bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–04–26
63 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.
  2. Diet-Induced Hepatic and Mitochondrial Lipid Remodeling Engages One-Carbon Metabolism Under Preserved Mitochondrial Function.
  3. Proteolytic control of mitochondrial protein translocases.
  4. RNA Sequencing Resolves Cryptic Pathogenic Variants in Mitochondrial Disease.
  5. Emerging Design Principles at the Forefront of Mitochondrial Transplantation Using Engineering Methodologies: Current Achievements and Future Directions.
  6. Proteostasis at the mitochondrial outer membrane: Quality control of mitochondrial protein transport.
  7. New Understanding and Treatment of Adult Mitochondrial Dysfunction: An Example of Personalized Precision Medicine.
  8. Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.
  9. Cholesterol overload promotes mitochondria-mediated apoptosis with impaired mitochondrial unfolded protein response and mitophagy in SH-SY5Y cells.
  10. Mitochondrial NADP+-isocitrate dehydrogenase Idp1 involves CoQ biosynthesis in parallel with NAD kinase Pos5.
  11. Membranes arrest the coarsening of mitochondrial condensates in human cells.
  12. Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.
  13. Mitochondria at the heart of aging: structure, function, and failure.
  14. Molecular analysis of a new patient COX15 mutation provides insight into the etiology of fatal infantile cardioencephalopathy.
  15. The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.
  16. Inhibiting the integrated stress response restores cognition.
  17. Aminoacyl-tRNA Synthetases: Variant Classification, Functional Assays, and Emerging Therapeutic Strategies.
  18. Structural and biochemical basis of ROC-dependent activation of LRRK2.
  19. Functional suppression accompanies internal mitochondrial reorganization during cellular reprogramming.
  20. Study on Leigh syndrome caused by SURF1 gene mutations and its mechanisms.
  21. Mitochondrial respirasome-like supercomplexes support metabolic flexibility in yeast.
  22. Presenilin 1 is located in the mitochondrial inner inner membrane and regulates mitochondrial cristae junction protein arrangement and cristae formation in HEK293 cells.
  23. iPSC generation from PBMCs of a MELAS patient for mitochondrial dysfunction studies.
  24. Vitamin B12 improves skeletal muscle mitochondrial biology in aged mice.
  25. Patterns of mitochondrial ATP predict tissue folding.
  26. TFAM promotes mitochondrial division by increasing mitochondrial Sirt3.
  27. DHCR24 Deficiency Drives Age-Related Meibomian Gland Dysfunction by Regulating Lipid Metabolic Imbalance and Cytosolic mtDNA-Induced cGAS-STING Activation.
  28. Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.
  29. An optimized translating ribosome affinity purification protocol for low-abundance Drosophila tissues.
  30. Structural Basis of Mitochondrial Transcription Regulation via Interactions of PolRMT and TFAM with Upstream Promoter DNA.
  31. The Mitochondrial NAD Transporter SLC25A51 in Adipocytes Regulates Adipose Tissue Mitochondrial Function and Systemic Metabolism During Aging.
  32. First reported case of adult-onset very long-chain acyl-coa dehydrogenase (vlcad) deficiency in Vietnam: a rare metabolic myopathy.
  33. Mitochondrial biology: Specialized powerhouses pack a punch.
  34. Targeting mitochondrial stress in heart failure: Translocator protein TSPO modulation links mitochondria, redox signalling and cardiac protection.
  35. Role of mitochondrial translation in modulating inflammatory disease outcome: current knowledge and future perspectives.
  36. Fiber type-specific expression of LACTB leverages a function in oxidative metabolism.
  37. Mitochondrial fission mediates an evolutionarily conserved antibacterial defense response.
  38. Cardiac Metabolic Remodeling Drives Dicarbonyl Stress-Induced Mitochondrial Dysfunction in Experimental Heart Failure with Preserved Ejection Fraction.
  39. Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids.
  40. Mitochondrial D-Loop Region Methylation Is Not Altered in Children with Autism Spectrum Disorder.
  41. The yeast mitochondrial Porin represses Snf1/AMP Kinase signaling to attenuate viral replication.
  42. De Novo Variants Associated With Autosomal Recessive Conditions: Case Series and Implications for Genetic Testing and Counseling.
  43. Multi-omic mapping of Drosophila protein secretomes reveals tissue-specific origins and inter-organ trafficking.
  44. PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy.
  45. A Nanotube Injector for Cytoplasmic Transfer and Enhanced Mitochondrial Function.
  46. Deletion of Mitochondrial Calcium Uniporter Enhances Calcium Signals by Slowing Calcium Clearance and Triggers Adaptive Transcriptomic Remodeling.
  47. Mitochondrial Sulfide Oxidation and Persulfidation in Mesenchymal Stromal Cell Osteogenesis: Redox Flux Control as a Unifying Framework.
  48. SPP1 is reduced in the human retina and optic nerve during glaucoma pathogenesis.
  49. Re-conceptualizing Parkinson's disease as a lifelong neurobiological trajectory: A framework for prevention.
  50. Gene Expression Profiles Reveal Altered Metabolic Signaling Pathway in Skeletal Muscle With Lipid Sensor Gpr120/Ffar4 Deficiency.
  51. C2CD5 in noradrenergic neurons regulates thermogenesis and lipid homeostasis via norepinephrine secretion.
  52. Revisiting LSDMCA: male lethality escape and genotype-phenotype correlations.
  53. MITOCHONDRIAL METABOLISM AS A DETERMINANT OF HETEROGENEOUS PLATELET FUNCTIONAL PHENOTYPES: IMPLICATIONS FOR ANTIPLATELET RESISTANCE.
  54. Histone Deacetylase 9 Gene Deletion Ameliorates Aging-Related Adipose Tissue Senescence and Mitochondrial Dysfunction in Mice.
  55. m6A epitranscriptomic remodeling links redox stress to mitochondrial quality control and programmed cell death in sepsis-induced myocardial dysfunction.
  56. Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
  57. Amino acid metabolism in retinal diseases: Mechanisms, diagnostics, and therapeutic opportunities.
  58. Targeting WWP1 ameliorates osteoarthritis by suppressing KLF15 ubiquitination to restore mtDNA and mitochondrial function.
  59. A generative AI framework unifies human multi-omics to model aging, metabolic health, and intervention response.
  60. Selective induction of mitochondrial fragmentation for cancer immunotherapy via mtDNA-Targeting AIE photosensitizer.
  61. Transplantation of active mitochondria condensed in liquid-liquid phase-separated hydrogels ameliorates myocardial ischemia-reperfusion injury.
  62. A cell-death protein has an unexpected role in intestinal repair.
  63. Ubiquitination of glycogen and metabolites in cells and tissues.
  1. Autophagy. 2026 Apr 23. 1-15
    Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.
    Madhuri Chaurasia, Milana Fraiberg, Nemanja Subic, Oren Shatz, Kamilya Kokabi, Olee Gogoi, Olena Trofimyuk, Bat Chen Tamim-Yecheskel, Saskia Freud, Alik Demishtein, Ekaterina Kopitman, Inna Goliand, Sabita Chourasia, Yoav Peleg, Elena Ainbinder, Nili Dezorella, Zvulun Elazar.
      HSAN9 is a rare progressive neurodegenerative disease in children linked to bi-allelic loss-of-function mutations in the TECPR2 gene. TECPR2 is a multi-domain protein harboring N-terminal WD repeats and C-terminal TECPR repeats, followed by a functional LIR motif that serves in phagophore targeting. Here, we demonstrate that the absence of TECPR2 results in impaired mitophagy, which can be restored by expressing its C-terminal domain. Accordingly, we uncover severe mitochondrial dysfunction and accumulation of mitochondrial content in primary fibroblasts derived from an HSAN9 patient, as well as in embryonic fibroblasts and dorsal root ganglia derived from an HSAN9 mouse model. Notably, these mitochondrial defects are mediated by mitochondrial stress through the activation of the integrated stress response (ISR), whereas mitochondrial function is restored by pharmaceutical or genetic suppression of ISR. Our findings establish a new connection between mitophagy and ISR in maintaining mitochondrial homeostasis during neurodegeneration.Abbreviations: Baf. A1: bafilomycin A1; CYCS: cytochrome c, somatic; HSAN9: hereditary sensory and autonomic neuropathy IX; ISR: integrated stress response; OA: oligomycin + antimycin A; ROS: reactive oxygen species; TECPR2: tectonin beta-propeller repeat containing 2.
    Keywords:  HSAN9; TECPR2; integrated stress response; mitophagy; neurodegeneration; unfolded protein response
    DOI:  https://doi.org/10.1080/15548627.2026.2660850
  2. Free Radic Biol Med. 2026 Apr 21. pii: S0891-5849(26)00321-7. [Epub ahead of print]
    Diet-Induced Hepatic and Mitochondrial Lipid Remodeling Engages One-Carbon Metabolism Under Preserved Mitochondrial Function.
    Fabrizia Carli, Sara Guerra, Ines Mateus, Riccardo Ducoli, Silvia Sabatini, Samantha Pezzica, Egeria Scoditti, Caroline Dewalle, Véronique Lenoir, Carina Prip-Buus, Amalia Gastaldelli.
       BACKGROUND: Diets rich in saturated fat and sugar drive hepatic steatosis, yet their impact on mitochondrial lipid composition and function remains poorly understood. We investigated how steatotic diets reprogram phospholipid synthesis, remodel the hepatic mitochondrial lipidome, and affect mitochondrial energy metabolism.
    METHODS: Mice were fed a high-fat/high-sucrose (HFHS) diet for 20 weeks alongside controls. Lipidomics, metabolomics and metabolic flux analysis using deuterated water (2H2O) were performed via high-resolution mass spectrometry in plasma, liver, and isolated hepatic mitochondria. Mitochondrial respiration was assessed via high-resolution respirometry (OROBOROS). A second cohort was fed a methionine choline-deficient (MCD) diet as a model of altered one-carbon metabolism.
    RESULTS: HFHS feeding caused marked hepatic lipid accumulation and extensive remodeling of plasma, liver, and mitochondrial lipidomes, including reduced synthesis of select phosphatidylcholines (PCs). Mitochondrial PCs concentrations were tightly linked to dietary modulation of one-carbon metabolism, which governs PC biosynthesis via methylation. Despite these changes, the mitochondrial PC/PE ratio remained stable and mitochondrial respiration and energy metabolism were preserved. To further evaluate the role of one-carbon metabolism in mitochondrial PC, we evaluated changes during MCD feeding. MCD reduced total mitochondrial lipids, particularly PC and PE synthesis and the mitochondrial PC/PE ratio. Remarkably, mitochondrial function remained intact in both dietary conditions.
    CONCLUSION: Steatotic and PC-depleting diets induce substantial remodeling of mitochondrial phospholipids without compromising mitochondrial respiratory capacity. These findings highlight the central role of one-carbon metabolism as a key regulator of mitochondrial membrane homeostasis and underscore the adaptive resilience of mitochondria under dietary and pro-fibrotic stress.
    Keywords:  Fluxomics; Hepatic Lipid Remodeling; MASLD Models; Mitochondrial Function; One-Carbon Metabolism
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.031
  3. Protein Sci. 2026 May;35(5): e70553
    Proteolytic control of mitochondrial protein translocases.
    Lara Kroczek, Thomas Langer.
      Mitochondria are essential organelles that drive numerous cellular processes, including energy metabolism, ion homeostasis, and programmed cell death. This functional versatility relies on a highly dynamic proteome whose composition is continuously remodeled to meet changing cellular and environmental demands. Central to this remodeling are mitochondrial proteases (termed mitoproteases), which maintain protein quality and regulate mitochondrial function through selective processing and degradation events. Their activity ensures rapid degradation of regulatory proteins and dynamically adjusts components of multiprotein complexes. Among their most critical targets are elements of the mitochondrial protein import machinery. By modulating translocase stability and by processing preproteins during translocation, mitoproteases enable precise control over the organelle's proteome, aligning mitochondrial function with the cell's metabolic state. This review discusses how mitoproteases maintain translocase integrity and dynamically regulate mitochondrial protein import and the mitochondrial proteome.
    Keywords:  mitochondrial proteases; mitochondrial protein import; mitochondrial remodeling; protein quality control
    DOI:  https://doi.org/10.1002/pro.70553
  4. Ann Clin Transl Neurol. 2026 Apr 25.
    RNA Sequencing Resolves Cryptic Pathogenic Variants in Mitochondrial Disease.
    Zhimei Liu, Xin Duan, Fatemeh Peymani, Jia Wang, Chengjia Bao, Chaolong Xu, Ying Zou, Zixuan Zhang, Yunxi Zhang, Tongyue Li, Martin Pavlov, Junling Wang, Minhan Song, Tianyu Song, Xiaodi Han, Mingxi Sun, Danmin Shen, Ruoyu Duan, Huafang Jiang, Manting Xu, Holger Prokisch, Fang Fang.
       OBJECTIVE: Mitochondrial diseases are the most common inherited metabolic disorders, characterized by pronounced clinical and genetic heterogeneity that complicates molecular diagnosis. Although DNA-based sequencing approaches have become standard in genetic testing, up to half of patients remain without a definitive diagnosis. We aimed to perform RNA sequencing (RNA-seq) of patient-derived skin fibroblasts to enhance the molecular diagnostic efficacy of mitochondrial disease in undiagnosed cases in China.
