bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–06–28
23 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
  2. Mitochondrial stress response drives microglial senescence.
  3. Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
  4. Proteolytic coordination of the OXPHOS Life Cycle.
  5. Pseudouridine synthase PUS1 and initiation factor mtIF2 are human mitoribosomal small subunit assembly factors.
  6. Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.
  7. A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.
  8. Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
  9. De Novo MFN2 p.Arg95Met in Severe Charcot-Marie-Tooth Disease Type 2A.
  10. Assembly of the catalytic module and the rotor of human ATP synthase.
  11. Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
  12. Variable mitochondrial phenotypes and reduced complex IV assembly factor SCO2 in LRRK2-G2019S fibroblasts.
  13. Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.
  14. A ratiometric fluorescent reporter of mitochondrial sodium.
  15. 'Edited' human embryos reveal secrets of our development - and fuel ethical debate.
  16. Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model.
  17. Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.
  18. MitoCatch directs mitochondria delivery and prevents cell degeneration.
  19. NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice.
  20. Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.
  21. AMPK Signalling in Heart Failure: From Metabolic Sensor to Context-Dependent Therapeutic Target.
  22. Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.
  23. Imbalanced mitochondrial fusion/fission in human placenta: a potential link to preeclampsia.
  1. Nat Neurosci. 2026 Jun 26.
    The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
    Maria Jose Perez J, Alicia Lam, Christin Weissleder, Federico Bertoli, Hariam Raji, Mariella Bosch, Ivan Nemazanyy, Stefanie Kalb, Mohammed Kehili, Insa Hirschberg, Dario Brunetti, Indra Heckenbach, Morten Scheibye-Knudsen, Michela Deleidi.
      Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41593-026-02320-1
  2. Nat Neurosci. 2026 Jun 26.
    Mitochondrial stress response drives microglial senescence.
    Luca Peruzzotti-Jametti, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s41593-026-02264-6
  3. Nat Commun. 2026 Jun 21.
    Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
    Denisa Hathazi, Camilla Lyons, Daniel Lagos, Oliver Podmanicky, Mariana Zarate-Mendez, Yu Nie, Juliane S Müller, Kieren S J Allinson, Huw Naylor, Majlinda Lako, Ibrahim Elsharkawi, Irena Muffels, Eva Morava, Tamas Kozicz, Patrick Chinnery, András Lakatos, Rita Horvath.
      Mitochondrial diseases frequently affect the brain leading to severe and disabling neurological symptoms. The heteroplasmic m.3243 A > G mutation in MT-TL1, encoding mt-tRNALeu, is responsible for ~80% of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is one of the most characteristic mitochondrial syndromes, leading to disability and early death. There are no animal models harbouring this mutation to provide precise mechanistic insights informing therapeutic interventions. Here, we generate a human iPSC-derived cerebral organoid slice model that recapitulates cortical architecture and mitochondrial pathology. Using biological assays and single-cell RNA sequencing, we uncover heteroplasmy-dependent transcriptional shifts and changes in key cellular processes in cortical neurons. Organoids with high heteroplasmy show a predominant impairment of deep-layer neurons triggered by mitochondrial stress, leading to axonal degeneration and apoptosis, similar to brain autopsy of a MELAS patient. Our findings provide insights into the vulnerability of long-range projection neurons in mitochondrial diseases, advancing our understanding of disease mechanisms with a view to potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-026-74103-y
  4. Biochem J. 2026 Jul 08. 483(7): 1253-1280
    Proteolytic coordination of the OXPHOS Life Cycle.
    Nataliia Nechytailo, Karolina Szczepanowska.
      The mitochondrial oxidative phosphorylation (OXPHOS) system consists of multimeric, highly ordered protein complexes critical for energy production and metabolic wiring in the cell. Recent discoveries in mitochondrial proteolysis, facilitated by advances in proteomic approaches, have transformed the view of mitochondrial proteases from a simple quality-control system into a dynamically coordinated network of enzymes that actively shape the status of the OXPHOS machinery. Mapping OXPHOS-associated proteolytic circuits has uncovered specialized functions of individual proteases and identified key interaction sites. The present review outlines how mitochondrial proteases regulate the OXPHOS life cycle: expression, delivery, assembly, long-term maintenance, and disposal of mitochondrial respiratory complexes. We summarize past findings and highlight emerging concepts, including asynchronous OXPHOS turnover, cofactor-driven proteolysis, and bioenergetics-coupled degradation. Progress in these areas will deepen our understanding of how proteases coordinate the OXPHOS life cycle.
