de novo thymidylate (dTMP) synthesis leads to uracil accumulation in DNA.
    OBJECTIVE: The purpose of this study was to determine how B12 availability affects mitochondrial DNA (mtDNA) integrity and mitochondrial function in skeletal muscle. B12 deficiency was modeled in young-adult mice. Intramuscular B12 injection in aged mice assessed the role of B12 supplementation in age-related changes in skeletal muscle.
    METHODS: Male methionine synthase knockdown (Mtr+/-) and wild-type littermates (Mtr+/+) were weaned to either an AIN93G-based control (C) diet containing 25 μg/kg vitamin B12 (Mtr+/+, n=8; Mtr+/-, n=9) or a B12-deficient (-B12) diet containing 0 μg/kg vitamin B12 (n=9 per genotype) for seven weeks. Aged (20-22mo) male C57BL/6N mice were acclimated to an AIN93G control diet four weeks, then received either weekly injections of saline (vehicle control [30 uL 0.9% NaCl], n=5) or B12 (0.65 μg per 30uL 0.9% NaCl; n=6) in each of two hindleg muscles [1.25 μg B12 total]) for eight weeks. Outcomes measured included maximal oxygen consumption rate (OCR), uracil in mtDNA (a biomarker of mtDNA integrity), mtDNA copy number, and mitochondrial mass. Data were analyzed using a two-way ANOVA in the Mtr+/- mouse model exposed to B12-deficient diets and by a student's t-test for B12 supplementation in aged mice.
    RESULTS: The tibialis anterior (TA) muscle from Mtr+/- mice exhibited 50% lower (p=0.01) maximal respiratory capacity of the electron transport chain than did TA from Mtr+/+ mice. Exposure to the -B12 diet lowered maximal capacity of complex I in mitochondrially rich muscle (soleus and mitochondria-rich portions of quadriceps and gastrocnemius) by 25% (p=0.02). Uracil in mitochondrial DNA (mtDNA) in red muscle and gastrocnemius was elevated ∼10 fold with exposure to -B12 diet (p=0.04 and p<0.001, respectively). In aged mice, gastrocnemius complex IV activity was increased 2-fold with intramuscular B12 supplementation (p=0.04).
    CONCLUSIONS: Exposure to a B12-deficient diet led to uracil accumulation in mtDNA and impaired maximal oxidative capacity in skeletal muscle. B12 supplementation improved complex IV maximal capacity in gastrocnemius from aged mice, a model of age-related skeletal muscle decline.
    Keywords:  Vitamin B12; mitochondrial DNA; oxidative phosphorylation; skeletal muscle; thymidylate; uracil
    DOI:  https://doi.org/10.1016/j.tjnut.2026.101367
  52. Am J Hum Genet. 2026 Jan 21. pii: S0002-9297(25)00486-0. [Epub ahead of print]
    MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy.
    Heba Morsy, Hyeonho Kim, Gyubin Jang, Maha S Zaki, Mariasavina Severino, Ibrahim M Abdelrazek, Haytham Hussien, Eleanor Self, Raidah Saleem Albaradie, Khadijah Bakur, Zahra Firoozfar, Stephanie Efthymiou, Mahmoud M Noureldeen, Amira Nabil, Javeria Raza Alvi, Fateme Molavi, Shahryar Alavi, Reza Alibakhshi, Vehap Topcu, Hanifenur Mancilar, Eyyup Uctepe, Ahmet Yesilyurt, Hesham Aldhalaan, Ehab Salah Showki Tous, Bader Alhaddad, Hasnaa M Elbendary, Annarita Scardamaglia, David Murphy, Vicente A Yépez, Julien Gagneur, Tarek I Omar, Marwa Abd Elmaksoud, Jana Vandrovocova, Ebtessam Abdalla, Mary M Reilly, Tipu Sultan, Fowzan S Alkuraya, Joseph G Gleeson, Ji Won Um, Henry Houlden, Jaewon Ko, Reza Maarofian.
      MDGA2 encodes a membrane-associated protein that is critical for regulating glutamatergic synapse development, modulating neuroligins (Nlgns), and maintaining excitatory-inhibitory synaptic balance. While MDGA2 functions have been extensively studied in murine and cellular models, its association with human developmental disorders has yet to be established. Through exome sequencing, we identified seven distinct homozygous loss-of-function variants in MDGA2 in nine individuals from seven consanguineous families, all presenting with developmental and epileptic encephalopathy (DEE). Clinically, these individuals exhibited a consistent phenotype including infantile hypotonia, severe neurodevelopmental delay, intractable seizures, along with distinct dysmorphic features. Neuroimaging findings included delayed/incomplete myelination, early-onset brain atrophy, white-matter thinning, basal ganglia volume loss, and small hippocampi. Functional studies of three representative nonsense variants revealed impaired MDGA2 membrane trafficking, disrupted Nlgn1 interaction, and perturbed MDGA2-mediated excitatory synaptic functions in mammalian expression systems and cultured hippocampal neurons. Our findings support the involvement of MDGA2 in a subtype of autosomal-recessive DEE. This not only underscores a loss-of-function pathogenic mechanism but also highlights the previously unrecognized role of MDGA2 in human synaptic development and regulation, significantly expanding our understanding of the genetic architecture of DEEs.
    Keywords:  MDGA2; epileptic encephalopathy; excitatory synapse; excitatory-inhibitory balance; neurodevelopmental disorder; neuroligin; synaptic suppression
    DOI:  https://doi.org/10.1016/j.ajhg.2025.12.015
  53. Nat Aging. 2026 Jan;6(1): 6-22
    Past, present and future perspectives on the science of aging.
    Fabrisia Ambrosio, Maxim N Artyomov, Steven N Austad, Nir Barzilai, Juan Carlos Izpisua Belmonte, Daniel W Belsky, Bérénice A Benayoun, Anne Brunet, Handan Melike Dönertaş, Dena B Dubal, Evandro F Fang, Jerome N Feige, Linda P Fried, David Furman, Xu Gao, Vadim N Gladyshev, Vera Gorbunova, Myriam Gorospe, Jing-Dong J Han, Oskar Hansson, Eiji Hara, Steve Horvath, Nancy Y Ip, George A Kuchel, Matt Kaeberlein, Dudley W Lamming, Becca R Levy, Guang-Hui Liu, Jinkook Lee, Terrie E Moffitt, Tohru Minamino, Linda Partridge, Parminder Raina, Thomas A Rando, John W Rowe, Michal Schwartz, Andrew J Scott, Felipe Sierra, David A Sinclair, Charlotte E Teunissen, Bruno Vellas, Eric Verdin, Keenan A Walker, Ashley E Webb, Tony Wyss-Coray, Ming Xu, Jin-Tai Yu, Alex Zhavoronkov, Yahyah Aman, Anna Kriebs, Qingzhong Ren, Hannah Walters, Sebastien Thuault.
      