    METHODS: We performed RNA-seq on skin fibroblasts from 140 pediatric patients with suspected mitochondrial disease who remained genetically undiagnosed after whole exome sequencing (WES). Aberrant RNA expression and splicing were identified using the detection of RNA outliers pipeline (DROP). Based on WES findings, patients were stratified into a candidate group (n = 28), in which RNA-seq evaluated the pathogenicity of WES-identified variants of uncertain significance and an unsolved group (n = 112), in which RNA-seq was used to pinpoint candidate genes. In six cases where RNA-seq identified the aberrant RNA event but WES did not detect the causative variants, whole genome sequencing (WGS) was performed.
    RESULTS: Integrative RNA-seq, WES, and WGS analysis resulted in a genetic diagnosis in 25% of patients overall (20/28 [71%] in the candidate group; 15/112 [13%] in the unsolved group). Aberrant splicing explained most candidate-group diagnoses, including variants misclassified by in silico predictors such as SpliceAI. 14% of protein-truncating variants predicted to undergo nonsense-mediated decay (NMD) escaped degradation, highlighting the functional limits of current predictions. The variants identified in the unsolved cohort included synonymous, missense, deep intronic, near-splice-site variants, and large deletions. The most frequent among them was a recurrent synonymous East Asian founder mutation in ECHS1, accounting for seven cases. Interestingly, across 233 pathogenic variants associated with aberrant RNA phenotypes compiled from this study and prior reports, half were noncoding and half were coding variants.
    CONCLUSION: RNA-seq substantially enhances molecular diagnosis in mitochondrial disease by exposing cryptic splicing, regulatory, and NMD-escape events invisible to DNA sequencing alone. These data advocate transcriptome analysis as an essential component of comprehensive genomic diagnostics in neurometabolic disease.
    Keywords:  RNA sequencing; mitochondrial diseases; pediatric; whole‐exome sequencing; whole‐genome sequencing
    DOI:  https://doi.org/10.1002/acn3.70379
  5. Chem Biol Drug Des. 2026 Apr;107(4): e70296
    Emerging Design Principles at the Forefront of Mitochondrial Transplantation Using Engineering Methodologies: Current Achievements and Future Directions.
    Naoto Yoshinaga, Keiji Numata.
      Mitochondrial transplantation has gathered much attention as therapeutics to improve multiple mitochondrial functions simultaneously. While the administration of naked mitochondria into the target tissue has demonstrated therapeutic outcomes sufficient to advance to clinical trials, there remain many limitations, including a low cellular uptake efficiency in the target tissue and dysfunction of the isolated mitochondria. To address these issues, engineering approaches have been developed to functionalize the isolated mitochondria. In this review, we focus on the three critical topics for efficient mitochondrial transplantation and outline emerging design rules and their limitations for each purpose: (i) tissue targeting, (ii) protection of mitochondria from external stresses, and (iii) improvement of cellular uptake efficiency. From these achievements, we also discuss the current limitations of mitochondrial transplantation and propose the future direction of the attractive therapeutic methodology.
    Keywords:  lipid; metal–organic framework; mitochondria transplantation; mitochondrial coating; peptide; polymer
    DOI:  https://doi.org/10.1111/cbdd.70296
  6. Protein Sci. 2026 May;35(5): e70587
    Proteostasis at the mitochondrial outer membrane: Quality control of mitochondrial protein transport.
    Shunsuke Matsumoto, Suzuka Ono, Toshiya Endo.
      Mitochondria are enclosed by a double-membrane structure composed of the outer and inner membranes, and this architectural organization underlies their diverse cellular functions. In particular, the mitochondrial outer membrane serves as an essential interface between the cytosol and the mitochondrial interior, regulating the flux of proteins, lipids, small molecules, and ions through the coordinated activities of its resident proteome. Consequently, structural and functional defects of outer membrane proteins are subject to continuous surveillance, and aberrant proteins are rapidly recognized and degraded. Defects in precursor translocation or translation can lead to the stalling of precursor proteins at the primary protein import gate, the TOM complex. Such situations are resolved by multiple quality control systems operating across both the mitochondria and the cytosol. In addition, proteins normally destined for the endoplasmic reticulum or peroxisomes may be mistargeted to mitochondria, and these mislocalized proteins are likewise managed through dedicated mechanisms that promote their degradation or re-targeting. In this review, we summarize current insights into the molecular factors and mechanisms that maintain proteostasis at the mitochondrial outer membrane.
    Keywords:  mitochondria; outer membrane; protein degradation; quality control; re‐targeting
    DOI:  https://doi.org/10.1002/pro.70587
  7. Am J Med. 2026 Apr 17. pii: S0002-9343(26)00288-3. [Epub ahead of print]
    New Understanding and Treatment of Adult Mitochondrial Dysfunction: An Example of Personalized Precision Medicine.
    Gabriela R Esnaola, Edward J Goetzl.
      The principal cellular energy-generating pathways of mitochondria used to produce adenosine triphosphate (ATP) are oxidative phosphorylation and β-oxidation of fatty acids. Under anaerobic conditions, glycolysis in the cytoplasm is an alternative mechanism for production of ATP. Mitochondrial diseases result from one or more of the over 350 mutations in mitochondrial DNA (10%) or nuclear DNA (90%) that cause defective mitochondrial ATP production. The most common manifestations in adults with mitochondrial DNA mutations are diminished vision, myopathy, cardiomyopathy, neuropathy, encephalopathy and diabetes. Uncommonly there are stroke-like syndromes. The most common manifestations in adults with nuclear DNA mutations are neuropathy with prominent ataxia, ophthalmoplegia, dysarthria, myopathy, cardiomyopathy, liver disease, neuroendocrine and renal cell tumors, and hypoglycemia. Adults, especially the elderly, may only develop manifestations in the course of stressful illnesses that unmask these mutations. Children may require mitochondrial transfer or gene editing therapy. These mutations should be sought in leukocytes or muscle tissue in adults who do not respond to usual treatment for severe stressful illnesses as they may benefit from newly-approved medications.
    Keywords:  Oxidative phosphorylation; anaerobic glycolysis; fatty acid β-oxidation; gene editing; mitochondrial transfer; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.amjmed.2026.04.018
  8. Redox Biol. 2026 Apr 14. pii: S2213-2317(26)00164-3. [Epub ahead of print]93 104166
    Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.
    Patrícia Coelho, Pedro Dionísio, Vilma Sardão Oliveira, Roberto A Dias, Matthias E Futschik, Robin Klemm, Ira Milosevic, Nuno Raimundo.
      Mitochondria and peroxisomes communicate to maintain lipid homeostasis, but how the latter adjust to mitochondrial dysfunction remains unclear. Here, we show that loss of complex I subunit NDUFS4 in mouse fibroblasts leads to impaired mitochondrial fatty acid oxidation, resulting in the accumulation of triacylglycerol and lipid droplet (LD) expansion. In this context, peroxisomal biogenesis is upregulated, but their β-oxidation capacity is impaired, suggesting an adaptive yet ineffective response. Additionally, lipid overload using a very-long-chain fatty acid (VLCFA) leads to peroxisomal proliferation but prevents LD expansion when peroxisomal β-oxidation is compromised. The data demonstrated that proper peroxisomal processing is necessary for lipid storage under mitochondrial stress conditions. Our findings reveal a peroxisomal maladaptive remodelling response that fails to compensate for mitochondrial dysfunction, leading to disruptions in LD homeostasis. We propose a critical axis involving peroxisomes-LD-mitochondria that buffers metabolic stress in mitochondrial diseases.
    Keywords:  Complex I dysfunction; Lipid homeostasis; Mitochondria-peroxisome crosstalk; NDUFS4-KO; Peroxisomes
    DOI:  https://doi.org/10.1016/j.redox.2026.104166
  9. Food Chem Toxicol. 2026 Apr 20. pii: S0278-6915(26)00180-8. [Epub ahead of print] 116106
    Cholesterol overload promotes mitochondria-mediated apoptosis with impaired mitochondrial unfolded protein response and mitophagy in SH-SY5Y cells.
    Juhyun Chung, Je Won Ko, Young Hye Kwon.
      Cholesterol accumulation in the brain has been implicated in mitochondrial dysfunction and neurodegeneration; however, its specific effects on mitochondrial quality control pathways, including the mitochondrial unfolded protein response (UPRmt) and mitophagy, remain poorly defined. In this study, SH-SY5Y human neuroblastoma cells were treated with 25 or 50 μg/mL water-soluble cholesterol for 24 h. UPRmt, mitophagy, and inflammasome activation were assessed using molecular and cellular approaches, including immunoblotting, quantitative RT-PCR, and fluorescence-based imaging. Cholesterol treatment increased intracellular cholesterol levels up to 1.7-fold and induced dose-dependent cytotoxicity and apoptosis. UPRmt was suppressed, as evidenced by reduced expression of mitochondrial chaperones and proteases. In parallel, cholesterol impaired mitophagy by disrupting autophagic flux, leading to the accumulation of damaged mitochondria. This was accompanied by increased cytosolic mitochondrial DNA (mtDNA), caspase 1 activation, and interleukin-1β secretion. These findings indicate that impaired mitochondrial clearance promotes mtDNA release, thereby linking mitochondrial dysfunction to inflammasome activation. Collectively, cholesterol overload disrupts UPRmt and mitophagy, thereby promoting mitochondrial dysfunction, inflammasome activation, and neuronal apoptosis.
    Keywords:  Apoptosis; Cholesterol; Inflammasome; Mitochondria; Mitophagy; SH-SY5Y cells; UPRmt
    DOI:  https://doi.org/10.1016/j.fct.2026.116106
  10. Biosci Biotechnol Biochem. 2026 Apr 23. pii: zbag059. [Epub ahead of print]
    Mitochondrial NADP+-isocitrate dehydrogenase Idp1 involves CoQ biosynthesis in parallel with NAD kinase Pos5.
    Shogo Nishihara, Yasuhiro Matsuo, Makoto Kawamukai.
      Mitochondrial NADPH is synthesized by isocitrate dehydrogenase (Idp1) from NADP+ and NAD kinase (Pos5) from NADH. Coenzyme Q levels in Schizosaccharomyces pombe were decreased by deletion of idp1 and further lowered by deletion of pos5. The NADP+/NADPH ratio of the ∆idp1 strain shifted to an oxidized state. The mitochondrial NADPH pool and its redox state are critical for CoQ biosynthesis.
    Keywords:  CoQ; Mitochondria; NADP; fission yeast
    DOI:  https://doi.org/10.1093/bbb/zbag059
  11. Commun Biol. 2026 Apr 23.
    Membranes arrest the coarsening of mitochondrial condensates in human cells.
    Sanjaya V B D Aththawala Gedara, Surya Teja Penna, Marina Feric.
      Mitochondria contain double membranes that enclose their contents. Within their interior, the mitochondrial genome and its RNA products are condensed into ~100 nm sized (ribo)nucleoprotein complexes. How these endogenous condensates maintain their roughly uniform size and spatial distributions within mitochondria remains unclear. Here, we engineer optogenetic tools (mt-optoIDR) that enable controlled formation of synthetic condensates within live mitochondria upon light activation in HeLa cells. Using high-resolution microscopy, we visualize the nucleation of small, yet elongated condensates (mt-opto-condensates), which recapitulate the morphologies of endogenous mt-condensates. These narrow size distributions are independent of mt-optoIDR sequence features, suggesting the mitochondrial environment influences condensate formation. Consistently, mt-opto-condensates fluctuate within voids in between cristae in tubular mitochondria. To directly isolate the contribution of the mitochondrial membranes, we overexpress the dominant negative membrane fusion mutant (Drp1K38A), which results in the formation of bulbous mitochondria with restructured cristae. Based on quantitative particle tracking, bulbous mitochondria support significantly increased dynamics and rapid coarsening of mt-opto-condensates into a single, prominent droplet-in contrast to the membrane confinement observed in tubular mitochondria. Together, these observations inform how membranes can constrain the growth and dynamics of the condensates they enclose, without the need for additional regulatory mechanisms.
    DOI:  https://doi.org/10.1038/s42003-026-10085-3
  12. Nat Commun. 2026 Apr 18. pii: 3589. [Epub ahead of print]17(1):
    Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.
    Tetiana Poliezhaieva, Yuting Li, Prerana Shrikant Chaudhari, Ulas Isildak, Pol Alonso-Pernas, Isabela Santos Valentim, Fengting Su, Lilia Espada, Melike Bayar, Li Fu, Andreas Koeberle, Handan Melike Dönertaş, Maria A Ermolaeva.
      Mitochondrial dysfunction is a prominent hallmark of aging contributing to the decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to "natural" aging of mitochondria are less clear. Here we use proteomics, lipidomics, genetics and functional tests in wild type Caenorhabditis elegans and long-lived clk-1(qm30) and isp-1(qm150) mitochondrial mutants to identify molecular pathways that support longevity amid persistent mitochondrial inefficiency. These tests and subsequent transcriptomics and metabolomics analyses in humans reveal aging-associated decline of phosphatidylcholine synthesis as a trigger of mitochondrial network disruption, which contributes to mitochondrial dysfunction during normal aging. Moreover, ectopic boosting of phosphatidylcholine levels via diet restores late life mitochondrial integrity in vivo in nematodes and reinstates metabolic resilience in human cell culture tests. We thus describe a previously unrecognized natural driver of mitochondrial decline in aging that is malleable by dietary interventions.
    DOI:  https://doi.org/10.1038/s41467-026-71508-7
  13. J Transl Med. 2026 Apr 24.
    Mitochondria at the heart of aging: structure, function, and failure.
    Hany E Marei.