    Keywords:  mitochondria; mitochondrial proteases; mitochondrial respiratory complexes; oxidative phosphorylation; regulatory proteolysis; turnover
    DOI:  https://doi.org/10.1042/BCJ20250120
  5. Nat Commun. 2026 Jun 24. pii: 5564. [Epub ahead of print]17(1):
    Pseudouridine synthase PUS1 and initiation factor mtIF2 are human mitoribosomal small subunit assembly factors.
    Vivek Singh, Dmitrii Shiriaev, Lorina Bilalli, Anas Khawaja, Joanna Rorbach.
      Assembly of the mitochondrial ribosome (mitoribosome) is a crucial step in mitochondrial gene expression. This process facilitates mitochondrial translation, which produces essential subunits of the oxidative phosphorylation machinery-the cell's primary energy-producing machinery. Disruptions in mitoribosome assembly can lead to severe human diseases. Given its fundamental importance, detailed structural analysis of mitoribosome assembly pathways is essential for advancing our understanding of mitochondrial function in both health and disease. In this study, we characterize twelve distinct assembly states of the mitoribosomal small subunit (mtSSU) isolated from human cells. Our findings reveal the intricate details of the final maturation stages of the mtSSU platform, decoding center, and the 3'-end of 12S rRNA. This process is governed by coordinated actions of assembly factors that ensure precise, stepwise rRNA folding and the integration of mitoribosomal proteins into the developing subunit. Our approach identifies pseudouridine synthase PUS1 and initiation factor mtIF2 as assembly factors, expanding their known roles beyond mt-tRNA maturation and translation, respectively. In addition, the identified assembly intermediates provide insight into the modular nature of mtSSU biogenesis in mitochondria and further link late-stage assembly to the acquisition of translational competence.
    DOI:  https://doi.org/10.1038/s41467-026-74700-x
  6. Nat Commun. 2026 Jun 23. pii: 5563. [Epub ahead of print]17(1):
    Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.
    Laura Pérez Pañeda, Jelena Misic, Tereza Kadavá, Nils-Göran Larsson, Albert J R Heck.
      Mitochondrial oxidative phosphorylation (OXPHOS) comprises multi-subunit protein complexes that operate in coordination with the tricarboxylic acid (TCA) cycle to generate ATP. Although these systems are metabolically interconnected, complex II is generally regarded as the only direct structural link between OXPHOS and TCA cycle. Here, we combine in-solution crosslinking mass-spectrometry (XL-MS), quantitative proteomics, complexome profiling and blue native PAGE (BN-PAGE) to explore how ATP synthase (complex V) is positioned within the mitochondrial metabolic network under physiological and pathological conditions. We demonstrate that in murine wild-type hearts, the F₁ catalytic head of ATP synthase forms extensive contacts with TCA cycle enzymes, establishing a previously unanticipated spatial link between OXPHOS and central carbon metabolism. We further report that loss of the mitochondrial RNA-stabilizing protein LRPPRC, which disrupts mtDNA gene expression in the mouse heart, results in ATP synthase destabilization and enhanced F1-TCA cycle interactions. Moreover, ATP synthase dysfunction promotes binding of the ATPase inhibitory factor 1 (ATIF1) to the F₁ head via its N-terminal inhibitory region, shifting the ATP synthase toward an energy-preserving state. Together, our findings show that impaired mitochondrial gene expression leads to secondary ATP synthase remodeling and reshaping of its interaction landscape, revealing how mitochondria may adapt to bioenergetic stress.
    DOI:  https://doi.org/10.1038/s41467-026-74730-5
  7. Mol Cell. 2026 Jun 26. pii: S1097-2765(26)00389-8. [Epub ahead of print]
    A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.
    Zhirong Li, Nuo Chen, Caixia Zhou, Lingna Xu, Xiyuan Wang, Hong Xu, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.