    DOI:  https://doi.org/10.1038/s43587-025-01046-2
  54. Nature. 2026 Jan 21.
    'Remote controlled' proteins illuminate living cells.
    Ewen Callaway.
      
    Keywords:  Molecular biology
    DOI:  https://doi.org/10.1038/d41586-026-00204-9
  55. Brain. 2026 Jan 23. pii: awag026. [Epub ahead of print]
    Ultrasound-assisted gene therapy mitigates Leigh syndrome pathology.
    Mathilde Faideau, Romain Clément, Sébastien Rigollet, Giorgia Benegiamo, Cassandra Cresson, Béatrice Blot, Robin Reynaud-Dulaurier, Sara Yjjou, Fanny Aprahamian, Sylvère Durand, Anthony Delalande, Emmanuel L Barbier, Vasile Stupar, Johan Auwerx, Michael Decressac.
      Leigh syndrome (LS) is a fatal neurometabolic disease caused by mutations in genes involved in mitochondrial energy harvesting. While there is currently no cure for this disease, pre-clinical studies showed that gene therapy can afford a therapeutic benefit in a relevant model of LS, the Ndufs4-KO mouse. However, similar results need to be obtained using methods that can be translated in patients. Here, we combined two tools that are approved for clinical interventions. We used low-intensity focused ultrasound (FUS) to transiently permeabilize the blood-brain barrier and thereby facilitate the passage of an AAV9 vector. This approach resulted in transgene expression in the brain and peripheral organs. When applied to one-month old Ndufs4-KO mice, this gene replacement strategy significantly extended the survival of the animals and ameliorated brain and cardiac function. These improvements were associated with the restoration of protein expression and mitochondrial function. These findings support the potential of combining FUS with AAV-mediated gene delivery to treat LS and they warrant further clinical translation. This study also provides the first evidence that ultrasound-assisted gene replacement can exert a therapeutic effect in a condition affecting the central nervous system.
    Keywords:  AAV vector; focused ultrasound; gene replacement; mitochondrial disease
    DOI:  https://doi.org/10.1093/brain/awag026
  56. Sci Rep. 2026 Jan 22.
    Mitochondrial dysfunction and Ca2+ dysregulation in human iPSC-derived neurons carrying presenilin-1 mutation arise under stress via an MCU-1-independent mechanism.
    Carlos Wilson, Pablo Galeano, María Mónica Remedi, Gisela Vanina Novack, Lorenzo Campanelli, Laura Gastaldi, Esteban Miglietta, Andres Hugo Rossi, Natividad Olivar, Luis Ignacio Brusco, Eduardo Miguel Castaño, Alfredo Cáceres, Laura Morelli.
      
    Keywords:  Alzheimer; Calcium homeostasis; Cultured neurons; Mitochondrial dysfunction; iPSC
    DOI:  https://doi.org/10.1038/s41598-026-35597-0
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