bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–04–05
twenty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Pearling drives mitochondrial DNA nucleoid distribution.
  2. Mitochondrial genomes on a string of pearls.
  3. Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.
  4. Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.
  5. Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.
  6. A splicing factor's unexpected detour to the mitochondrial surface.
  7. Mitochondrial transfer as a therapeutic target for peripheral neuropathy.
  8. Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.
  9. The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.
  10. Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes.
  11. Peripheral frataxin levels govern long-term clinical progression in Friedreich ataxia.
  12. NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.
  13. STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
  14. The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
  15. Structures of folding intermediates on BAM show diverse substrates fold by a conserved mechanism.
  16. Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine.
  17. Overexpression of miR-455-3p enhances mitophagy, synaptic and mitochondrial proteins in Alzheimer's disease.
  18. Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
  19. Mitochondrial IRF3 drives pulmonary fibrosis by impairing mitophagy and triggering ferroptosis.
  20. Mitochondria and the epigenome: maternal co-inheritance and crosstalk from oocyte to embryo.
  1. Science. 2026 Apr 02. 392(6793): 102-109
    Pearling drives mitochondrial DNA nucleoid distribution.
    Juan C Landoni, Matthew D Lycas, Josefa Macuada, Willi Stepp, Roméo Jaccard, Christopher J Obara, Andrew S Moore, David Hoffman, Jennifer Lippincott-Schwartz, Wallace Marshall, Gabriel Sturm, Suliana Manley.
      The distribution of mitochondrial DNA-containing nucleoids is essential for mitochondrial function and genome inheritance; however, no known mechanisms can explain nucleoid segregation or their regular positioning. In this work, we found that mitochondria frequently undergo a reversible biophysical instability termed "pearling," transforming from a tubular into a regularly spaced beads morphology. Physiological pearling imposed a characteristic length scale and simultaneously mediated nucleoid disaggregation and established internucleoid distancing with high precision. Pearling onset was triggered by calcium influx, whereas the density of lamellar cristae invaginations modulated pearling prevalence and preserved nucleoid spacing following recovery. The dysregulation of mitochondrial calcium influx or inner membrane cristae integrity caused aberrant nucleoid clustering. Our results identify pearling as a mechanism governing nucleoid distribution and inheritance and offer insights into its regulation.
    DOI:  https://doi.org/10.1126/science.adu5646
  2. Science. 2026 Apr 02. 392(6793): 26-28
    Mitochondrial genomes on a string of pearls.
    Jelle van den Ameele, Julien Prudent.
      Transient membrane constrictions, or "pearling," underlie the regular spacing of mitochondrial genomes.
    DOI:  https://doi.org/10.1126/science.aeg3426
  3. Brain Commun. 2026 ;8(2): fcag095
    Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.
    Alessandra Torraco, Charlotte L Alston, Giulia Barcia, Daniela Verrigni, Teresa Rizza, Michela Di Nottia, Anastasia Altobelli, Diego Martinelli, Daria Diodato, Stephanie Efthymiou, Melis Kose, Yamna Kriouile, Albert Z Lim, Silvia Morlino, Barbara Siri, Nebal Waill Saadi, Antonio Novelli, Henry Houlden, Carlo Dionisi-Vici, Robert McFarland, Agnès Rötig, Enrico Bertini, Robert W Taylor, Rosalba Carrozzo.