      How mitochondrial respiration is tightly regulated by energy demand remains incompletely defined. When mammalian cells switch from glucose to galactose as a carbon source, we observed the enhanced assembly of respiratory chain complexes accompanied by a marked reduction in TMEM141, a mitochondrial inner membrane protein. Loss of TMEM141 increased mitochondrial respiration and promoted complex I assembly, whereas galactose-induced complex I assembly was markedly blunted in TMEM141-deficient cells. TMEM141 interacts with the complex I assembly factor TIMMDC1, limiting its association with complex I subunits. TMEM141 is degraded by the mitochondrial proteases AFG3L2 and YME1L1, and galactose treatment strengthens their interactions. TMEM141 deficiency increases oxidative damage and mtDNA release, leading to activation of the cGAS-STING pathway. In Drosophila, dTMEM141 localizes to mitochondria, modulates mitochondrial activity, and is required for glial cell integrity in the eye. Together, our findings reveal TMEM141 as a negative regulator of complex I assembly that adapts to oxidative phosphorylation (OXPHOS) demands.
    Keywords:  Drosophila; OXPHOS; mitochondria; mitochondrial protease; respiration complex
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.018
  8. Biomed Pharmacother. 2026 Jun 26. pii: S0753-3322(26)00735-3. [Epub ahead of print]201 119699
    Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
    Li-Tzu Wang, Han-Ying Jhuang.
      Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.
    Keywords:  Clinical trials; Gene therapy; Leber hereditary optic neuropathy; MELAS; Primary mitochondrial disease; Translational medicine; Trial design
    DOI:  https://doi.org/10.1016/j.biopha.2026.119699
  9. J Peripher Nerv Syst. 2026 Sep;31(3): e70136
    De Novo MFN2 p.Arg95Met in Severe Charcot-Marie-Tooth Disease Type 2A.
    Hsi-Yen Lee, Wen-Ling Cheng, Shin-Hung Pan, Chia-Ju Lee, Yau-Huei Wei, Chin-San Liu.
       BACKGROUND AND AIMS: Mitofusin 2 (MFN2)-related Charcot-Marie-Tooth disease type 2A (CMT2A) is often associated with early onset, severe progressive weakness, distal wasting, and reduced motor and sensory response amplitudes.
    CASE REPORT: We report a 30-year-old Taiwanese woman with infancy-onset, severe axonal sensorimotor neuropathy, progressive distal weakness and wasting, optic atrophy, bilateral sensorineural hearing loss, hypophonia, and wheelchair dependence from adolescence. Nerve conduction study was consistent with severe chronic axonal sensorimotor polyneuropathy. Whole-exome sequencing identified a heterozygous de novo Mitofusin 2 (MFN2) variant, NM_014874.4:c.284G>T, predicting p.Arg95Met.
    INTERPRETATION: This case expands the genotypic spectrum of MFN2-related Charcot-Marie-Tooth disease type 2A and supports the clinical importance of the Arg94/Arg95 region in severe early-onset MFN2 neuropathy.
    Keywords:  Charcot–Marie–tooth disease type 2A; MFN2; optic atrophy; p.Arg95Met; sensorineural hearing loss
    DOI:  https://doi.org/10.1111/jns.70136
  10. EMBO J. 2026 Jun 26.
    Assembly of the catalytic module and the rotor of human ATP synthase.
    Jiuya He, Joe Carroll, Shujing Ding, Jiao Li, Ian M Fearnley, John E Walker.
      Human ATP synthase is a molecular rotary machine bound in inner mitochondrial membranes, built from twenty-eight subunits of seventeen kinds, two encoded in mitochondrial DNA, the remainder in nuclear genes. The machine consists of a rotor and an interacting stator. Turning of the rotor driven by a transmembrane proton motive force effects a cycle of structural changes in the catalytic part of the stator, producing three ATP molecules per rotation. Here, to establish how the stator and rotor are assembled, we deleted subunits and known assembly factors from human cells, purified and accumulated assembly intermediate complexes, and characterized them by gel analysis and mass spectrometry, allowing us to propose pathways of assembly of the rotor and the catalytic F1-module of the stator. These observations provide opportunities for further development by structural analysis of the accumulated intermediates. The compositions of the various assembly intermediates support the view that ATP synthase arose via independent evolution of its three constituent structural components, the catalytic F1-module, the peripheral stalk module, and the membrane-associated Fo-module.