      
    Keywords:  Aging; Mitochondria; Mitochondrial biogenesis; Mitochondrial dysfunction; Mitophagy; NAD+; Oxidative stress; PGC-1α; Rejuvenation; Sirtuins
    DOI:  https://doi.org/10.1186/s12967-026-08047-8
  14. J Biol Chem. 2026 Apr 17. pii: S0021-9258(26)00347-9. [Epub ahead of print] 111475
    Molecular analysis of a new patient COX15 mutation provides insight into the etiology of fatal infantile cardioencephalopathy.
    Jayda A Carroll-Deaton, Iryna Bohovych, Faith T Emetu, Jonathan V Dietz, Elise D Rivett, Elinor Stanley, Eric L Hegg, Jennifer L Fox, Oleh Khalimonchuk.
      Mitochondrial disease can result from mutations in the enzymes responsible for biosynthesis of heme a and hemylation of respiratory complex IV of the electron transport chain, also known as cytochrome c oxidase (CcO). One of these enzymes, which is essential for assembly and function of CcO and thus function of the electron transport chain, is heme a synthase, COX15. A previously unknown fatal missense mutation of COX15, c.232G>A (p.Gly78Arg), was recently described in a case report by Galvão de Oliveira et al. Here, we show that the p.Gly78Arg-mimicking substitution in the homologous Cox15 protein in Saccharomyces cerevisiae (Gly95Arg) causes Cox15 protein instability and recapitulates the CcO defect observed in the patient. We demonstrate that the CcO defect observed with this Cox15 variant stems from insufficient heme a synthesis, and consequently, insufficient CcO hemylation and decreased levels of CcO. Our results provide insights into the etiology of the disease caused by this variant, suggesting that Cox15 protein instability and consequent attenuation of heme a synthase function is the main molecular factor behind the resulting multisystemic mitochondrial disorder in humans.
    Keywords:  COX15; Cytochrome c oxidase; Heme; Heme A Synthase; Mitochondria; Yeast model
    DOI:  https://doi.org/10.1016/j.jbc.2026.111475
  15. Autophagy. 2026 Apr 23.
    The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.
    Shu-Q Cao, Juan Ignacio Jiménez-Loygorri, Patricia Boya, Evandro F Fang.
      Mitochondrial quality control is essential for maintaining neuronal function and resilience during aging, yet pharmacological strategies that effectively restore mitophagy to maintain mitochondrial homeostasis remain limited. Emerging evidence suggests that dietary molecules may influence mitochondrial health, although the underlying mechanisms are largely unknown. Here, we summarize our recent finding whereby we have identified a robust mitophagy inducer: α-amyrin (αA). This molecule is a lipid-like pentacyclic triterpenoid abundant in edible plants, such as passion fruit. Mechanistically, αA targets dual leucine zipper kinase (DLK), a neuron-enriched stress kinase that plays a central role in axonal degeneration signaling. Under pathological stress, DLK activates the degeneration mediator SARM1, which can sequester the key autophagy/mitophagy protein ULK1 leading to compromised autophagy and mitophagy. By specifically binding to DLK, αA releases ULK1 from SARM1-mediated restriction and promotes ULK1-dependent mitophagy, restoring mitochondrial homeostasis. This mechanism reveals the DLK-SARM1-ULK1 cascade as a previously underappreciated regulatory interface linking neuronal stress signaling to mitochondrial surveillance pathways. More broadly, these findings introduce lipid-like dietary molecules as potential "mitochondrial guardians" that preserve organelle integrity through physiological activation of mitophagy. Targeting the DLK-SARM1-ULK1 axis with such molecules may represent a promising strategy for maintaining mitochondrial health and mitigating neurodegenerative processes associated with aging.
    Keywords:  DLK; ULK1; lipid-like molecule; mitophagy; α-amyrin
    DOI:  https://doi.org/10.1080/15548627.2026.2664599
  16. Nat Rev Drug Discov. 2026 Apr 24.
    Inhibiting the integrated stress response restores cognition.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-026-00066-w
  17. J Inherit Metab Dis. 2026 May;49(3): e70184
    Aminoacyl-tRNA Synthetases: Variant Classification, Functional Assays, and Emerging Therapeutic Strategies.
    M I Mendes, D E Smith, V Spek, A M Bosch, W E Corpeleijn, M Engelen, S A Fuchs, A Hadchouel, I U Heinemann, R H Houtkooper, E M M Hoytema van Konijnenburg, S Kemp, M Langeveld, C D M Karnebeek, A Pop, V M Siu, N I Wolf, G S Salomons.
      Aminoacyl-tRNA synthetases (aaRS) are essential enzymes that charge tRNAs with their corresponding amino acids, playing a critical role in protein synthesis. All 37 nuclear-encoded ARS genes, comprising both cytosolic (ARS1) and mitochondrial (ARS2) isoforms, have now been linked to human disease. Pathogenic variants in these genes cause a wide range of phenotypes, from dominant peripheral neuropathies to recessive multisystemic disorders. Despite the high number of ARS variants identified, functional validation remains difficult, with over 80% of missense variants classified as VUS in public databases. Additionally, the role of non-canonical aaRS functions in disease remains an area requiring further exploration. Our laboratory developed a high-throughput LC-MS/MS-based aminoacylation assay to measure aaRS activity in patient-derived fibroblasts, aiding in variant classification. This functional approach has contributed to the diagnosis of nearly 200 patients and has uncovered complex variant effects, including thermolabile and splicing-defective forms. Therapeutically, amino acid supplementation and dietary interventions have shown effect in select cases, while gene therapy is being explored for dominant ARS-related neuropathies. Amenability to targeted interventions further underlines the need for correct interpretation of genetic variants, which are increasingly recognized as genetic testing is progressively used in the diagnostic work-up and functional assays. Additionally, natural history studies are essential to improve diagnosis, understand disease mechanisms, and guide and evaluate personalized treatment. This review underscores the critical need for integrated genomic and functional approaches to advance variant interpretation and therapeutic development in the era of NGS.
    DOI:  https://doi.org/10.1002/jimd.70184
  18. PNAS Nexus. 2026 Apr;5(4): pgag112
    Structural and biochemical basis of ROC-dependent activation of LRRK2.
    Yangshin Park, Chunxiang Wu, Kayla Tennessen, Li Wan, Neo C Hoang, Cardea W Hoang, Jingling Liao, Quyen Q Hoang.
      Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease, yet the molecular mechanism governing LRRK2 activation remains incompletely understood. LRRK2 is a large multidomain enzyme whose kinase activity is regulated by intramolecular interactions and by its Ras of complex proteins (ROC) GTPase domain. Here, we combine cryo-electron microscopy, X-ray crystallography, and structure-guided biochemical perturbations to define how ROC conformational switching regulates LRRK2 activation. Cryo-EM reconstructions reveal that monomeric full-length LRRK2 samples three distinct conformational states-autoinhibited, intermediate, and activated-indicating that large-scale activation-associated rearrangements can occur through an intrinsic intramolecular pathway, independently of Rab29 binding, higher-order oligomerization, or membrane association. A 1.6-Å crystal structure of an extended ROC construct reveals intrinsic conformational plasticity within the GTPase switch regions that likely underlies these transitions. Structure-guided disulfide engineering identifies a functional coupling between residue R1441 and switch II that directly modulates GTPase activity in both isolated ROC and full-length LRRK2. Disruption of this coupling phenocopies the disease-associated R1441H mutation. Together, these findings establish ROC as a dynamic conformational engine that drives a multistep intramolecular activation mechanism in LRRK2, providing mechanistic insight into how pathogenic mutations promote aberrant kinase activation.
    Keywords:  GTPase; LRRK2; Parkinson's disease; cryo-EM; kinase
    DOI:  https://doi.org/10.1093/pnasnexus/pgag112
  19. Histochem Cell Biol. 2026 Apr 20. pii: 25. [Epub ahead of print]164(1):
    Functional suppression accompanies internal mitochondrial reorganization during cellular reprogramming.
    N Diak, L Sieroń, K Janelt, L Chajec, A Fus-Kujawa, A Dziedzic-Kowalska, A Trybus, K Raszczok, K Bajdak-Rusinek.
      During the conversion of fibroblasts into induced pluripotent stem cells (iPSCs), cellular metabolism shifts from oxidative phosphorylation toward glycolysis; however, how functional and structural mitochondrial adaptations are coordinated remains incompletely understood. Here, we examined selected aspects of mitochondrial function, targeted gene expression, and ultrastructure in fibroblasts and iPSCs derived from healthy donors and patients with osteogenesis imperfecta (OI). Targeted gene expression analysis was performed in all four cell types, while functional and ultrastructural assays focused on OI-derived cells. Flow cytometry revealed reduced mitochondrial mass and reactive oxygen species (ROS) levels in iPSCs compared with fibroblasts. Mitochondrial membrane potential showed modestly reduced fluorescence depending on the probe used. Quantitative transmission electron microscopy demonstrated internal mitochondrial reorganization in iPSCs, including altered morphology and simplified cristae architecture, despite preservation of overall membrane integrity. These findings indicate that reprogramming induces coordinated functional downscaling and structural remodeling of mitochondria. Furthermore, differential expression of matrix metalloproteinases suggests that extracellular matrix remodeling accompanies metabolic adaptation during reprogramming.
    Keywords:  Cellular reprogramming; Induced pluripotent stem cells; Metabolic remodeling; Mitochondrial function; Mitochondrial ultrastructure; Transmission electron microscopy
    DOI:  https://doi.org/10.1007/s00418-026-02472-y
  20. Front Neurol. 2026 ;17 1793054
    Study on Leigh syndrome caused by SURF1 gene mutations and its mechanisms.
    Chunmei Wang, Longlong Lin, Yuanfeng Zhang, Simei Wang, Xiaona Luo, Xuqin Chen.
      Leigh syndrome (LS) is a prevalent mitochondrial encephalomyopathy in childhood, triggered by mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). The protein encoded by the SURF1 gene localizes to the inner mitochondrial membrane and is involved in the biosynthesis of the cytochrome c oxidase (COX) complex. We enrolled 5 children harboring SURF1 gene variants whose clinical manifestations were highly consistent with LS. The clinical characteristics and potential pathogenic mechanisms of the disease were elucidated by systematic analysis of their clinical data. Among the 5 patients, 4 were female and 1 was male, with ages ranging from 13 months to 2 years and 7 months. Next-generation sequencing (NGS) results revealed 6 variant sites in the SURF1 gene among the 5 patients, of which 2 were known variants and 4 were unreported novel variants, namely c.314-317delTGCC (p.L105Qfs*7), c.588+1_588+3delGTA (splicing), c.655G>T (p.Glu219), and c.515+3G>C. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed on the peripheral blood of 4 patients, and the results demonstrated that the messenger RNA (mRNA) expression level of the SURF1 gene was significantly lower than that in their parents. Using 10 healthy children as controls, we analyzed the ratios of mitochondria-related NADH-ubiquinone oxidoreductase core subunit 1 (ND1), Cytochrome c oxidase subunit I (COX1), Cytochrome c oxidase subunit II (COX2), NADH-ubiquinone oxidoreductase chain 4 (ND4), Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a nuclear reference gene. Mitochondrial DNA content was determined by measuring the ND1/GAPDH ratio using RT-qPCR, and further verified with COX1, COX2, and ND4. These ratios were all significantly decreased, indicating reduced mitochondrial DNA (mtDNA) copy number/mtDNA depletion. Iterative Threading ASSEmbly Refinement (I-TASSER)-based three-dimensional (3D) structural analysis indicated that all 6 variant sites induced alterations in the spatial structure of the SURF1 protein. The SURF1 protein is a hydrophilic protein, protein hydrophobicity and stability analyses showed that the 4 unreported novel variants could reduce the hydrophilicity, increase the hydrophobicity, and decrease the structural stability of the protein. The Saccharomyces cerevisiae Homolog of Yeast 1 (Shy1) domain serves as the key structural basis for SURF1 to exert its mitochondrial functions. We found that all 6 variant sites in the SURF1 gene were located within the Shy1 domain.
    Keywords:  Chinese children; Leigh syndrome; Shy1 domain; mitochondrial DNA depletion; splice-site variant
    DOI:  https://doi.org/10.3389/fneur.2026.1793054
  21. Nat Commun. 2026 Apr 21.
    Mitochondrial respirasome-like supercomplexes support metabolic flexibility in yeast.
    Mazzen H Eldeeb, Zoe Cosner, Andreas Carlström, Jeffri-Noelle Mays, Gabriella F Rodriguez, Jens Berndtsson, Martin Ott, Flavia Fontanesi.
      The mitochondrial respiratory chain (MRC) complexes, crucial for aerobic energy transduction in eukaryotes, form conserved higher-order structures called supercomplexes (SCs). The elucidation of SC physiological relevance is critical for our understanding of mitochondrial function and bioenergetics but has been hindered by the limited availability of experimental models isolating SC formation as the sole variable. In baker's yeast, SCs comprise III2IV1 and III2IV2 configurations, which enhance respiratory rates by facilitating cytochrome c diffusion along the SC surface. However, the roles of distinct SC conformations and MRC plasticity remain unclear. To address these questions, we engineered a yeast strain expressing a covalently-linked III2IV2 SC, structurally like the wild-type. Expression of this tethered SC supports robust respiratory activity but selectively impacts cytosolic NADH-driven respiration, due to distinct interactions with the NADH dehydrogenase Nde1. We propose that in yeast mitochondria, substrate-specific respirasome-like SCs contribute to the optimization of electron fluxes and support metabolic flexibility.
    DOI:  https://doi.org/10.1038/s41467-026-72228-8
  22. Acta Biochim Biophys Sin (Shanghai). 2026 Apr 25.
    Presenilin 1 is located in the mitochondrial inner inner membrane and regulates mitochondrial cristae junction protein arrangement and cristae formation in HEK293 cells.