      NDUFAF6 encodes a mitochondrial complex I assembly factor essential for the proper biogenesis and stability of the nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH)-ubiquinone oxidoreductase complex. Pathogenic variants in NDUFAF6 have been increasingly recognized as a cause of mitochondrial disease, particularly Leigh syndrome, a severe neurodegenerative disorder characterized by bilateral symmetrical lesions in the central nervous system. To date, fewer than 50 patients with NDUFAF6-related mitochondrial disease have been reported, displaying a broad phenotypic spectrum ranging from early-onset neurodevelopmental regression to milder, more chronic presentations. The molecular mechanisms underlying these phenotypes are linked to impaired complex I assembly and reduced enzymatic activity, highlighting the critical role of NDUFAF6 in mitochondrial function. Here we present a cohort of 27 patients (14 males and 13 females) from 18 families harbouring biallelic variants in the NDUFAF6 gene. The patient's mean age was 9.15 ± 8.30 years (range: 4 weeks to 25 years); 12 patients (37%) had died by the time the data were collected for this article. The clinical presentation showed wide phenotypic variability, from mild to severe psychomotor regression (74%) most commonly before the age of 5 years, hypotonia (22%), movement disorders (30%), and hypertonia (15%). Bilateral striatal necrosis lesions were the most characteristic features on cranial MRI (67%) although white matter abnormalities were also noted (15%), occasionally accompanied by cystic formations, suggestive of early neurodevelopmental anomalies. Genomic sequencing was applied, leading to the identification of 19 distinct variants in the NDUFAF6 gene, including nine novel variants not previously reported and either absent or extremely rare in public population databases. Functional studies confirmed the pathogenicity of these variants, demonstrating a deleterious effect on NDUFAF6 protein expression and a consequent impairment in complex I assembly and stability. To date, this represents the largest reported cohort of patients with NDUFAF6-associated mitochondrial disease. Our findings provide a comprehensive overview of clinical characteristics-including age of symptom onset, phenotypic variability, and patient outcomes-aiming to improve prognostic information and facilitate genetic counselling in clinical practice.
    Keywords:  Assembly factors; Leigh syndrome; Mitochondrial disease; NADH–ubiquinone oxidoreductase; Respiratory chain complexes
    DOI:  https://doi.org/10.1093/braincomms/fcag095
  4. FEBS Lett. 2026 Mar 30.
    Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.
    Sahitya Ranjan Biswas, Porter L Tomsick, Alicia M Pickrell, Paul D Morton.
      Primary mitochondrial disorders (PMDs) are inherited metabolic diseases that most often present with neurological symptoms in infancy or adolescence, underscoring the central importance of mitochondrial function to brain health. Historically, the field has emphasized neurodegeneration-consistent with the high energetic demands of postmitotic neurons. However, neurodevelopmental manifestations are now recognized as common early phenotypes, frequently preceding clinical regression in many PMDs. Given the pivotal role of mitochondria in neural stem/progenitor cell maintenance and cell fate decisions, defects in the respiratory chain are poised to disrupt neurogenesis and gliogenesis. Evidence for such developmental vulnerabilities is reviewed here. Likewise, because mitochondrial metabolism and dynamics shift across the oligodendrocyte lineage-from oligodendrocyte precursor cell expansion to differentiation and the energetically intensive phase of myelin synthesis-callosal atrophy in mitochondrial leukoencephalopathies may, at least in part, reflect developmental shortcomings in oligodendrogenesis and myelination. This possibility warrants focused investigation in cellular and in vivo models.
    Keywords:  mitochondria; mitochondria disorders; neural stem cells; oligodendrocytes; white matter
    DOI:  https://doi.org/10.1002/1873-3468.70335
  5. Am J Hum Genet. 2026 Mar 30. pii: S0002-9297(26)00113-8. [Epub ahead of print]
    Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.
    Natalie B Tan, Matthias Gautschi, Michael Raum, Daniella H Hock, Robert Kopajtich, Jia Wang, Xiao Qian, Tanavi Sharma, Timothy E Green, Jean-Marc Nuoffer, Katrina M Bell, Katarzyna Pospieszny, Tegan Stait, Chloe Pike, Michelle Cao, Susan M White, David R Thorburn, Theresa Brunet, Matias Wagner, Wolfgang Müller-Felber, Leopold Zeng, Thomas Klopstock, André Schaller, Jing Liu, David A Stroud, Holger Prokisch.