    DOI:  https://doi.org/10.1038/s44318-026-00842-9
  11. bioRxiv. 2026 Jun 10. pii: 2026.06.09.730804. [Epub ahead of print]
    Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
    Michel Thiebaut de Schotten, Cynthia C Liu, Catherine Kelly, Ke Bo, Tor D Wager, Eugene V Mosharov, Martin Picard.
      Mitochondria support the bioenergetic processes that enable brain function and cognition, but we have lacked a label-free, non-invasive approach to explore how brain mitochondria are linked to ageing, disease, and cognition in humans. A recently introduced MitoBrainMap neuroimaging framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here, we tested whether this framework captures meaningful age- and pathology-related mitochondrial variation. Consistent with existing literature, we find that MR-predicted mitochondrial density and tissue respiratory capacity consistently declined with age, whereas mitochondrial respiratory capacity-an index of mitochondrial quality-was relatively preserved across the lifespan. Moreover, the relations among specific mitochondrial features predicted from our algorithm were consistent with their biological organization, supporting preliminary construct validity for MR-predicted mitochondrial features. In patients with rare mitochondrial diseases, predicted maps revealed region-specific alterations in mitochondrial density and respiratory chain components, particularly the expected compensatory upregulation of complex II, but not of other mitochondrial genome-encoded components. Finally, the MR-based mitochondrial features were associated with the energetic stress marker GDF15 measured in blood, as well as with cognitive performance measures, linking the novel predictions of brain mitochondria to systemic stress and behavior. These findings introduce a first-generation, label-free, neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.
    DOI:  https://doi.org/10.64898/2026.06.09.730804
  12. Sci Rep. 2026 Jun 25.
    Variable mitochondrial phenotypes and reduced complex IV assembly factor SCO2 in LRRK2-G2019S fibroblasts.
    Ruby Wallis, Ella Simmonite, Harry Cooper, Olivia Cracknell, Amandeep Kaur, Elizabeth J New, Jan Aasly, Oliver Bandmann, Heather Mortiboys.
      LRRK2-G2019S is the most common pathogenic LRRK2 mutation which accounts for up to 13% of cases of familial Parkinson's disease. The LRRK2-G2019S mutation has incomplete penetrance which increases with age. Molecular mechanisms which contribute to the disease status in LRRK2-G2019S mutation carriers are yet to be fully defined. Here, we aimed to further investigate the specific mitochondrial effects of LRRK2-G2019S penetrance in a cohort of patient-derived fibroblasts from manifesting and non-manifesting LRRK2-G2019S carriers compared to controls to further elucidate the pathogenic mechanism of the mutation. We find a significant reduction of 50% in the expression of the complex IV assembly factor SCO2 in LRRK2-G2019S manifesting fibroblasts. In contrast, SCO2 levels remained similar to controls in non-manifesting LRRK2-G2019S carriers. A small reduction in complex IV subunit expression accompanied this reduction in SCO2 in manifesting LRRK2-G2019S carriers. Despite the role of SCO2 in copper incorporation into complex IV, we identified no differences in the unbound mitochondrial copper content in a limited number of manifesting or non-manifesting LRRK2-G2019S carriers compared to controls. However, LRRK2-G2019S carriers exhibit variable cellular phenotypes in mitochondrial morphology, mitochondrial membrane potential and cellular ATP or ROS production which does not differ significantly between manifesting and non-manifesting carriers. We conclude that mitochondrial complex IV deficiency could be a pathogenic mechanism of the LRRK2-G2019S mutation which may be attributed to a reduction in SCO2, however there is evident heterogeneity in the cellular phenotype of LRRK2-G2019S carriers which may suggest underlying compensatory mechanisms.
    Keywords:  G2019S mutation; Leucine-rich repeat kinase-2 (LRRK2); Manifesting; Mitochondria; Non-manifesting; Parkinson’s disease; Penetrance
    DOI:  https://doi.org/10.1038/s41598-026-58797-0
  13. Nat Cell Biol. 2026 Jun 26.
    Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.