    Pan You, Pengjin Zhu, Hui Yu, Luwen Wang, Bo Su.
      Presenilin 1 (PS1), a key pathogenic factor in familial Alzheimer's disease, is implicated in the regulation of mitochondrial functions, yet its precise sub-mitochondrial localization and underlying mechanisms remain poorly understood. In this study, we generate PS1-knockout cell lines to investigate the role of PS1 in mitochondrial structure and function. Our results indicate that PS1 is directly localized in the mitochondrial inner membrane. PS1 deficiency leads to reduced ATP production, impaired mitochondrial respiration capacity, decreased mitochondrial membrane potential, disrupted Ca 2+ homeostasis, and elevated ROS accumulation. Moreover, loss of PS1 leads to abnormal mitochondrial cristae structure. Further analysis reveals that PS1 interacts with mitochondrial inner membrane proteins. Its absence promotes ATAD3A oligomerization and disrupts its arrangement at mitochondrial cristae junctions, leading to expansion of the mitochondria-associated membrane and instability of mitochondrial DNA. Our findings demonstrate that PS1 acts as a central regulator of mitochondrial cristae morphogenesis by modulating protein interaction networks at cristae junctions, thereby illuminating fundamental molecular mechanisms contributing to mitochondrial dysfunction in Alzheimer's disease.
    Keywords:  ATAD3A; mitochondrial DNA; mitochondrial dysfunction; presenilin 1
    DOI:  https://doi.org/10.3724/abbs.2026064
  23. Stem Cell Res. 2026 Apr 16. pii: S1873-5061(26)00088-7. [Epub ahead of print]94 103992
    iPSC generation from PBMCs of a MELAS patient for mitochondrial dysfunction studies.
    Gautam Sharma, Abhay Srivastava, Cheryl Rockman-Greenberg, Sanjiv Dhingra.
      Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a multisystemic mitochondrial disorder primarily caused by a heteroplasmic point mutation at mitochondrial DNA (mtDNA) position 3243 (m.3243A > G) in the MT-TL1 gene, which encodes mitochondrial tRNA^Leu(UUR). In this study, we report the successful reprogramming of peripheral blood mononuclear cells (PBMCs) from a male patient diagnosed with MELAS into induced pluripotent stem cells (iPSCs). This patient-specific iPSC platform enables investigation into the relationship between heteroplasmy levels and disease manifestation and provides a valuable tool for screening potential therapeutic strategies aimed at mitigating mitochondrial dysfunction in MELAS.
    DOI:  https://doi.org/10.1016/j.scr.2026.103992
  24. Geroscience. 2026 Apr 24.
    Vitamin B12 improves skeletal muscle mitochondrial biology in aged mice.
    Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.
      Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced age, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.
    Keywords:  Aging; Mitochondria; Sarcopenia; Skeletal muscle; Vitamin B12
    DOI:  https://doi.org/10.1007/s11357-026-02264-1
  25. Sci Adv. 2026 Apr 24. 12(17): eaee6175
    Patterns of mitochondrial ATP predict tissue folding.
    Bezia Lemma, Megan Rothstein, Pengfei Zhang, Bridget Waas, Marcus Kilwein, Safiya Topiwala, Sherry X Zhang, Anvitha Sudhakar, Katharine Goodwin, Elizabeth R Gavis, Ricardo Mallarino, Andrej Kosmrlj, Celeste M Nelson.
      The construction of tissue shapes during embryonic development results from patterns of gene expression and mechanical forces fueled by chemical energy from ATP hydrolysis. We find that chemical energy is similarly patterned during apical constriction, which is widely used across the animal kingdom to fold epithelial tissues. Time-lapse imaging, spatial transcriptomics, and measurements of oxygen consumption rate reveal that mitochondrial density, potential, and ATP increase at the apical side of epithelial cells before actomyosin contraction and tissue folding, which is prevented by inhibiting oxidative phosphorylation. Mitochondrial enrichment and apical bias are conserved during apical constriction in flies, chicks, and mice, and these patterns can be used to predict computationally patterns of tissue folding. These findings highlight a spatial dimension of bioenergetics in development.
    DOI:  https://doi.org/10.1126/sciadv.aee6175
  26. Cell Death Dis. 2026 Apr 21.
    TFAM promotes mitochondrial division by increasing mitochondrial Sirt3.
    Shixian Zhai, Zihong Huang, Zewei Luo, Chunchun An, Lu Gao, Tongsheng Chen.
      Mitochondrial transcription factor A (TFAM) plays a crucial role in mitochondrial fission beyond its canonical function in mtDNA maintenance. However, how TFAM regulates mitochondrial fission remains only partially understood. Fluorescence microscopy and TEM analyses showed that TFAM knockdown inhibited mitochondrial fission, whereas TFAM overexpression promoted mitochondrial fragmentation, and this mitochondrial morphology phenotype was supported by TEM-based ultrastructural observations in zebrafish embryos with tfam disruption. Depletion of Drp1 and MFF in TFAM-overexpressing cells led to elongated mitochondria, indicating that TFAM promotes Drp1- and MFF-dependent mitochondrial fission, which was further supported by the inhibitory effects of Mdivi-1 (Drp1 inhibitor) and Compound C (AMPK inhibitor) on TFAM-induced mitochondrial fission. Western blot and immunofluorescence analyses revealed that TFAM overexpression enhanced the mitochondrial localization and Sirt3-dependent mitochondrial protein deacetylation of Sirtuin 3 (Sirt3), increased phosphorylation of AMPK and MFF, and promoted mitochondrial recruitment of phosphorylated Drp1. Proteinase K protection and cycloheximide chase assays further supported intramitochondrial localization of Sirt3 and increased stability of mitochondrial Sirt3 upon TFAM overexpression. FRET imaging and co-immunoprecipitation demonstrated a direct TFAM-Sirt3 interaction mediated by TFAM's HMG-box A domain. Targeted mutagenesis or deletion of the HMG-box A domain disrupted the TFAM-Sirt3 interaction, impaired Sirt3 mitochondrial localization and Sirt3-dependent mitochondrial protein deacetylation, and abolished TFAM-mediated mitochondrial fission. Analysis of TCGA data showed that high TFAM-SIRT3 co-expression is associated with overall survival across cancers, particularly in Kidney Renal Clear Cell Carcinoma (KIRC), where TFAM is downregulated (whereas SIRT3 is not). Together, these findings demonstrate that TFAM promotes mitochondrial fission via direct interaction with Sirt3, thereby activating the AMPK/MFF/Drp1 pathway.
    DOI:  https://doi.org/10.1038/s41419-026-08750-w
  27. Int J Biol Sci. 2026 ;22(7): 3886-3908
    DHCR24 Deficiency Drives Age-Related Meibomian Gland Dysfunction by Regulating Lipid Metabolic Imbalance and Cytosolic mtDNA-Induced cGAS-STING Activation.
    Yuchen Cai, Tianyi Zhou, Jiaming Sun, Xueyao Cai, Wenjun Shi, Junzhao Chen, Christos C Zouboulis, Hao Sun, Yao Fu, Liangbo Chen.
      Dysregulated lipid metabolism and chronic inflammation are hallmarks of aging, yet their interplay in age-related tissue disorders remains poorly defined. In the ocular surface, age-related meibomian gland dysfunction (ARMGD) is highly prevalent but mechanistically unclear, leading to significant visual impairment without targeted therapies. To identify key molecular drivers of ARMGD, we performed integrated multi-omics screening of aging mouse meibomian glands (MGs) and identified DHCR24, a key cholesterol metabolism enzyme, as a critical regulator of gland homeostasis. Single-cell sequencing identified age-associated downregulation of Dhcr24 predominantly in meibocytes. Based on this finding, we generated a meibocyte-specific Dhcr24 knockout (cKO) model, which exhibited typical ARMGD pathology including glandular atrophy, disrupted lipid homeostasis, and inflammatory activation. Further in vitro studies using SZ95 sebocytes demonstrated that DHCR24 deficiency induces mitochondrial dysfunction and cytosolic mitochondrial DNA (mtDNA) leakage, triggering cGAS/STING-dependent inflammatory senescence. Notably, AAV-mediated restoration of DHCR24 in mice reversed age-related gland pathology. Our findings establish DHCR24 as a dual-target regulator that maintains cholesterol metabolic homeostasis while suppressing mtDNA-driven inflammation via the cGAS-STING pathway, highlighting its therapeutic potential for ARMGD and related disorders characterized by lipid-inflammatory imbalance.
    Keywords:  DHCR24; aging; cGAS-STING; lipid dysregulation; meibomian glands; mtDNA
    DOI:  https://doi.org/10.7150/ijbs.129636
  28. Behav Brain Res. 2026 Apr 22. pii: S0166-4328(26)00218-4. [Epub ahead of print] 116242
    Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.
    Caizhen Shi, Kunpeng Jia, Yanjie Guo, Shenghao Qian, Bingbing Wang, Yue Qiu, Li Dan, Zhuokun Dang, Kun Xue, Feng Gao, Lin Zhao.
      Disulfidptosis is a recently identified form of regulated cell death driven by disulfide stress and cytoskeletal collapse under conditions of impaired reducing capacity. Neurodegenerative diseases (NDs), including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by oxidative stress, mitochondrial dysfunction, metabolic impairment, protein aggregation, and cytoskeletal instability-features that may provide a permissive intracellular context for disulfidptosis. However, its occurrence and pathological relevance in these disorders remain incompletely understood. In this review, we examine the potential involvement of disulfidptosis in neurodegenerative diseases from a disease-centered perspective. We emphasize that current evidence is largely indirect and based on mechanistic overlap rather than direct experimental validation in neural systems. Accordingly, we distinguish between direct evidence, indirect mechanistic support, and pathophysiological plausibility. We further discuss cell-type-specific susceptibility across neurons and glial cells, analyze its relationship with other cell death pathways, and consider potential therapeutic implications. Overall, disulfidptosis is best regarded as a context-dependent and emerging mechanism that may contribute to neuronal vulnerability under specific metabolic and redox constraints. Clarifying its disease relevance will be essential for determining its significance in neurodegeneration and its potential as a therapeutic target.
    Keywords:  cell death; disulfidptosis; mitochondria; neurodegenerative diseases; protein aggregation; redox imbalance
    DOI:  https://doi.org/10.1016/j.bbr.2026.116242
  29. iScience. 2026 May 15. 29(5): 115530
    An optimized translating ribosome affinity purification protocol for low-abundance Drosophila tissues.
    Leonor Miller-Fleming, Wing Hei Au, Alexander J Whitworth.
      Localized protein translation enables spatially restricted cellular dynamics, particularly in neurons, where specific mRNAs are translated in axons and dendrites far from the cell body. Translating ribosome affinity purification (TRAP) has been used to study axonal translation in rodents and cell-type-specific translation in Drosophila, but existing protocols are not optimized for axons, where material is extremely limited. Here, we present a highly sensitive TRAP protocol for isolating ribosome-bound mRNAs from low-input samples, enabling recovery of axonal mRNAs from Drosophila larval and adult (leg) motor neurons. RNA-seq identified axonally translated transcripts, including mRNAs encoding ribosomal and mitochondrial proteins, similar to those reported in axons of other species, indicating conservation of axonal translation in Drosophila. This low-input method enables analysis of local translation with Drosophila genetics across developmental stages, genetic backgrounds, and disease models, and can be adapted for rare genotypes, other tissues and model systems requiring high sensitivity.
    Keywords:  genetics; molecular biology; neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.115530
  30. bioRxiv. 2026 Apr 11. pii: 2026.04.09.717523. [Epub ahead of print]
    Structural Basis of Mitochondrial Transcription Regulation via Interactions of PolRMT and TFAM with Upstream Promoter DNA.
    Rory E Shakey, Caitlin Schroeder, Xiangyu Deng, Jamie Smith, Alfredo J Hernandez, Yang Gao.
      Mitochondrial DNA (mtDNA) transcription is essential for cellular energy production and is carried out by a streamlined transcription system in which transcription factor A (TFAM), transcription factor B2 (TFB2M), and the mitochondrial RNA polymerase (PolRMT) assemble at defined promoters to initiate transcription. Previous structural studies elucidated the core initiation mechanism but relied on truncated promoter templates that excluded upstream regulatory DNA interactions. Here, we present two conformations of mitochondrial transcription initiation complexes assembled on the heavy-strand promoter (HSP): a TFAM-bound complex with extended upstream DNA and a TFAM-free complex containing short linear DNA. The TFAM-bound structure reveals a transcription-stimulatory interface between PolRMT and the upstream promoter region (UPR) enabled by TFAM-induced promoter bending. Consistent with this structural observation, UPR truncation reduces transcription from all mtDNA promoters, an effect abolished by mutation of the PolRMT interface. In contrast, the TFAM-free structure reveals a transcription-inhibitory interaction of linear upstream DNA with the PolRMT tether helix, which would sterically clash with TFAM binding. Deletion of the tether helix increases off-target transcription, supporting an autoinhibitory role that enhances promoter specificity. Together, these findings reveal how TFAM-shaped promoter architecture and PolRMT regulatory elements coordinate mitochondrial transcription initiation and regulation.
    DOI:  https://doi.org/10.64898/2026.04.09.717523
  31. Aging Cell. 2026 May;25(5): e70509
    The Mitochondrial NAD Transporter SLC25A51 in Adipocytes Regulates Adipose Tissue Mitochondrial Function and Systemic Metabolism During Aging.