      NDUFA5 encodes a structural subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) located in the peripheral arm of the enzyme complex. Complex I is the largest enzyme of the mitochondrial respiratory chain and is essential for oxidative phosphorylation. There are many well-characterized conditions associated with nuclear-encoded mitochondrial complex I dysfunction, including Leigh syndrome, leukoencephalopathy, lethal infantile mitochondrial disease, hypertrophic cardiomyopathy, and exercise intolerance. The vast majority of these nuclear-encoded mitochondrial complex I deficiencies are autosomal-recessive conditions. To date, variants in NDUFA5 have not been associated with mitochondriopathy in humans. We identified a cohort of four individuals from three unrelated families with bi-allelic variants in NDUFA5. All individuals present with variable multisystem disease in the setting of a mitochondrial complex I deficiency, biochemically proven via an array of respiratory chain enzymology, blue native PAGE, and mass-spectrometry-based proteomics in peripheral blood mononuclear cells, lymphoblastoid cell lines, fibroblasts, and skeletal muscle. Transcriptomics and RT-PCR demonstrated aberrant mRNA expression in all affected individuals. Finally, we generated zebrafish ndufa5 F0 mutants that exhibited defects of morphological development, locomotor deficits, and abnormal brain activity. Our data demonstrate that bi-allelic variants in NDUFA5 cause a mitochondrial complex I deficiency, characterized by a variable multisystem phenotype that encompasses severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome.
    Keywords:  CI deficiency; NDUFA5; complex I deficiency; mitochondrial disease; mitochondriopathy
    DOI:  https://doi.org/10.1016/j.ajhg.2026.03.003
  6. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00167-X. [Epub ahead of print]86(7): 1195-1196
    A splicing factor's unexpected detour to the mitochondrial surface.
    Ana-Maria Raicu, L Stirling Churchman.
      In this issue of Molecular Cell, Garcia et al.1 reveal an unexpected role for the splicing factor U2AF in repressing translation and influencing the localization of nuclear-encoded mitochondrial mRNAs to the outer mitochondrial membrane.
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.011
  7. Trends Mol Med. 2026 Apr 02. pii: S1471-4914(26)00061-4. [Epub ahead of print]
    Mitochondrial transfer as a therapeutic target for peripheral neuropathy.
    Junlin Wei, Fang Wang.
      Satellite glial cells transfer mitochondria to sensory neurons via myosin 10-dependent tunneling nanotubes. Ji et al. show that this transfer is impaired in diabetic neuropathy, causing energy failure. Restoring it via cell or mitochondrial transplantation alleviates pain and promotes nerve regeneration, revealing a new therapeutic strategy for peripheral neuropathy.
    Keywords:  diabetic peripheral neuropathy; mitochondrial transfer; neuroprotection; satellite glial cells; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.molmed.2026.03.004
  8. iScience. 2026 Apr 17. 29(4): 115184
    Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.
    Edziu Franczak, McLane M Montgomery, Zoe S Terwilliger, Raphael T Aruleba, Polina Krassovskaia, Ilya N Boykov, James T Hagen, Emely A Pacheco, Brett R Chrest, Tonya N Zeczycki, Kayla J Vandiver, P Darrell Neufer, Joseph M McClung, Kelsey H Fisher-Wellman.
      Oxidative phosphorylation (OxPhos) relies on coordinated synthesis of nuclear- and mitochondrial-encoded protein subunits comprising mitochondrial respiratory complexes. Despite a causal link between accumulated mtDNA mutations and age-related diseases, the impact of mtDNA mutation burden on cellular bioenergetics across major organ systems remains only partially resolved. Herein, we leveraged a comprehensive mitochondrial phenotyping platform to assess the phenotypic consequences of heightened mtDNA mutation burden across 8 murine tissues using the polymerase γ (PolG) mutator mouse, incapable of mtDNA proofreading. Despite reductions in OxPhos protein expression, maximal mitochondrial respiratory capacity remained largely intact in PolG Mut mice. Further analysis revealed partial functional deficits in NADH-linked respiration exhibited in brown adipose, colon, kidney, lung, and bone marrow-derived mononuclear cells. In contrast, respiration routed from CII-CIII-CIV was largely preserved across all tissues. Together, these findings suggest that NADH oxidation at respiratory complex I (CI) is the primary functional consequence of heightened mtDNA mutational load.