      
    DOI:  https://doi.org/10.1038/s41556-026-02008-5
  14. Nat Chem Biol. 2026 Jun 22.
    A ratiometric fluorescent reporter of mitochondrial sodium.
    Koushambi Mitra, Soyoung Kim, Daphne Oettinger, Sanjeev Uthishtran, Qian Zhao, Aneesh Tazhe Veetil, Joseph R Ramirez, Hening Lin, Senthil Arumugam, Yamuna Krishnan.
      Cells cope with salt stress, hypoxia or elevated cytosolic Ca2+ by regulating their mitochondrial Na+ levels. The discovery of the mitochondrial Na+/Ca2+ exchanger and its disease relevance has revealed the need to map mitochondrial Na+ in situ. Here we describe a ratiometric fluorescent reporter for Na+, denoted MitRatiNa, that reports mitochondrial Na+ levels independent of membrane potential and in diverse cell lines. Na+ in individual mitochondria varies greatly and, depending on cell type, can be as low as 1-5 mM or as high as 40 mM on average. We demonstrate that mitochondrial Na+ increases during cytosolic Ca2+ elevation, inhibition of glycolysis or respiration. Mitochondria in skin fibroblasts from healthy humans show a high Na+ population that disappears in fibroblasts of persons with mitochondrial diseases. The newfound ability to map absolute Na+ at the resolution of single mitochondria enables the dissection of regulatory mechanisms for mitochondrial Ca2+ and Na+ and potential identification of new therapeutic avenues.
    DOI:  https://doi.org/10.1038/s41589-026-02253-7
  15. Nature. 2026 Jun 25.
    'Edited' human embryos reveal secrets of our development - and fuel ethical debate.
    Heidi Ledford.
      
    Keywords:  Ethics; Gene therapy; Genomics
    DOI:  https://doi.org/10.1038/d41586-026-02027-0
  16. Cell Death Dis. 2026 Jun 23.
    Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model.
    Jarmon G Lees, Haoxiang Zhang, Lebei Jiao, Anne M Kong, Ren Jie Phang, Li Li, Nan Su, Sebastian Bass-Stringer, Hei-Yi H Woo, Anthony S Mukhtar, Alice Pébay, Mirella Dottori, Louise Corben, Martin Delatycki, Roger Peverill, Stephen Wilcox, Jarny Choi, Jeffrey M Pullin, Davis McCarthy, Jill S Napierala, Marek Napierala, Shiang Y Lim.
      Friedreich ataxia (FRDA) is a progressive neuromuscular degenerative disorder caused by GAA repeat expansions in the FXN gene, leading to frataxin deficiency and multisystem pathology. Cardiomyopathy is the leading cause of mortality in individuals with FRDA. To investigate the cellular and molecular mechanisms underlying FRDA-associated cardiac dysfunction, we employed induced pluripotent stem cell (iPSC) lines derived from three individuals with FRDA, each paired with an isogenic control line generated through CRISPR/Cas9-mediated excision of the pathogenic GAA repeat expansion. Correction of the mutation restored FXN expression to levels comparable to healthy donor iPSCs, and all lines differentiated efficiently into cardiomyocytes. Functional analysis revealed significant contractile abnormalities in FRDA cardiomyocytes and multicellular cardiac microtissues, including prolonged contraction and relaxation times and faster beating rates, consistent with clinical observations of cardiac contractile dysfunction. FRDA cardiomyocytes also exhibited pathological features such as increased cell size, irregular calcium transients, elevated mitochondrial reactive oxygen species levels, increased mitochondrial fission and increased cell death. These phenotypes were exacerbated by pathological levels of iron supplementation in culture media, highlighting the heightened sensitivity of frataxin-deficient cardiomyocytes to iron-induced metabolic stress. RNA sequencing revealed a distinct transcriptional profile associated with frataxin deficiency. MEG3 and PCDHGA10 were consistently dysregulated across all three FRDA-iPSC lines and may represent early molecular markers of FRDA cardiomyopathy. Functional interrogation of these candidates demonstrated that targeted silencing of MEG3 or PCDHGA10 in FRDA cardiomyocytes significantly reduced disease‑associated cell death without affecting FXN expression. Notably, PCDHGA10 silencing also normalized elevated mitochondrial reactive oxygen species, whereas MEG3 silencing did not, highlighting gene‑specific contributions to FRDA cardiomyocyte survival. Collectively, these findings identify MEG3 and PCDHGA10 as functionally relevant regulators of FRDA cardiomyocyte pathology.