    Daiki Kojima, Keisuke Yaku, Shotaro Kosugi, Ryunosuke Mitsuno, Kenji Kaneko, Yoshinaga Kawano, Akihito Hishikawa, Seiya Mizuno, Manami Katoh, Akiko Satoh, Shinya Toyokuni, Tatsuhiko Azegami, Kenichiro Kinouchi, Shintaro Yamaguchi, Hiroshi Itoh, Takeshi Kanda, Toshimasa Yamauchi, Takashi Nakagawa, Kaori Hayashi, Jun Yoshino.
      Nicotinamide adenine dinucleotide (NAD) is a classical coenzyme regulating cellular energy metabolism. Emerging evidence demonstrates the causal relationship between defective NAD metabolism and various age-associated diseases. The major purpose of the present study was to investigate the role of adipocyte mitochondrial NAD biology in age-associated metabolic diseases. To this end, we focused on solute carrier family 25 member 51 (SLC25A51), a recently identified mitochondrial NAD transporter. We found that aging was associated with decreased adipose tissue SLC25A51 expression in both humans and mice. We next generated and analyzed novel knockout and overexpression models, which we have named adipocyte-specific Slc25a51 knockout (ASKO) and Slc25a51 overexpressing (ASLO) mice. ASKO mice had a marked decrease in adipose tissue mitochondrial NAD levels and exhibited age-associated systemic metabolic complications, such as obesity, glucose intolerance, insulin resistance, hyperinsulinemia, metabolic inflexibility, dyslipidemia, and hepatosteatosis. Mechanistically, loss of Slc25a51 reduced mitochondrial respiratory function, fatty acid oxidation capacity, and adiponectin production in adipose tissue, likely contributing to the development of systemic metabolic complications. Conversely, ASLO mice were protected from obesity and insulin resistance caused by aging. In conclusion, our results provide novel mechanistic and therapeutic insights into understanding the critical role of adipocyte mitochondrial NAD transporter SLC25A51 in the pathophysiology of age-associated metabolic diseases, particularly obesity and insulin resistance.
    Keywords:  NAD; adipocyte; aging; insulin resistance; obesity
    DOI:  https://doi.org/10.1111/acel.70509
  32. Mol Genet Metab Rep. 2026 Mar;46 101286
    First reported case of adult-onset very long-chain acyl-coa dehydrogenase (vlcad) deficiency in Vietnam: a rare metabolic myopathy.
    Vinh Phuc Kieu, Thang Van Viet Nguyen, Anh Duc Vu.
      Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare genetic metabolic disorder involving impaired fatty acid β-oxidation. It is caused by mutations in the Acyl-CoA Dehydrogenase Very Long Chain (ACADVL) gene, which encodes the VLCAD enzyme. The clinical presentation is diverse, ranging from a severe neonatal-onset form to a milder adult-onset form. We describe the first reported case in Vietnam, which is a 20-year-old man who presented with exercise intolerance, myalgia, and recurrent rhabdomyolysis triggered by fasting and exertion. Acylcarnitine profiling suggested a fatty acid oxidation disorder, and whole-exome sequencing identified the diagnosis of VLCAD deficiency with c747G > T (p.Trp249Cys) mutation. It has not previously been reported in the Vietnamese population. This case highlights the important role of neonatal screening and genetic testing in the early diagnosis of metabolic myopathies. In addition, it raises awareness of genetic disorders among healthcare providers and the public in developing countries.
    Keywords:  Fatty acid oxidation disorders (FAODs); Rhabdomyolysis; Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101286
  33. Curr Biol. 2026 Apr 20. pii: S0960-9822(26)00307-6. [Epub ahead of print]36(8): R332-R335
    Mitochondrial biology: Specialized powerhouses pack a punch.
    Daniel Tapias-Gomez, Jonathan R Friedman.
      A new study reveals that a specialized population of mitochondria in the Caenorhabditis elegans uterine anchor cell is remodeled and enriched in machinery needed for optimal local energy production to support invasion of the basement membrane.
    DOI:  https://doi.org/10.1016/j.cub.2026.03.018
  34. J Physiol. 2026 Apr 19.
    Targeting mitochondrial stress in heart failure: Translocator protein TSPO modulation links mitochondria, redox signalling and cardiac protection.
    Laurent Chatre.
      
    Keywords:  drug; heart failure; inflammation; mitochondria
    DOI:  https://doi.org/10.1113/JP291041
  35. J Biol Chem. 2026 Apr 16. pii: S0021-9258(26)00327-3. [Epub ahead of print] 111455
    Role of mitochondrial translation in modulating inflammatory disease outcome: current knowledge and future perspectives.
    Swarnali Basu, Rukshar Khan, Shiva Sharma, Priyanka Prajapati, Veena Ammanathan, Sumit Rungta, Amit Lahiri.
      Mitochondrial translation is crucial for maintaining cellular respiration, energy balance, calcium signaling, apoptosis, immune surveillance, and the regulation of inflammatory responses. This specialized process, involving mitochondrial rRNAs, tRNAs, mitoribosomes, and nuclear-encoded translation factors, ensures the synthesis of mitochondrially encoded proteins that support oxidative phosphorylation. The mitochondrial translation cycle is tightly regulated by RNA-binding proteins, mitochondrial unfolded protein response, and stress-responsive pathways such as mTOR, particularly during metabolic shifts and immune activation. Emerging evidence highlights mitochondrial translation as a critical modulator of inflammation. In this review, we describe the alteration in mitochondrial-specific translation dynamics in immune cells, its adaptation to stress, and its interplay with organelle-wide signaling via mito-nuclear and mito-cytosolic communication. We focus on the alterations in mitochondrial translation machinery including mitoribosomal proteins, rRNA, tRNA synthetases or other regulatory factors linked to inflammatory diseases, including neurodegeneration, IBD, metabolic and cardiovascular disorders. We further examine how mitochondrial translation influences immune responses through mitochondrial DNA/RNA release, activation of mitochondrial damage-associated molecular patterns, and inflammasomes such as NLRP3. Collectively, mitochondrial translation functions as an immune centric-checkpoint that presents promising therapeutic target for intervention in inflammation-driven diseases.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111455
  36. Histochem Cell Biol. 2026 Apr 18. pii: 24. [Epub ahead of print]164(1):
    Fiber type-specific expression of LACTB leverages a function in oxidative metabolism.
    Kirsi-Marja Alanen, Rabah Soliymani, Jaakko Sarparanta, Satu Kuure, Kirsi Sainio, Zydrune Polianskyte, Muhammad Yasir Asghar, Ehsan Zangene, Annunziata Cascone, Maciej Lalowski, Peter Hackman, Johan Lundin, Dan Lindholm, Ove Eriksson.
      Skeletal muscle is composed of type I and type II fibers, each characterized by specific metabolic machinery. LACTB is a conserved mitochondrial protein implicated in lipid utilization and tumorigenesis, but its precise function in the cellular metabolism remains unclear. To gain novel insight into the functional role of LACTB, we investigated skeletal muscle to determine whether LACTB is segregated by fiber type. The expression of LACTB was determined by immunohistochemistry (IHC) and immunoblotting in skeletal muscle from healthy human subjects and the laboratory rat. The specificity of the antibody was assessed using recombinant human LACTB protein and endogenous LACTB in isolated mitochondria. IHC results were validated in a cellular model of myoblast differentiation using the C2C12 and L6 cell lines. The results demonstrated that LACTB is highly enriched in adult type I muscle fibers. During development, LACTB expression commences in type I primary myotubes at the time of their formation around week 20 of gestational age. LACTB expression in myoblasts is low but increases rapidly upon the induction of myotube differentiation. We conclude that LACTB plays a distinct role in mitochondria of type I fibers, most likely acting in oxidative metabolism related to energy use from lipids. This defines LACTB as a mitochondrial marker for type I fibers.
    Keywords:  LACTB; Mitochondria; Muscle differentiation; Serine protease; Type I muscle fiber; Type II muscle fiber
    DOI:  https://doi.org/10.1007/s00418-026-02476-8
  37. Sci Immunol. 2026 Apr 24. 11(118): eaed2623
    Mitochondrial fission mediates an evolutionarily conserved antibacterial defense response.
    Ronan Kapetanovic, Syeda Farhana Afroz, James E B Curson, Ina Kirmes, Divya Ramnath, Stephan Nothjunge, Jinting Liu, Jordan D Atkinson, Arnaud Ahier, Karoline D Raven, Marta Bosch, Bernhard Keller, Grace M E P Lawrence, Kaustav Das Gupta, Melanie R Shakespear, Charles Ferguson, Claudia J Stocks, Nilesh J Bokil, Gabriele Matthias, Tam T K Nguyen, Zeinab G Khalil, Robert C Reid, Karl A Hansford, Philip M Hansbro, Matthew A Cooper, Mark A Schembri, Antje Blumenthal, Kate Schroder, David P Fairlie, Albert Pol, Patrick Matthias, Robert G Parton, Steven Zuryn, Matthew J Sweet.
      Animals engage pleiotropic immune defense mechanisms to survive infections. Here, we present a function for mitochondrial fission in host defense. Challenge of macrophages with Escherichia coli increased mitochondrial fission, with this response promoting bacterial clearance in mammalian macrophages and Caenorhabditis elegans. E. coli-induced mitochondrial fission engaged dual antibacterial responses via the mitochondrial unfolded protein response (UPRmt) and inducible lipid droplet production. Mitochondrial fission-triggered UPRmt, characterized by activation of activating transcription factor 5 (ATF5) in mouse macrophages and the paralog ATFS-1 in C. elegans, curtailed inducible lipid droplets to cross-regulate these pathways. The intramacrophage pathogen Salmonella enterica suppressed antibacterial mitochondrial fission, but restoring this response by inhibiting mitochondrial fusion-promoting histone deacetylase 6 (HDAC6) reactivated lipid droplet production and bacterial clearance. Therefore, we propose that mitochondrial fission is an ancient host defense pathway that can be exploited for anti-infective design.
    DOI:  https://doi.org/10.1126/sciimmunol.aed2623
  38. Am J Physiol Heart Circ Physiol. 2026 Apr 21.
    Cardiac Metabolic Remodeling Drives Dicarbonyl Stress-Induced Mitochondrial Dysfunction in Experimental Heart Failure with Preserved Ejection Fraction.
    Ankit Aryal, Parnia Mobasheran, Luther Bishop, Sabyasachi Chatterjee, Scott Jennings, Huijing Xia, Eric Lazartigues, Qinglin Yang.
      Heart failure (HF) affects over 60 million people worldwide, with increasing prevalence as HF with preserved ejection fraction (HFpEF) among adults. Although metabolic remodeling and mitochondrial dysfunction are central features of HFpEF, the direct mechanistic link between altered cardiac metabolism and mitochondrial impairment remains elusive. Here, we investigated how cardiac metabolic remodeling drives mitochondrial impairment, leading to diastolic dysfunction in HFpEF, independent of extracardiac metabolic syndrome. Infusion of angiotensin-II (1.5 μg/g/day) and phenylephrine (50 μg/g/day) in 8-10-week-old male and female mice reproduced hallmark HFpEF features, including preserved EF, elevated E/E' ratio, reduced physical endurance, and impaired lung function. Cardiac mitochondria showed markedly reduced respiration, diminished complex II abundance, and impaired mitochondrial supercomplexes, accompanied by a ~20% reduction in mitochondrial calcium retention capacity and increased susceptibility to opening of the mitochondrial permeability transition pore (mPTP). Metabolomic analysis suggests a shift in mitochondrial metabolism from fatty acid (FA) to the utilization of alternative glucose substrates, characterized by reduced mitochondrial FA trafficking despite increased FA translocase. Dicarbonyl and glycative stress were substantially elevated, with mitochondrial protein glycation increased by 7-fold. Mass spectrometry identified 18 mitochondrial proteins present in a significantly glycated form, with potential implications for impairing metabolic flexibility, reducing electron transport efficiency, and promoting susceptibility to mPTP opening. Our findings demonstrate that metabolic remodeling contributes to dicarbonyl and glycative stress, which in turn compromises the integrity of mitochondrial electron transport complexes, respiratory function, and calcium retention capacity in the HFpEF heart, highlighting mitochondrial dicarbonyl detoxification and anti-glycation strategies as promising therapeutic avenues.
    Keywords:  Heart failure with preserved ejection fraction; metabolic remodeling; mitochondrial health; mitochondrial respiration
    DOI:  https://doi.org/10.1152/ajpheart.00029.2026
  39. Nat Commun. 2026 Apr 20. pii: 3570. [Epub ahead of print]17(1):
    Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids.
    Carmen Menacho, Satoshi Okawa, Iris Álvarez-Merz, Annika Wittich, Mikel Muñoz-Oreja, Pawel Lisowski, Mario López Martín, Tancredi Massimo Pentimalli, Shiri Zakin, Mathuravani Thevandavakkam, Caleb Jerred, Selene Lickfett, Laura Petersilie, Agnieszka Rybak-Wolf, Annette Seibt, Diran Herebian, Gizem Inak, Susanne Brodesser, Andrea Zaliani, Barbara Mlody, Justin Donnelly, Kasey Woleben, Francesc Xavier Soriano, Jose C Fernandez-Checa, Natascia Ventura, Sidney Cambridge, Ertan Mayatepek, Antonella Spinazzola, Markus Schuelke, Nikolaus Rajewsky, Andrea Rossi, Alex Peralvarez-Marin, Felix Distelmaier, Ethan Perlstein, Ian J Holt, Emma Puighermanal, Ole Pless, Christine R Rose, Antonio Del Sol, Alessandro Prigione.