    Keywords:  Biochemistry; Genomics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115184
  9. J Biol Chem. 2026 Mar 31. pii: S0021-9258(26)00283-8. [Epub ahead of print] 111413
    The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.
    Jayashree S Ladke, Azmi Khan, Anshit Singh, Henning J Jessen, Ullas Kolthur-Seetharam, Manish Jaiswal, Rashna Bhandari.
      Inorganic polyphosphate (polyP) is a linear polymer of phosphate residues linked by phosphoanhydride bonds. PolyP remains poorly understood in mammals due to its low abundance and lack of information on its metabolism. We developed a DAPI fluorescence-based assay to quantify the low levels of polyP present in mammalian cell lines and tissues, detecting an enrichment of polyP in the mitochondria compared with the nucleus and post-mitochondrial fraction. Mitochondrial polyP synthesis was found to depend on active FoF1 ATP synthase and an intact proton gradient across the inner mitochondrial membrane. Additionally, orthophosphate (Pi) is essential for mitochondrial polyP production, and ATP enhances Pi-driven polyP synthesis in isolated mitochondria. We discovered that the inositol pyrophosphate 5-InsP7, synthesized by IP6K1, regulates mitochondrial polyP levels. Mice and cells deficient in IP6K1 showed a significant reduction in mitochondrial polyP synthesis compared with wild type controls. Cells lacking IP6K1 also showed impaired mitochondrial respiration. The expression of active IP6K1, but not its catalytically inactive form, restored mitochondrial polyP synthesis in IP6K1 deficient cells, but mitochondrial respiration was rescued by expression of either active or inactive IP6K1. These data show that IP6K1 regulates mitochondrial function and polyP production both through the synthesis of 5-InsP7 and via a catalytic activity-independent mechanism. Our findings uncover a link between 5-InsP7, an energy sensor, and polyP, an energy store, in the regulation of mammalian mitochondrial homeostasis.
    Keywords:  ATP synthase; cell metabolism; inorganic polyphosphate; inositol phosphate; inositol pyrophosphates; mitochondria; mitochondrial membrane potential; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.jbc.2026.111413
  10. Aging Cell. 2026 Apr;25(4): e70462
    Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes.
    Yiting Lei, Meng Yang, Xiaoyun Jiang, Yujie Zhang, Yuzhi Chen, Weiheng Xie, Qihui Dai, Weihong Qin, Xiuqin Deng, Xiaojun Zhang, Zhongjun Zhou, Gonghua Huang, Xinguang Liu.
      Cellular senescence of white adipose tissues (WAT) represents an early hallmark of aging; however, the involved mechanisms remain incompletely understood. Here, we identified the cytosolic phosphoenolpyruvate carboxykinase (Pck1) as a key regulator of mitochondrial function and inflammaging in WAT. Pck1 expression was downregulated in both gonadal WAT and inguinal WAT during aging, and adipocyte-specific Pck1 deficiency accelerated inflammaging and metabolic disorders. Untargeted metabolomic and isotope-tracing analyses revealed that loss of Pck1 impaired cataplerosis, the export of tricarboxylic acid (TCA) cycle intermediates, resulting in accumulation of fumarate in adipocytes. Supplementation with exogenous fumarate disrupted mitochondrial homeostasis of adipocytes, promoted oxidative stress and triggered cytosolic release of mitochondrial DNA (mtDNA), leading to the activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway that may contribute to inflammaging and chronic obesity. These were phenocopied with Pck1-deficient adipocytes. Conversely, overexpression of fumarate hydratase (Fh1) reduced fumarate level substantially and attenuated adipocyte inflammaging. Collectively, these findings identify Pck1 as a pivotal regulator of mitochondrial metabolic homeostasis and suggest that targeting Pck1 may represent a promising therapeutic strategy for age-related diseases.