    DOI:  https://doi.org/10.1038/s41419-026-09030-3
  17. Hum Mol Genet. 2026 Jun 12. pii: ddag023. [Epub ahead of print]35(12):
    Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.
    Rianne J Baelde, Leander A Vonk, Edgar E Nollet, Ricardo A Galli, Alexcia Fortes Monteiro, Sultan Bastu, Bornale Das, Michel van Weeghel, Bauke V Schomakers, Kasper T Vinten, Marloes van den Berg, Jolanda van der Velden, Riekelt H Houtkooper, Nicol C Voermans, Edoardo Malfatti, Coen A C Ottenheijm, Josine M de Winter.
      Nemaline Myopathy type 6 (NEM6) is a congenital myopathy caused by variants in Kelch-repeat-and-BTB-(POZ)-Domain-Containing-13 (KBTBD13). The majority of the NEM6 patients harbor the Dutch founding variant KBTBD13R408C (c.1222C > T, p.Arg408Cys) and experience skeletal muscle weakness and sarcomere-based hypercontractility. Histological characterization of NEM6 patient biopsies by NADH staining shows the presence of cores, suggesting mitochondrial dysfunction. We aimed to elucidate the role of mitochondrial dysfunction in NEM6 pathology and tested the ability of the NAD+ precursor nicotinamide riboside (NR) to improve mitochondrial performance. We performed a natural history study in homozygous Kbtbd13R408C-knockin mice (NEM6 mouse model) to investigate the onset and progression of mitochondrial dysfunction in NEM6. We performed high-resolution respirometry, metabolic treadmill experiments and histoenzymatic NADH and SDH stainings on cryosections. Additionally, we used multi-omics analyses to investigate impacted pathways and metabolite dysregulation and performed NR supplementation for eight weeks to prevent the onset of mitochondrial dysfunction in NEM6 mice. Throughout disease progression, NEM6 mice display decreased mitochondrial respiration, impaired metabolic performance and the presence of cores with histoenzymatic reactions. Multi-omics studies revealed that the TCA cycle is heavily impacted and that NAD+ levels are decreased throughout disease progression. We aimed to restore NAD+ levels by supplementation of NR. Remarkably, NR treatment in 1-months-old NEM6 mice, prevented the onset of mitochondrial dysfunction. In conclusion, these results provide insight in the onset and progression of mitochondrial dysfunction in NEM6 and offer proof-of-concept for NR as a therapeutic strategy.
    Keywords:  Congenital myopathy; Mitochondria; NAD+ metabolism; Nemaline myopathy; Skeletal muscle
    DOI:  https://doi.org/10.1093/hmg/ddag023
  18. Cell Res. 2026 Jun 25.
    MitoCatch directs mitochondria delivery and prevents cell degeneration.
    Ana Paula Mendonça, Luca Scorrano.
      
    DOI:  https://doi.org/10.1038/s41422-026-01274-0
  19. Sci Adv. 2026 Jun 26. 12(26): eaec9499
    NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice.
    Inés Muela-Zarzuela, Elisabet Alcocer-Gómez, Juan M Suarez-Rivero, Evon Low, Abbas Ishaq, Mikel Azkargorta, Amparo Luque-Sierra, Franz Martin, Félix Elortza, Antonio Astorga-Gamaza, Rosa Antón, Sofía Bali, Joaquin Tamargo-Azpilicueta, Alejandra Guerra-Castellano, Irene Díaz-Moreno, Lukasz A Joachimiak, Javier Oroz, Jesús Ruiz-Cabello, Thomas von Zglinicki, Alberto Sanz, Mario D Cordero.