      Leigh syndrome (Leigh) is an untreatable mitochondrial disorder characterized by lactic acidosis and basal ganglia and midbrain pathology, leading to psychomotor regression and early death. We previously uncovered impaired neuronal morphogenesis in Leigh cerebral organoids carrying SURF1 gene variants. Leveraging this phenotype, we here develop a deep learning algorithm tailored for cell type-specific drug repurposing screening. In parallel, we perform a survival drug screen in a yeast model of Leigh. The two approaches independently converge on azole compounds, two of which - talarozole and sertaconazole - rescue neuronal morphogenesis in Leigh neurons and lower lactate release and improve growth rate in Leigh midbrain organoids. Mechanistically, these compounds modulate the retinoic acid pathway and membrane-associate lipid metabolism. The findings highlight azoles as promising candidates for Leigh and demonstrate the potential of combining in silico screens with human brain organoids as new approach methodologies (NAMs) to advance the discovery of therapeutics addressing rare neurodevelopmental disorders.
    DOI:  https://doi.org/10.1038/s41467-026-71391-2
  40. Epigenomes. 2026 Apr 04. pii: 25. [Epub ahead of print]10(2):
    Mitochondrial D-Loop Region Methylation Is Not Altered in Children with Autism Spectrum Disorder.
    Andrea Stoccoro, Carmela Serpe, Antonia Parmeggiani, Vincenzo Davide Catania, Mario Lima, Alessandro Ghezzo, Cristina Panisi, Marida Angotti, Beatrice Pranzetti, Provvidenza Maria Abruzzo, Cinzia Zucchini, Lucia Migliore, Marina Marini, Fabio Coppedè.
      Background/Objectives: Although the etiopathogenesis of autism spectrum disorder (ASD) remains incompletely elucidated, current evidence supports a multifactorial model involving genetic and environmental factors that interact to induce a heterogeneous range of symptoms. In recent years, epigenetic mechanisms, particularly DNA methylation, have been recognized as key contributors to ASD pathophysiology. Alterations in mitochondrial DNA (mtDNA) methylation are also emerging as relevant contributors in several human conditions. The mitochondrial D-loop, a non-coding control region essential for mtDNA replication and transcription, is considered a hotspot for epigenetic regulation and its methylation levels have been found altered in various diseases, such as cancer, metabolic disorders, and neurological illness. However, to date, no studies have investigated mtDNA methylation changes in ASD. Methods: We analyzed the average methylation levels of a fragment containing ten CpG sites within the D-loop region and the mtDNA copy number in peripheral blood samples from 49 children with ASD and 50 neurotypically developing (NT) controls using Methylation-Sensitive High-Resolution Melting and quantitative PCR. Results: No significant differences in D-loop methylation levels were observed between ASD and NT children. Similarly, the mtDNA copy number did not differ between the two groups. No significant correlations were found between D-loop methylation or mtDNA copy number and either ASD severity or age. Conclusions: This is the first study investigating mtDNA methylation in ASD. Our results indicate that methylation of the D-loop region and the mtDNA copy number are not altered in ASD children. Further studies including larger cohorts and extended mtDNA regions are warranted to confirm and expand these findings.
    Keywords:  D-loop region; autism spectrum disorder; epigenetics; mitochondrial DNA copy number; mitochondrial DNA methylation
    DOI:  https://doi.org/10.3390/epigenomes10020025
  41. Genetics. 2026 Apr 24. pii: iyag106. [Epub ahead of print]
    The yeast mitochondrial Porin represses Snf1/AMP Kinase signaling to attenuate viral replication.
    Sabrina Chau, Serena Marek, Aayushee Khanna, Janhavi Sathe, Sunil Laxman, Marc D Meneghini.
      Although fungi are broadly infected with mycoviruses, the antiviral mechanisms fungal cells use to oppose viral replication are not well understood. Here we discover a new mitochondrially controlled signaling mechanism in the budding yeast Saccharomyces cerevisiae that limits replication of L-A, an RNA mycovirus that endemically infects this organism. We show that Por1, the mitochondrial voltage dependent anion channel, prevents hyper-replication of L-A in stationary phase cells that have exhausted media nutrients. By investigating known stationary phase regulators, we find that deletion of the AMP-activated Kinase homolog SNF1 reverses hyper-replication of L-A observed in por1Δ cells. This epistatic relationship suggests that Por1 negatively regulates Snf1 in stationary phase cells and derepressed Snf1 promotes L-A hyper-replication. We confirm this model, first demonstrating that POR1 prevents the accumulation of activated Snf1 throughout stationary phase. By investigating Snf1 signaling targets we show that this POR1-SNF1 regulatory mechanism acts in stationary phase cells to limit amino acid availability that sustain L-A replication. POR1-SNF1 signaling represents a novel physiological control mechanism to limit viral replication in a eukaryotic cell.
    Keywords:  Glyoxylate cycle; RNA virus; Snf1/AMP Kinase; Yeast; mitochondrial voltage dependent anion channel
    DOI:  https://doi.org/10.1093/genetics/iyag106
  42. Am J Med Genet A. 2026 Apr 19.
    De Novo Variants Associated With Autosomal Recessive Conditions: Case Series and Implications for Genetic Testing and Counseling.
    Annie D Niehaus, Devon E Bonner, Jennefer Carter, Kayleigh Avello, Natalie Jacob, Matthew B Neu, Rodrigo Mendez, Wanqiong Qiao, Stuart A Scott, Rebecca J Levy, Lauren Mattas, Jennifer Schymick, Michael Van Andel, Francesco Muntoni, Juliane Mueller, Anna Sarkozy, Stephanie DiTroia, Melanie O'Leary, Ashana Neale, Anne O'Donnell-Luria, Camilo Toro, Lynne A Wolfe, Julian A Martinez-Agosto, Stephen B Montgomery, Matthew T Wheeler, Jonathan A Bernstein, Christina G Tise.
      The vast majority of individuals with autosomal recessive (AR) conditions demonstrate biparental inheritance of the disease-causing alleles; however, de novo variants also contribute to AR disease. This report represents the largest cohort to-date of rare AR conditions in which one of the disease-causing alleles was inherited and one occurred de novo. Clinical and research staff at Stanford University, clinical sites of the Undiagnosed Diseases Network (UDN) and Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium, and a large clinical genetic testing laboratory were contacted to identify cases of an AR diagnosis resulting from an inherited and de novo disease-causing variant in trans. Fifteen cases of AR conditions caused by one inherited and one de novo variant in a gene consistent with the clinical phenotype were identified; all had undergone trio exome or genome sequencing with genetic confirmation of reported relationships. Variants were confirmed to be in trans in eight of the 15 cases. The de novo variant was confirmed (n = 7) or presumed (n = 7) to have arisen on the paternal allele in 14/15 (93%) of cases. Phenotypic and/or molecular evidence of an AR condition should prompt parental segregation analysis to inform diagnosis, recurrence risks, and variant classification. Additional studies are needed to determine the incidence of this phenomenon given the implications for the interpretation of genetic testing and counseling for AR conditions.
    Keywords:  autosomal recessive; de novo; recurrence risk counseling; variant classification
    DOI:  https://doi.org/10.1002/ajmg.a.70162
  43. Nat Commun. 2026 Apr 20.
    Multi-omic mapping of Drosophila protein secretomes reveals tissue-specific origins and inter-organ trafficking.
    Justin A Bosch, Pierre Michel Jean Beltran, Cooper Cavers, James Thai LaGraff, Randy Melanson, Ankita Singh, Weihang Chen, Yanhui Hu, Sudhir Gopal Tattikota, Ying Liu, Yousuf Hashmi, John M Asara, Tess Branon, Alice Y Ting, Steven A Carr, Norbert Perrimon.
      Secreted proteins regulate many aspects of animal biology and are attractive targets for biomarkers and therapeutics. However, comprehensively identifying the "secretome", along with their tissues of origin, remains extremely challenging. To address this, we employed multiple 'omics methods to define a tissue-secretome map of 535 blood plasma proteins derived from specific cell-types and organs in Drosophila melanogaster. This map was enabled by methodological improvements including a collection of transgenic flies to label endogenous secreted proteins in 10 major tissue types, large-scale blood isolation, whole animal snRNA-seq, and 40 CRISPR knock-in strains. Using this map, we identify features of circulating proteins: most originate from specific tissues including unusual sources (e.g. glia), many are uncharacterized, and some are shed ectodomains of transmembrane proteins. In addition, in vivo experiments revealed circulating proteins with tissue-specific expression, as well as proteins that are deposited in a different tissue from where they are synthesized, suggesting potential inter-organ functions. Our secretome map will serve as a resource to investigate blood protein function, discover candidate tissue-tissue communication signals, and mine for homologues of human biomarkers.
    DOI:  https://doi.org/10.1038/s41467-026-71763-8
  44. Nat Cardiovasc Res. 2026 Apr;5(4): 328-350
    PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy.
    Yao Wei Lu, Zhuomin Liang, Kerry Dorr, Samantha Ruiz, Xiaoran Huang, Denise Fangnibo Hanvi, Sheri M Juntilla, Gisela Beutner, Shuhan Lyu, Haipeng Guo, Tiago Fernandes, Ramon A Espinoza-Lewis, Tingting Wang, Kathryn Li, Xue Li, Gurinder Bir Singh, Yi Wang, Rui Deng, Douglas Cowan, John D Mably, William T Pu, Jessie Huang, George A Porter, Frank Conlon, Hong Chen, Da-Zhi Wang.
      Mutations in the AARS2 gene are linked to infantile cardiomyopathy; however, the underlying molecular mechanism remains unknown. Here we report that PCBP1, a poly(rC) binding protein, interacts with the AARS2 transcript to mediate its alternative splicing. Cardiomyocyte-specific deletion of Pcbp1 in mice impairs normal splicing and causes premature termination of Aars2, leading to defects in heart development and postnatal lethality. Similarly, mice with a deletion in Aars2 that mimics a disease-causing splicing lesion display heart developmental abnormalities, reminiscent of those in patients with infantile mitochondrial cardiomyopathy. Mechanistically, loss of Pcbp1 or Aars2 in the heart reduces oxidative phosphorylation, a hallmark of patients with AARS2 mutations. This reduction in mitochondrial-encoded proteome activates mitonuclear communication and the unfolded protein response pathway, thereby inducing a compensatory nuclear-encoded mitochondrial gene program. Our findings provide insights into the PCBP1-AARS2 regulatory axis in mitochondrial cardiomyopathy.
    DOI:  https://doi.org/10.1038/s44161-026-00798-3
  45. Small Sci. 2026 Mar;6(3): e202500598
    A Nanotube Injector for Cytoplasmic Transfer and Enhanced Mitochondrial Function.
    Bingfu Liu, Zhuhang Dai, Bowen Zhang, Kazuhiro Oyama, Chenxi Li, Yukun Chen, Mingyin Cui, Takeo Miyake.
      The intercellular transportation of molecules is crucial for regulating cell communication and function. However, the existing techniques for molecule transfer across cell barriers often cause cellular damage or have low transfer efficiencies. To address these limitations, this study proposes an innovative nanotube membrane-based injector (nanoinjector) system capable of extracting diverse cytoplasmic molecules from source cells and transferring them to target cells. The developed system demonstrates high efficiency, with over 95% viability and 90% transfer efficiency. Additionally, it enables mitochondrial transfer, which enhances cellular adenosine triphosphate (ATP) production by up to 25% within 24 h. This study explores the impact of intracellular content transport, enabled by this new tool, on cellular activities, with promising implications for cell surgery and therapy.
    Keywords:  adenosine triphosphate synthesis; mitochondria transfer; molecular delivery; nanotubes membrane
    DOI:  https://doi.org/10.1002/smsc.202500598
  46. J Biol Chem. 2026 Apr 17. pii: S0021-9258(26)00345-5. [Epub ahead of print] 111473
    Deletion of Mitochondrial Calcium Uniporter Enhances Calcium Signals by Slowing Calcium Clearance and Triggers Adaptive Transcriptomic Remodeling.
    Rajesh Bhardwaj, Abdull J Massri, Gary S Bird, Anant B Parekh.
      Mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) following store-operated Ca2+ entry (SOCE) supports cellular bioenergetics, yet how mitochondria shape SOCE and cytosolic Ca2+ signaling remains incompletely understood. Combining gene deletion and functional Ca2+ imaging techniques with a rigorous transcriptomic filter, we find larger cytosolic Ca2+ signals in CRISPR/Cas9-generated Mcu knockout cells. This increase arises primarily from slower cytosolic Ca2+ clearance rather than increased store-operated Ca2+ release-activated Ca2+ (CRAC) channel activity. Compensatory upregulation of cytosolic Ca2+ regulators, such as the plasma membrane Ca2+ ATPase (PMCA) pump that extrudes excess cytosolic Ca2+, is insufficient to restore normal Ca2+ homeostasis. Re-expression of wild-type MCU restored the cytosolic Ca2+ dynamics but a channel pore-dead MCU mutant did not. Deletion of Mcu resulted in major alterations in the transcriptome and re-expression of the protein significantly restored 15% of more than 200 common genes that showed differential expression in two independent knockout clones. Our results identify a set of candidate MCU-dependent genes that may contribute to the regulation of cellular Ca2+ signaling, and show how cytosolic Ca2+ signals can be enhanced in the absence of MCU without an increase in CRAC channel activity.
    Keywords:  Ca(2+) release-activated Ca(2+) (CRAC) channel; Calcium homeostasis; Cytosolic calcium clearance; Mitochondrial calcium uniporter (MCU); Plasma membrane Ca(2+) ATPase (PMCA); Store-operated calcium entry (SOCE); Transcriptomics
    DOI:  https://doi.org/10.1016/j.jbc.2026.111473
  47. Free Radic Biol Med. 2026 Apr 21. pii: S0891-5849(26)00431-4. [Epub ahead of print]
    Mitochondrial Sulfide Oxidation and Persulfidation in Mesenchymal Stromal Cell Osteogenesis: Redox Flux Control as a Unifying Framework.