    Keywords:  Pck1; TCA cycle; aging; cGAS/STING signaling; cellular senescence; white adipose tissue
    DOI:  https://doi.org/10.1111/acel.70462
  11. BMJ Neurol Open. 2026 ;8(1): e001561
    Peripheral frataxin levels govern long-term clinical progression in Friedreich ataxia.
    Christian Rummey, Ian A Blair, Clementina Mesaros, Teerapat Rojsajjakul, Yina Dong, George Wilmot, Theresa Zesiewicz, Kathy Mathews, Joseph C Hoyle, Lauren Seeberger, Louise A Corben, Martin Bruce Delatycki, Richard S Finkel, Richard H Roxburgh, Antoine Duquette, Grace Yoon, Christopher M Gomez, S H Subramony, Susan Perlman, Shana Mccormack, David R Lynch.
       Background: Novel therapeutics for Friedreich ataxia employ diverse strategies to increase frataxin protein levels, and a better understanding of the relation to clinical outcomes could strengthen their use as pharmacodynamic markers, and potentially as surrogate endpoint in therapeutic development. An elaborate modelling framework was developed to evaluate the suitability of frataxin as a biomarker across assays, tissues and disease stages.
    Methods: Frataxin levels generated previously through two distinct assay platforms and from two separate clinical cohorts: whole blood frataxin was measured by a lateral-flow immunoassay (LF cohort), and a triple-quadrupole LC-MS/MS method (TQ cohort), which enables separate quantification of mature frataxin (FXN-M) and erythrocyte-specific frataxin (FXN-E). Results were compared descriptively with control and heterozygous carriers, and several distinct modelling strategies were employed to correlate them with clinical function.
    Results: Both cohorts represented the relevant disease spectrum, with minor differences in both genetic and clinical severity, which correlated with frataxin levels. Heterozygous carriers showed intermediate levels. Modelling confirmed the predictive value of frataxin across multiple clinical assessments, such as age of symptom onset, age at loss of ambulation and long-term progression. GAA1, the shorter repeat expansion, was confirmed as the dominant predictor of frataxin itself, and, in most situations, clinical function.
    Discussion and conclusion: Although isoform biology and tissue-specific expression remain important considerations, peripheral frataxin quantification provides biologically grounded measure of the pathophysiology and disease progression, with strong potential for application in therapeutic trials. Frataxin is a valid clinical biomarker, and our findings support advancing its candidacy as a surrogate endpoint in Friedreich ataxia.
    Keywords:  CLINICAL NEUROLOGY
    DOI:  https://doi.org/10.1136/bmjno-2026-001561
  12. Front Biosci (Landmark Ed). 2026 Mar 19. 31(3): 49714
    NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.
    George B Stefano.
      Alzheimer's disease (AD) is increasingly associated with mitochondrial dysfunction and disrupted metabolism. Thus, the maintenance of nicotinamide adenine dinucleotide (NAD+) homeostasis is proposed as a potential therapeutic strategy. Toward this end, we suggest that AD-related mitochondrial dysfunction might be viewed as a regulatable, redox-dependent vulnerability rather than an inherently degenerative and irreversible process. This perspective advances an evolutionary model in which NAD+-mediated redox systems represent a conserved regulatory axis, and that destabilization of this axis during aging may increase susceptibility to degeneration. Here, we assess the potential of a therapeutic approach that combines this understanding of mitochondrial energy metabolism with results from preclinical studies demonstrating the impact of pharmacologic correction of NAD+ homeostasis (e.g., P7C3-A20) as contextual motivation. We explicitly elevate redox balance, rather than absolute NAD+ abundance, as the mechanistically dominant variable that shapes mitochondrial resilience, inflammatory tone, and neurovascular stability. Accordingly, the key unresolved issue is whether specific physiologic benefits might accrue from increased NAD+ availability per se or rather, the restoration of the NAD+/NADH redox ratio, with important implications for the interpretation of the results of directed metabolic interventions. Within this framework, metabolic failure in AD can be understood as an upstream permissive condition that explains, rather than replaces, canonical amyloid-β and tau-associated pathologies. While extended human lifespan may expose late-life vulnerabilities in otherwise conserved metabolic systems, claims of causal primacy, disease reversibility, and cross-neurodegenerative generalization remain premature, underscoring the need for redox-resolved, genetic, and clinical validation.