      The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer's disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative disorders. Consequently, drug development efforts have focused on partial inhibition of NLRP3 using compounds that reduce its expression or activity. Paradoxically, although many studies have used Nlrp3 knockout mouse models, Nlrp3 haploinsufficient mice-more representative of the effects of pharmacological inhibition-are rarely included and remain poorly characterized. Here, we report the long-term effects of Nlrp3 haploinsufficiency during aging. Although no overt differences were observed in early life, by 16 months of age, Nlrp3 heterozygous mice exhibited signs of accelerated inflammatory aging, driven by compensatory overexpression of NLRP1. Mechanistic studies provide evidence of a previously unidentified interaction between NLRP1 and NLRP3, forming a hybrid inflammasome that drives NLRP1-mediated inflammatory overactivation when NLRP3 expression is reduced. Accordingly, anti-inflammatory treatment provided notable but moderate improvement of the inflammatory phenotype, whereas genetic inhibition of Nlrp1 more consistently reduced inflammation and extended health span. Our findings reveal a previously unidentified compensatory interaction between NLRP1 and NLRP3 and suggest that multiinflammasome inhibition may offer a more effective strategy for treating aging and age-related diseases.
    DOI:  https://doi.org/10.1126/sciadv.aec9499
  20. Cell Commun Signal. 2026 Jun 22.
    Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.
    Qingqi Zhang, Junyan Gao, Yiting Yang, Ping Guo, Huiqin Gao, Shuaiyong Zhao, Shuanglin Zhang, Yaping Shi, Guanxing Xie, Yutong Han, Hao Liu, Yunzeng Zou.
      Mitochondria-associated endoplasmic reticulum membrane (MAM), which serves as a signaling hub for interactions between the endoplasmic reticulum (ER) and mitochondria, dynamically coordinates innate immune processes by regulating calcium homeostasis, lipid metabolism, mitochondrial dynamics, mitochondrial protein modifications, and autophagy. MAM regulates calcium homeostasis to govern mitochondrial energy metabolism and inflammasome activation; maintains lipid metabolism for membrane integrity to support antiviral signaling pathways; controls mitochondrial fission and fusion dynamics, processes that are closely associated with mitochondrial DNA (mtDNA) release; regulates mitochondrial protein modifications to fine-tune the function of proteins localized at MAM; and facilitates the clearance of damaged mitochondria and leaked mtDNA through autophagy. Most critically, MAM dysfunction and innate immune dysregulation form a vicious cycle: immune activation disrupts MAM integrity, and MAM abnormalities exacerbate the release of mitochondrial damage-associated molecules, continuously driving overactivation of pathways such as inflammasomes and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, thereby promoting the development of autoimmune diseases. This review synthesizes current literature on the molecular mechanisms by which MAM regulates innate immunity. We summarize how disruptions in MAM-mediated mitochondrial homeostasis contribute to innate immune imbalance. By integrating these findings, we highlight potential intervention nodes. This underscores the clinical relevance of targeting MAM in immune-related pathological conditions.
    Keywords:  Innate immunity; Mitochondria-associated endoplasmic reticulum membrane (MAM); Mitochondrial homeostasis; MtDNA
    DOI:  https://doi.org/10.1186/s12964-026-03013-9
  21. Biomedicines. 2026 Jun 17. pii: 1362. [Epub ahead of print]14(6):
    AMPK Signalling in Heart Failure: From Metabolic Sensor to Context-Dependent Therapeutic Target.
    Rayan Arzouni, Reem Aazar, Seif Asakrieh, Seif Cattan, Aleksandar Jovanović.
      Heart failure (HF) is a complex clinical syndrome characterized not only by impaired cardiac function but also by profound disturbances in myocardial energy metabolism. AMP-activated protein kinase (AMPK), a central cellular energy sensor, plays a critical role in maintaining metabolic homeostasis by coordinating pathways involved in substrate utilization, mitochondrial function, autophagy, and stress adaptation. Experimental evidence supports a cardioprotective role of AMPK activation, including improved energetic efficiency, attenuation of pathological remodeling, and enhanced cellular resilience. However, emerging data indicate that AMPK signaling is highly context-dependent, with its effects varying according to HF phenotype, disease stage, and isoform-specific activity. While indirect AMPK modulation through established therapies such as metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors has demonstrated clinical benefit, the specific contribution of AMPK to these effects remains incompletely defined. Furthermore, direct pharmacological activation is limited by challenges including tissue specificity, off-target effects, and potential adverse outcomes associated with sustained activation. This review provides a comprehensive overview of AMPK signaling in HF, focusing on its role in metabolic remodeling, mitochondrial regulation, and interaction with key cardioprotective pathways. We also examine current clinical and translational evidence and discuss emerging strategies aimed at achieving isoform-selective and tissue-specific modulation. Collectively, these insights support a shift from broad AMPK activation toward precision-based therapeutic approaches tailored to the disease context.