    Davide Ciaramellano, Luigi Brunetti, Bruna Sinjari, Giovanna Murmura, Elisabetta Ferrara.
      Hydrogen sulfide (H2S) regulates mitochondrial metabolism and thiol-dependent redox signaling. Central to its biological activity is mitochondrial sulfide oxidation, initiated by sulfide:quinone oxidoreductase (SQOR), which couples H2S catabolism to electron transport and persulfide generation. While sulfide signaling has been extensively characterized in stress adaptation and metabolic regulation, its integration with stem-cell fate decisions remains incompletely defined. Osteogenic differentiation of mesenchymal stromal cells (MSCs) requires coordinated mitochondrial remodeling, tightly constrained reactive oxygen species (ROS) signaling, and redox-sensitive transcriptional control, including RUNX2 stability. Emerging evidence indicates that H2S modulates these processes through persulfidation, respiratory modulation, and NRF2-dependent adaptation in a dose- and kinetics-dependent manner. We propose a redox-flux framework in which SQOR-dependent sulfide oxidation functions as a regulatory interface linking mitochondrial bioenergetics, reactive sulfur species signaling, and osteogenic lineage commitment. Translational relevance is discussed in relation to exposure paradigms, including sustained low-dose sulfide models, that may inform experimentally testable hypotheses on redox-adaptive osteogenesis.
    Keywords:  Hydrogen sulfide; Mesenchymal stromal cells; Mitochondrial redox signaling; Osteogenic differentiation; Protein persulfidation; Reactive sulfur species; Sulfide:quinone oxidoreductase (SQOR)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.141
  48. Am J Pathol. 2026 Apr 18. pii: S0002-9440(26)00101-X. [Epub ahead of print]
    SPP1 is reduced in the human retina and optic nerve during glaucoma pathogenesis.
    Alan Nicol, Emma Lardner, Gustav Stålhammar, Sebastian A Lewandowski, James R Tribble, Pete A Williams.
      SPP1 has emerged as an important protein in neurodegenerative disease. In glaucoma, a neurodegenerative disease where retinal ganglion cells degenerate, this is particularly related to its expression in resistant subtypes of retinal ganglion cell. Overexpression of SPP1 provides neuroprotection. However, whether SPP1 expression profiles in the rodent match human glaucoma has yet to be determined and is important in understanding the translational relevance of SPP1 based therapies. We utilize a cohort of highly preserved and well characterized human donor retina to perform antibody labeling and quantification of SPP1 in human retina and optic nerve and compare this to RNA sequencing data. We demonstrate that SPP1 expression is highest in glia cells, but antibody labeling demonstrates its presence throughout the retina. In human glaucoma, SPP1 labelling is reduced in the ganglion cell complex (representing retinal ganglion cell axons, somas, and dendrites) and optic nerve (retinal ganglion cell axons). These data support the relevance of SPP1 as a target for neuroprotection in human glaucoma.
    Keywords:  Osteopontin; collagen; glaucoma; histopathology; single cell RNA-sequencing
    DOI:  https://doi.org/10.1016/j.ajpath.2026.03.013
  49. Neuroprotection. 2026 Mar;4(1): 14-29
    Re-conceptualizing Parkinson's disease as a lifelong neurobiological trajectory: A framework for prevention.
    Ayodeji Johnson Ajibare, Abraham Olufemi Asuku, Olabode Oluwadare Akintoye.
      Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder. No disease-modifying therapies exist. This review proposes that PD susceptibility begins with epigenetic changes and neuroimmune activity-factors that alter gene expression and immune responses-during the vulnerable PD lifespan. Human evidence is mostly indirect or contradictory. We present this as a testable trajectory, drawing on diverse epidemiologic, experimental, and mechanistic evidence to identify intervention opportunities. We adopt a life-course perspective focused on the brain's plasticity. We focus on critical developmental periods that increase PD vulnerability by rendering dopaminergic neurons more susceptible to damage. Specifically, we examine two key mechanisms: the induction of a pro-inflammatory epigenetic state and mitochondrial dysfunction, frequently triggered by early-life stress, malnutrition, or neurotoxicant exposure. We discuss how these mechanisms can be studied across epidemiologic, experimental, and mechanistic research. Integrated evidence suggests that early adverse exposures may set the stage for higher PD susceptibility. This occurs through epigenetic, neuroimmune programming, and mitochondrial vulnerabilities in dopaminergic systems. In contrast, endogenous neuroplasticity promotes neuroprotection. Long-term physical activity, cognitive training, and enriched environments build strong neurobiological reserves by enhancing neurogenesis, improving synaptic function, and reducing neuroinflammation. A life course perspective shows how factors interact over time to shape neurobiological pathways of vulnerability or resilience to PD. This review synthesizes current mechanistic understanding, identifies preventive strategies, and aims to apply this knowledge to clinical practice and public health policies to reduce the global burden of PD.
    Keywords:  Parkinson's disease; epigenesis; genetic; neuroimmunomodulation; neuronal plasticity; risk factors
    DOI:  https://doi.org/10.1002/nep3.70030
  50. Genes Cells. 2026 May;31(3): e70114
    Gene Expression Profiles Reveal Altered Metabolic Signaling Pathway in Skeletal Muscle With Lipid Sensor Gpr120/Ffar4 Deficiency.
    Junfeng Shi, Taito Nakayama, Keiko Iida, Ryohei Shirai, Kenya Ueno, Ayako Hirata, Takeo Awaji, Kei Maruyama, Yuuki Kawamura, Yoshinori Takei, Akira Hirasawa.
      Obesity is driven by a chronic imbalance between energy intake and energy expenditure (EE), and reduced EE has been implicated in its development. We previously demonstrated that deficiency of Gpr120/Ffar4, a lipid sensor, led to decreased EE. Since skeletal muscle is a major contributor to EE, we investigated whether Gpr120 is involved in skeletal muscle energy metabolism. We generated gene expression profiles of skeletal muscle in WT mice and Gpr120-deficient (KO) mice under a normal diet (ND) and a high fat diet (HFD) using microarray analysis and found that Gpr120 was associated with mitochondrial gene expression in response to HFD. We also discovered that the enrichment patterns of Gene Ontology (GO) terms in skeletal muscle of Gpr120-deficient mice were common to those of genetically modified mouse models associated with Ampk, Pgc1α, and Errγ, suggesting that these signaling factors may be involved in Gpr120-mediated signaling. Moreover, analyses including ChIP-seq of Errγ, morphological evaluation of mitochondria by electron microscopy, and measurements of mtDNA content and muscle strength demonstrated that Gpr120 was involved in regulating mitochondrial structure, gene expression, and skeletal muscle function. Together, our findings suggest that Gpr120 regulates mitochondrial homeostasis and function in skeletal muscle, possibly through signaling from distant organs.
    DOI:  https://doi.org/10.1111/gtc.70114
  51. iScience. 2026 Apr 17. 29(4): 115446
    C2CD5 in noradrenergic neurons regulates thermogenesis and lipid homeostasis via norepinephrine secretion.
    Chaitanya K Gavini, Gwenaël Labouèbe, François Gorostidi, Virginie Mansuy-Aubert.
      Thermogenesis and lipid utilization are important components of energy expenditure; they are regulated within a complex network of behavioral, hormonal, and molecular pathways that collectively maintain energy balance. Norepinephrine (NE) released by sympathetic neurons plays a critical role in modulating these processes. Here, we identify the trafficking protein C2CD5 as a key regulator of NE secretion and thermogenic function. C2CD5 is expressed in dopamine β-hydroxylase (DBH)-positive sympathetic neurons, and its expression is suppressed by obesogenic diets. Using conditional knockout mice lacking C2CD5 in DBH+ neurons, we show that loss of C2CD5 reduces NE secretion, impairs thermogenesis, lowers energy expenditure, and promotes adiposity. These effects are mitigated by NE supplementation. Our findings reveal a functional role for C2CD5 in linking sympathetic tone to systemic metabolic regulation and suggest it may represent a targetable node for metabolic disorders.
    Keywords:  Molecular biology; Neuroscience; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2026.115446
  52. Eur J Hum Genet. 2026 Apr 21.
    Revisiting LSDMCA: male lethality escape and genotype-phenotype correlations.
    Alfonso Manuel D'Alessio, Alessia Indrieri, Giuseppina Vitiello, Manuela Morleo, Susan Schelley, Gregory M Enns, Chiara Passarelli, Roberta Tammaro, Valeria Tiranti, Camille Peron, Wallid Deb, Antonio Novelli, Bertrand Isidor, Achille Iolascon, Brunella Franco.
      Mitochondrial disorders (MDs) are a diverse group of genetic conditions primarily affecting the oxidative phosphorylation (OXPHOS) system and cellular energy production. Among MDs, Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA), or Microphthalmia with Linear Skin Lesions (MLS) syndrome, is a rare X-linked dominant male-lethal disorder characterized by ocular malformations, linear skin defects, and multisystem developmental anomalies. These features are associated with pathogenic variants in genes related to mitochondrial function, including HCCS, COX7B, and NDUFB11 or chromosomal rearrangements of the Xp22 region encompassing HCCS. Despite progress, genotype-phenotype correlations remain insufficiently defined. In this study, we report three novel mutations in three patients with LSDMCA, broadening the phenotypic spectrum of the disorder. Whole exome sequencing revealed pathogenic missense variants in HCCS [NM_005333.5: c.625 G > C; p.(Asp209His)] and COX7B [NM_001866.3: c.221 C > T; p.(Pro74Leu)] in two unrelated patients. Functional studies confirmed that the COX7B variant impairs mitochondrial respiratory chain (MRC) function. A third patient harbored a novel frameshift pathogenic variant in NDUFB11 [NM_001135998.3: c.145_152dup; p.(Thr52Glnfs*66)], further implicating mitochondrial dysfunction in LSDMCA pathogenesis. Notably, the COX7B variant was identified in a biological male (46, XY) without X-chromosome structural rearrangements, marking the first such reported case of LSDMCA. Our data suggest that certain missense variants, resulting in mild impairment of the gene product, may allow male survival, thereby expanding the known phenotype of this rare disorder. This report advances our understanding of genotype-phenotype correlations in LSDMCA and highlights the impact of mitochondrial dysfunction during embryonic development.
    DOI:  https://doi.org/10.1038/s41431-026-02098-7
  53. Free Radic Biol Med. 2026 Apr 22. pii: S0891-5849(26)00445-4. [Epub ahead of print]
    MITOCHONDRIAL METABOLISM AS A DETERMINANT OF HETEROGENEOUS PLATELET FUNCTIONAL PHENOTYPES: IMPLICATIONS FOR ANTIPLATELET RESISTANCE.
    Camila Velandia Franco, Ramiro Araya-Maturana, Eduardo Fuentes.
      Platelets are increasingly recognized as a heterogeneous circulating cell population whose functional behavior cannot be fully explained by receptor-agonist signaling alone; instead, their bioenergetic state emerges as a molecular determinant that shapes both physiological hemostasis and disease-associated hyperreactivity. This review synthesizes evidence supporting energetic specialization in platelets, where glycolytic ATP predominantly supports rapid responses such as shape changes and aggregation; mitochondrial oxidative phosphorylation (OXPHOS) instead is critical for high-demand functions, particularly sustained granule secretion and thrombus amplification. Building on this framework, we propose that mitochondria act as a molecular "switch" that sets the threshold between an aggregatory phenotype and procoagulant fate, for which mitochondrial membrane potential (ΔΨm) instability and sustained opening of the mitochondrial permeability transition pore (mPTP) drive commitment to a procoagulant crisis. Mitochondrial quality-control pathways, including fission/fusion dynamics and mitophagy, emerge as a key regulator that preserve this threshold; their impairment increases susceptibility to stress and predisposes platelets to pathological activation. In cardiometabolic disorders (e.g., type 2 diabetes and obesity), mitochondrial remodeling, oxidative stress, and a shift toward a more glycolytic profile are associated with intrinsically heightened reactivity and pharmacodynamic failure manifesting as high on-treatment platelet reactivity (HTPR), underscoring the need for functional stratification. Collectively, these findings support a bioenergetically informed framework in which mitochondrial function defines platelet functional heterogeneity and contributes to thrombotic risk. Integrating platelet mitochondrial biology into translational research may enable improved risk stratification and the development of precision antithrombotic strategies that preserve essential hemostatic function.
    Keywords:  antiplatelet; metabolism; mitochondria; phenotypes; platelet
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.145
  54. Aging Cell. 2026 May;25(5): e70519
    Histone Deacetylase 9 Gene Deletion Ameliorates Aging-Related Adipose Tissue Senescence and Mitochondrial Dysfunction in Mice.
    Brandee Goo, Samah Ahmadieh, Praneet Veerapaneni, Hong Shi, David S Kim, Mourad Ogbi, Ronnie Chouhaita, Nicole Cyriac, Stephen Cave, Lingling Liu, Yong Zhang, Quansheng Du, Ha Won Kim, Yun Lei, Xin-Yun Lu, Neal L Weintraub.