    Keywords:  Alzheimer’s disease; cognition; evolution; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammatory diseases; nicotinamide adenine dinucleotide
    DOI:  https://doi.org/10.31083/FBL49714
  13. Cell Rep. 2026 Mar 27. pii: S2211-1247(26)00261-5. [Epub ahead of print]45(4): 117183
    STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
    Jin-Yi Lin, Ze-Bo Huang, Shi-Qi Zhang, Yong Wu, Ling-Jun Cheng, Xiangzheng Gao, Sofie Lautrup, Shu-Qin Cao, Junping Pan, Dade Rong, Ruixue Ai, Hayden Weng Siong Tan, Liming Wang, Haihe Wang, Han-Ming Shen, Evandro F Fang, Guang Lu.
      PINK1 is a master regulator of PINK1-parkin-mediated mitophagy, a key process for maintaining mitochondrial homeostasis. The precise regulation of PINK1 is therefore essential for orchestrating mitophagy. While proteolytic processing of PINK1 and degradation of cleaved PINK1 via the N-end rule under basal conditions have been extensively characterized, the mechanisms governing full-length PINK1 degradation upon mitochondrial damage remain enigmatic. Here, we demonstrate that PINK1 undergoes ubiquitination and proteasomal degradation during mitophagy through the coordinated action of STUB1 and VCP/p97. Depletion of STUB1 stabilizes full-length PINK1, which paradoxically impairs mitophagy through the acceleration of parkin degradation. At the organismal level, the STUB1-VCP axis plays an important role in neuronal mitophagy-related memory and learning capacities in the roundworm C. elegans. Congruently, this axis is impaired in the postmortem brain tissues from patients with Alzheimer's disease compared with cognitively normal controls. Collectively, our findings support STUB1-VCP as a molecular calibrator that fine-tunes full-length PINK1 levels to enable efficient mitophagy and maintain mitochondrial homeostasis.
    Keywords:  Alzheimer’s disease; CP: metabolism; CP: molecular biology; PINK1; STUB1; VCP/p97; autophagy; mitophagy; parkin; ubiquitination-proteasome system
    DOI:  https://doi.org/10.1016/j.celrep.2026.117183
  14. Sci Adv. 2026 Apr 03. 12(14): eaea4279
    The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
    Sarah J Shemtov, Eric McGann, Lucy Carrillo, Sangmin Lee, Herbert Anson, Eric Hwang, Claire S Chung, Jaye L Weinert, Maria-Eleni Anagnostou, Guan-Ju D Lai, Bert M Verheijen, Junxiang Wan, Ivetta Vorobyova, Monica Sanchez-Contreras, Cheryl A Conover, Max A Thorwald, Pinchas Cohen, Scott R Kennedy, Jean-François Gout, Suraiya Haroon, Marc Vermulst.
      Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.
    DOI:  https://doi.org/10.1126/sciadv.aea4279
  15. Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2534936123
    Structures of folding intermediates on BAM show diverse substrates fold by a conserved mechanism.
    Benjamin D Thomson, Melissa D Marquez, Shaun Rawson, Thiago M A Dos Santos, Stephen C Harrison, Daniel Kahne.
      The outer membranes of mitochondria, chloroplasts, and Gram-negative bacteria contain β-barrel membrane proteins that are assembled by conserved multisubunit machines. In bacteria, the β-barrel assembly machine (BAM) folds over a hundred compositionally different substrates into barrels that vary greatly in size. Some larger barrels require globular proteins to plug the barrel lumen. How a single machine can assemble such different barrels is unknown. Here we report three structures representing progressively folded stages of a 16-stranded barrel engaged with BAM, as well as the structure of a late-stage folding intermediate of a 26-stranded substrate folding around its soluble lipoprotein plug on BAM. We find that BAM catalyzes folding of these substrates by a uniform mechanism in which BAM undergoes major distortions to accommodate the nascent barrel.