    Keywords:  AMPK; HFpEF; HFrEF; SGLT2 inhibitors; autophagy; heart failure; metabolism; metformin; mitochondrial dysfunction; precision medicine
    DOI:  https://doi.org/10.3390/biomedicines14061362
  22. Mol Neurobiol. 2026 Jun 26. pii: 728. [Epub ahead of print]63(1):
    Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.
    Sanket Pramanik, Biplab Debnath, Aganta Chakraborty, Anas Islam, Shrabasti Mullick, Priya Chaudhary, Rajarshi Nath, Dinesh Kumar Chellappan, Mohini Mondal, Sumel Ashique.
      Mitochondrial dysfunction is a common pathological feature of neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although these disorders are primarily driven by disease-specific genetic and proteopathic mechanisms, increasing evidence suggests that secondary mitochondrial DNA (mtDNA) damage and heteroplasmy shifts may exacerbate bioenergetic failure and neuronal vulnerability. Distinguishing primary disease mechanisms from downstream mtDNA alterations is critical to accurately evaluate emerging therapeutic strategies. Recent advances in mtDNA-targeted genome editing have enabled the direct manipulation of mitochondrial genomes. Mitochondrially targeted zinc finger nucleases and TALENs can selectively alter mutant mtDNA to induce heteroplasmy shifts, whereas DddA-derived cytosine base editors allow precise base editing without double-strand breaks. However, each platform has distinct limitations related to the target scope, off-target risk, design complexity, and delivery efficiency. The application of CRISPR/Cas-based systems to mammalian mtDNA remains constrained by the unresolved challenges in guiding RNA import. This review critically examines mitochondrial dysfunction and mutant mtDNA accumulation in neurodegenerative diseases. It also evaluates current and emerging mtDNA-editing techniques, and highlights key translational barriers. We highlighted that mtDNA-targeted interventions can be a promising approach for disease-modifying or adjunctive strategies, rather than curative approaches.
    Keywords:  DdCBE (DddA-derived Cytosine Base Editors); Heteroplasmy Correction; MitoTALENs; Mitochondria-Targeted CRISPR/Cas Systems; Mitochondrial Genome Editing; Neurodegenerative Disorders; Oxidative Stress & Mitochondrial Dysfunction; Precision Medicine
    DOI:  https://doi.org/10.1007/s12035-026-06008-2
  23. Sci Rep. 2026 Jun 26.
    Imbalanced mitochondrial fusion/fission in human placenta: a potential link to preeclampsia.
    Jianying Liu, Yujing Xu, Hong Sun, Shasha Yu, Rong Hou, Ruofan Wang, Qian Li, Xiaoyi Yin, Yuchun Zhu, Guanglei Wang.
      We aimed to examine how placental dysfunction and impaired mitochondrial fusion/fission balance correlate with preeclampsia (PE) in human placentas, shedding light on the underlying etiology of PE. Twenty-eight pregnant women who received antenatal care at the Obstetrics Medical Center of Weifang People's Hospital between November 2024 and May 2025. They were divided into a PE group (n = 14) and a normal control group (n = 14). Placental tissues from pregnant women with PE or with healthy control were analyzed. Compared to controls, the PE group exhibited impaired placental function (evidenced by decreased PlGF and increased sFlt-1) and disrupted mitochondrial dynamics (characterized by reduced MFN1/2 and elevated p-DRP1). These alterations were accompanied by increased oxidative stress and apoptosis, alongside decreased ATP production. Imbalanced mitochondrial fusion/fission may contribute to placental dysfunction through mechanisms involving oxidative stress, disturbed energy metabolism, and cell apoptosis, leading to the occurrance of PE.
    Keywords:  Fission; Fusion; Mitochondrial; Oxidative stress; Placenta; Preeclampsia
    DOI:  https://doi.org/10.1038/s41598-026-57067-3
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