      Cellular senescence and mitochondrial dysfunction are prevalent in adipose tissues and disrupt metabolic homeostasis during aging, but the mechanisms are poorly understood. Here, we investigated the role of histone deacetylase 9 (HDAC9), an epigenetic regulator of adipogenic differentiation, in aging-related adipose tissue senescence and mitochondrial dysfunction. HDAC9 expression correlated positively with age in mouse adipose tissues. Compared to age-matched wild-type (WT) mice, Hdac9 knockout (KO) mice gained less weight and had reduced fat mass during aging, in conjunction with reduced senescence-associated beta-galactosidase (SABG) staining and expression of senescence markers in adipose tissues. Additionally, preadipocytes isolated from Hdac9 KO mice exhibited reduced baseline and stress-induced senescence compared to WT mice. Mechanistically, HDAC9 gene deletion resulted in coordinated upregulation of mitochondria-associated genes, in association with increased mitochondrial DNA content and adipose tissue mitochondrial oxygen consumption parameters (e.g., increased basal respiration, proton leak). Furthermore, thiosulfate sulfurtransferase (TST), whose downregulation is associated with mitochondrial dysfunction, was reduced in adipose tissues of aging mice and upregulated by HDAC9 gene deletion. Finally, silencing TST in preadipocytes upregulated expression of senescence markers and increased SABG staining. We conclude that deletion of HDAC9 ameliorates the development of adipose tissue senescence and mitochondrial dysfunction with aging, at least in part via upregulation of TST, suggesting that targeting HDAC9 may be a promising strategy to maintain healthy adipose tissue during aging.
    Keywords:  HDAC9; adipose tissue; mitochondria; senescence; thiosulfate sulfurtransferase
    DOI:  https://doi.org/10.1111/acel.70519
  55. Redox Biol. 2026 Apr 19. pii: S2213-2317(26)00176-X. [Epub ahead of print]93 104178
    m6A epitranscriptomic remodeling links redox stress to mitochondrial quality control and programmed cell death in sepsis-induced myocardial dysfunction.
    Meilian Chen, Binlan Fu, Qiaomin Wu.
      Sepsis-induced myocardial dysfunction (SIMD) is a major contributor to sepsis-related mortality and is characterized by excessive oxidative stress, mitochondrial dysfunction, and heterogeneous forms of programmed cell death. However, how cardiomyocytes interpret redox stress and commit to distinct death pathways remains incompletely understood. Increasing evidence suggests that N6-methyladenosine (m6A), the most abundant internal RNA modification, functions as a dynamic post-transcriptional regulator linking redox signaling to mitochondrial homeostasis and cell fate decisions. This review summarizes recent advances indicating that m6A-dependent regulatory networks integrate mitochondrial reactive oxygen species (mtROS), mitochondrial quality control (MQC), and downstream cell death pathways in SIMD. Under septic conditions, sustained inflammation and oxidative stress perturb the balance of m6A writers, erasers, and readers, leading to maladaptive remodeling of mitochondrial dynamics, mitophagy, and biogenesis. Such epitranscriptomic dysregulation is associated with mtROS accumulation, impaired mitochondrial renewal, and a shift from adaptive redox compensation toward irreversible cardiomyocyte injury. Importantly, emerging evidence suggests that m6A remodeling does not uniformly activate cell death but modulates redox signal processing in a context-dependent manner. Preferential amplification of inflammatory sensing and inflammasome signaling may bias mtROS toward pyroptotic execution, whereas compromised antioxidant capacity, iron handling, and lipid metabolism may increase vulnerability to ferroptosis. On this basis, we propose the m6A-ROS-MQC axis as a unifying, hypothesis-driven framework for understanding SIMD pathogenesis, in which m6A acts as a redox-responsive epitranscriptomic regulator coordinating mitochondrial adaptation and programmed cell death decisions.
    Keywords:  Ferroptosis; Mitochondria; Oxidative stress; Pyroptosis; Sepsis; m6A
    DOI:  https://doi.org/10.1016/j.redox.2026.104178
  56. Cell Metab. 2026 Apr 22. pii: S1550-4131(26)00148-8. [Epub ahead of print]
    Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
    Ignacio Heras-Murillo, Diego Mañanes, Josep Calafell-Segura, Adrián Belinchón García, Clara Borràs-Eroles, Pablo Munné, Annalaura Mastrangelo, Sarai Martínez-Cano, Pablo Hernansanz-Agustín, María A Zuriaga, José J Fuster, Marten Szibor, Ignacio Melero, José Antonio Enríquez, Navdeep S Chandel, Esteban Ballestar, Stefanie K Wculek, David Sancho.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.010
  57. Exp Eye Res. 2026 Apr 20. pii: S0014-4835(26)00189-2. [Epub ahead of print]268 111033
    Amino acid metabolism in retinal diseases: Mechanisms, diagnostics, and therapeutic opportunities.
    Xiongyi Yang, Jiao Xia, Ya Zhao, Qian Liu, Xueyun Fu, Biao Yan.
      Amino acid metabolism serves as a central hub linking retinal energy supply, neurotransmission, and cell signaling, which is critical for maintaining retinal structure and function. This review summarizes the molecular mechanisms by which abnormal amino acid metabolism contributes to retinal diseases. The major mechanisms include: 1) excitotoxicity caused by disruption of glutamate-glutamine cycle; 2) mitochondrial oxidative stress and epigenetic changes due to accumulation of branched-chain and sulfur-containing amino acids; 3) remodeling of immune microenvironment due to altered tryptophan and arginine metabolism; 4) neurotoxic lipid production and signaling imbalance resulting from serine and glycine deficiency. Clinically, we highlight the emerging roles of intraocular fluid metabolomics-based liquid biopsy and artificial intelligence-assisted multimodal imaging in early diagnosis and molecular classification. We further summarize emerging treatment approaches, including metabolic substrate supplementation, interventions targeting key enzymes and transporters, and development of responsive nanodelivery systems. Overall, restoration of amino acid metabolic homeostasis represents a promising strategy for the prevention and treatment of retinal diseases.
    Keywords:  Amino acid metabolism; Immune microenvironment; Retinal disease
    DOI:  https://doi.org/10.1016/j.exer.2026.111033
  58. Mol Genet Genomics. 2026 Apr 24. pii: 99. [Epub ahead of print]301(1):
    Targeting WWP1 ameliorates osteoarthritis by suppressing KLF15 ubiquitination to restore mtDNA and mitochondrial function.
    Zhiling Li, Wanli Lan, Yong Luo, Ping Liu, Xinyi Li, Hongxing Li.
      
    Keywords:  KLF15; Mitochondrial DNA; Osteoarthritis; TFAM; WWP1
    DOI:  https://doi.org/10.1007/s00438-026-02417-z
  59. Cell Metab. 2026 Apr 21. pii: S1550-4131(26)00108-7. [Epub ahead of print]
    A generative AI framework unifies human multi-omics to model aging, metabolic health, and intervention response.
    Jiawei Chen, Ya Ren, Yong Zhou, Ziyang Wang, Kehang Mao, Zhengqing Yu, Jiyang Li, Xiaoxiao Guo, Hao Xu, Yiyang Wang, Yi Wang, Bo Pang, Hongxiao Liu, Huiru Tang, Jing-Dong J Han.
      Understanding aging and complex diseases requires diverse data, ranging from molecular profiles to imaging and routine clinical tests. However, most multi-omic datasets measure only a subset of modalities and are confounded by batch effects. Here, we present AURORA (AI unification and reconstruction of omics reassembly atlas), a generative deep-learning platform that integrates seven modalities (including transcriptomics, metabolomics, microbiome, 3D and thermal facial imaging, and clinical laboratory tests) across 581,763 samples from 425,258 individuals. AURORA harmonizes batch effects and reconstructs missing data across modalities, enabling highly accurate multimodal aging clocks and disease risk predictors. It also supports personalized in silico perturbation analyses to predict intervention and drug responses, validated using longitudinal cohorts. As a proof of concept, we provide a prototype AI agent that converts single-input modalities into a multimodal report for users and researchers. Together, AURORA links non-invasive inputs to comprehensive aging biomarkers and therapeutic discovery.
    Keywords:  aging clocks; biological aging; digital twin; disease risk prediction; drug repurposing; facial imaging; generative AI; in silico perturbation; multi-omics integration; personalized medicine
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.014
  60. Biomaterials. 2026 Apr 15. pii: S0142-9612(26)00235-8. [Epub ahead of print]333 124211
    Selective induction of mitochondrial fragmentation for cancer immunotherapy via mtDNA-Targeting AIE photosensitizer.
    Wen-Jin Wang, Ying-Xin Hao, Yu-Meng Wang, Zhuo-Yang Xin, Man Zhang, Hao-Tian Xin, Jing Feng, Kang Li, Zheng Zhao, Ben Zhong Tang, Kang-Nan Wang.
      Mitochondrial damage in tumor cells has recently emerged as a mechanism of immunogenic cell death, with precise triggers acting as potent antitumor immunostimulants. Here, we developed PyTPAMa, an asymmetric AIE-active photosensitizer that selectively accumulates in mitochondria and binds mitochondrial DNA (mtDNA) and induces mitochondrial fragmentation to trigger strong immunostimulation. Upon light activation, PyTPAMa generates a spatially confined, hybrid Type I/II ROS burst that disrupts the mitochondrial network, causing mitochondrial fragmentation, opening the mitochondrial permeability transition pore, and releasing mtDNA into the cytosol. This activates the NLRP3-GSDMD inflammasome, initiating pyroptosis and orchestrating systemic antitumor immunity. RNA sequencing reveals widespread silencing of mitochondrial genes and reprogramming of the NLRP3 inflammasome and antigen-presentation pathways. As a programmable immune ignition switch, PyTPAMa induces immunogenic cell death in vitro, transforms distant "cold" tumors into immune-infiltrated lesions in vivo, and achieves 96% suppression of bilateral 4T1 tumors without systemic toxicity. This work establishes mitochondrial fragmentation as a programmable immune switch and validates PyTPAMa for fragmentation-driven cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Immunogenic cell death (ICD); Mitochondrial fragmentation; Pyroptosis; mtDNA leakage
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124211
  61. Nat Commun. 2026 Apr 22.
    Transplantation of active mitochondria condensed in liquid-liquid phase-separated hydrogels ameliorates myocardial ischemia-reperfusion injury.
    Jiacong Ai, Yingxian Xiao, Qishan Li, Yafang Xiao, Weirun Li, Junyao Deng, Weichao Ding, Rui Zhang, Shushan Mo, Yan Zeng, Xuelin Fan, Xueyi Wang, Zhenhua Li.
      Mitochondrial dysfunction is a major contributor to myocardial ischemia-reperfusion injury, and limits cardiac recovery after blood flow is restored. Although mitochondria transplantation may help restore cellular energy metabolism, its therapeutic benefit is reduced by extracellular calcium-induced mitochondrial damage. Here we show that a thermosensitive phase-separated hydrogel made of gelatin and PEG can condense, protect and deliver freshly isolated mitochondria. Compared with conventional single-phase hydrogels, this system remains injectable at physiological temperature and enables rapid mitochondria release after transplantation. Furthermore, the phase-separated structure improves mitochondrial packing and preserves activity through spatial confinement and calcium chelation by gelatin. In vitro, condensed mitochondria show improved membrane potential and ATP production. In vivo, transplanted mitochondria are efficiently internalized by cardiomyocytes, improving cardiac function and reducing tissue injury after myocardial ischemia-reperfusion. These findings identify phase-separated hydrogels as a promising platform for mitochondria transplantation.
    DOI:  https://doi.org/10.1038/s41467-026-71765-6
  62. Nature. 2026 Apr;652(8112): 1135-1137
    A cell-death protein has an unexpected role in intestinal repair.
    Ayijiang Yisimayi, Judy Lieberman.
      
    Keywords:  Cell biology; Molecular biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-00810-7
  63. Nature. 2026 Apr 22.
    Ubiquitination of glycogen and metabolites in cells and tissues.
    Marco Jochem, Simon A Cobbold, Craig A Goodman, Catharina Kueng, Anthony Cerra, Laura F Fielden, Man Lyang Kim, Philipp Schenk, Ria Agarwal, Xiangyi S Wang, Simon R Scutts, Michael Pandos, Lin Tang, Thomas Hermanns, Shane M Devine, Martin Brzozowski, Yuri Shibata, Niall D Geoghegan, Catriona A McLean, Bernhard C Lechtenberg, Kay Hofmann, Paul Gregorevic, David Komander.
      Ubiquitin signalling covers a vast realm of protein modifications, yet may still be underestimated due to non-proteinaceous substrates, such as sugars, lipids, and nucleotides1 . The breadth of ubiquitinated non-protein substrates, their abundance, and cellular roles are currently unclear, since current ubiquitinomic and proteomic techniques are blind to non-proteinaceous modifications. We report Non-Protein Ub-clipping (NoPro-clipping) as a mass-spectrometry-based technique that combines ubiquitin clippases with sortase labelling. Targeted and untargeted workflows unveil a vast new canvas of ubiquitin modifications in mammalian cells, and in mouse and human tissues. We find ubiquitinated glycogen in any glycogen-containing tissue in mice, with highest abundance in liver and skeletal muscle. Ubiquitination can deliver glycogen to lysosomes, and leads to reduced glycogen levels. Glycogen ubiquitination is modulated in glycogen storage diseases and regulated by the Met1-polyubiquitin machinery. Strikingly, glycogen depletion in the liver during fasting coincides with elevated glycogen ubiquitination, suggesting that ubiquitin is a previously unknown component of physiological glycogen catabolism. We also reveal ubiquitination of endogenous glycerol and spermine in cells and tissues. NoPro-clipping hence unveils unexpected endogenous non-proteinaceous targets of ubiquitination, broadening the role of ubiquitin from a protein modifier to a general modifier of biomolecules.
    DOI:  https://doi.org/10.1038/s41586-026-10548-x
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