    Keywords:  beta-barrel assembly machine; cryo-electron microscopy; folding intermediates; protein folding
    DOI:  https://doi.org/10.1073/pnas.2534936123
  16. Nat Commun. 2026 Apr 01.
    Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine.
    Go Mori, Masayoshi Yamamoto, Kaori Ishikawa, Hiroaki Tamashiro, Hayate Suzuki, Seiya Mizuno, Kazuto Nakada, Atsushi Kawaguchi.
      mRNA vaccines against SARS-CoV-2 have been widely adopted to combat the COVID-19 pandemic. However, myocarditis has emerged as a rare but severe adverse effect, predominantly affecting young males. Here, we show that mitochondrial vulnerability is associated with mRNA vaccine-associated myocarditis. In our case-control study, patients with postvaccination myocarditis exhibited mitochondrial abnormalities. To examine the impact of mitochondrial damage, mRNA vaccines were administered to Polg+/D257A mice, which heterozygously express a proofreading-deficient mitochondrial DNA polymerase that sensitizes mitochondria to stress. mRNA vaccination in Polg+/D257A mice reduced left ventricular ejection fraction and induced cardiac immune cell infiltration. Bazedoxifene, a selective estrogen receptor modulator, prevented the reduction of cardiac function in Polg+/D257A mice, suggesting a protective role for estrogen signaling. Notably, mRNA vaccination induced mitochondrial reactive oxygen species, resulting in RIPK3 activation, a necroptosis-related kinase, in cardiomyocytes. Collectively, we propose that mitochondrial vulnerability is a potential risk factor for myocarditis following mRNA vaccination, possibly through reactive oxygen species-mediated necroptosis signaling.
    DOI:  https://doi.org/10.1038/s41467-026-71295-1
  17. Mitochondrion. 2026 Apr 01. pii: S1567-7249(26)00041-3. [Epub ahead of print] 102151
    Overexpression of miR-455-3p enhances mitophagy, synaptic and mitochondrial proteins in Alzheimer's disease.
    Jangampalli Adi Pradeepkiran, Madhuri Bandaru, Md Ariful Islam, Sudhir Kshirsagar, Rainier Vladlen Alvir, Upasana Mukherjee, P Hemachandra Reddy.
      MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression, neural development and plasticity in Alzheimer's disease (AD). Our lab recently discovered molecular links between miR-455-3p and AD. miR-455-3p is known to regulate APP expression, thereby influencing amyloid beta (Aβ) generation. Using pronuclear injection and CRISPR/Cas9 technologies, we created miR-455-3p transgenic (TG) and knockout (KO) mice. Remarkably, the miR-455-3p TG mice displayed an extended lifespan (by approximately 5 months) compared to wild-type (WT) mice, whereas miR-455-3p KO mice had a reduced lifespan (by 4 months). Behaviorally, miR-455-3p TG mice outperformed cognitive tasks such as the Morris water maze and Y-maze, indicating improved spatial memory and learning. To explore miR-455-3p's role in AD progression, we crossed miR-455-3p TG and miR-455-3p KO mice with the humanized amyloid beta knock-in (hAbKI) mouse model, which mimics late-onset AD features. The resulting experimental groups included WT, miR-455-3p TG, miR-455-3p KO, hAbKI, miR-455-3p TG X hAbKI, and miR-455-3p KO X hAbKI. In the current study, we investigated mitochondrial dynamics, mitochondrial biogenesis, mitophagy and synaptic proteins in all six groups of 12-month-old male and female mice. We focused on examining the expression of, mitophagy regulators (PINK1, Parkin), and synaptic markers (PSD95, Synaptophysin), mitochondrial biogenesis regulators (PGC1α, NRF1, TFAM) and dynamic proteins (DRP1, FIS1, Mfn1/2, OPA1) in the cortex of 12-month-old animals using western blot and immunofluorescence analyses. We also studied spine density in hippocampal sections for the mice groups in a Golgi-cox staining assay. We found miR-455-3p overexpression enhances mitophagy, mitochondrial biogenesis, dynamics proteins and spine density, in hAbKI mice. Depleted miR-455-3p exacerbates mitochondrial defects, defective mitophagy and synaptic loss in hAbKI mice. Our findings highlight miR-455-3p as a promising therapeutic target that modulates multiple pathological pathways in AD. This is the first genetic crossing study of miR-455-3p TG/KO mice with late onset AD, hAbKI mice.
    Keywords:  Alzheimer’s disease; Humanized Abeta knockin mice; Mir-455-3p transgenic mice; Mitochondria; Mitochondrial biogenesis; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2026.102151
  18. Aging Cell. 2026 Apr;25(4): e70452
    Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
    Amélia Lalou, Ioanna Daskalaki, Ilias Gkikas, Sandra Rodríguez-López, Jean-David Morel, Giorgia Benegiamo, Adrien Faure, Arwen W Gao, Joaquim Barmaz, Qi Wang, Terytty Yang Li, Feng Gao, Danaé Broustail, Kristina Schoonjans, Giovanni D'Angelo, Johan Auwerx.
      Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.
    Keywords:   Caenorhabditis elegans ; aging; doxycycline; drug repositioning; longevity; miglustat; mitochondria; terbinafine
    DOI:  https://doi.org/10.1111/acel.70452
  19. Cell Signal. 2026 Apr 01. pii: S0898-6568(26)00169-5. [Epub ahead of print] 112517
    Mitochondrial IRF3 drives pulmonary fibrosis by impairing mitophagy and triggering ferroptosis.
    Zhang Jiashu, Liu Jingbao, Fang Hua, Sun Meiqi, Liu Jing, Wang Mengyao, Zhang Wei.
       BACKGROUND: Pulmonary fibrosis (PF) is a progressive, lethal lung disease with limited treatments. Although inflammation is involved, how it triggers specific oxidative cell death in epithelial cells remains unclear. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is active in PF, but research has focused on its upstream inflammatory role. The function of its key effector, interferon regulatory factor 3 (IRF3), especially through non-canonical mechanisms, is largely unknown. We hypothesized that activated IRF3 translocates to mitochondria to disrupt quality control and promote ferroptosis, linking inflammation to fibrosis.
    METHODS: We employed a bleomycin-induced mouse PF model and TGF-β-stimulated A549 cells. Techniques included molecular analyses (western blot, RT-qPCR, Co-IP), imaging (TEM, immunofluorescence), mitophagy flux assays, and measurement of ferroptosis markers (Fe2+, MDA). Interventions involved H151, si-IRF3, Ferrostatin-1, and Mdivi-1.
    RESULTS: In PF, phosphorylated IRF3 translocated to mitochondria, interacting with PINK1 to impair mitophagy, shown by decreased PINK1, accumulated p62, and reduced LC3-II/LC3-I ratio. This triggered ferroptosis, evidenced by upregulated ACSL4, downregulated GPX4, elevated Fe2+/MDA, and mitochondrial damage. In TGF-β-stimulated A549 cells, IRF3 knockdown or STING inhibition restored mitophagy and suppressed ferroptosis. Mdivi-1 reversed si-IRF3's protection. In vivo, H151 treatment suppressed the IRF3-mitophagy-ferroptosis axis and alleviated PF.
    CONCLUSIONS: Mitochondrial IRF3 integrates cGAS-STING signaling with mitophagic dysfunction and ferroptosis to drive PF, revealing a novel therapeutic target.
    Keywords:  Alveolar epithelial cells; Ferroptosis; IRF3; Mitophagy; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112517
  20. Cell Commun Signal. 2026 Mar 30.
    Mitochondria and the epigenome: maternal co-inheritance and crosstalk from oocyte to embryo.
    Song-Hee Lee, Xiang-Shun Cui.
      
    Keywords:  DNA methylation; Embryo; Epigenetic regulation; Inheritance; Mitochondria; Oocyte
    DOI:  https://doi.org/10.1186/s12964-026-02844-w
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