bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–10–19
fifty-one papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
  2. From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
  3. POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.
  4. Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.
  5. Exploring rare mitochondrial DNA in Leber hereditary optic neuropathy.
  6. MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
  7. Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders.
  8. The role of mitochondrial genetics in Parkinson's disease: Long-read sequencing as an emerging method.
  9. Amino acid supplementation in patients affected by leukoencephalopathies associated with mitochondrial aminoacyl tRNA synthetase pathogenic variants: Pilot clinical trial in adults and review of literature.
  10. Faulty mitochondria cause deadly diseases: fixing them is about to get a lot easier.
  11. Postnatal Developmental Dynamics of Mitochondrial Complex I in Mouse Tissues.
  12. Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).
  13. Lon/Pim1 mediated degradation of presequence translocase-associated motor components Pam16 and Pam18 in Saccharomyces cerevisiae.
  14. Evaluation of Serum FGF21 Levels in Patients with Mitochondrial Aminoacyl-tRNA Synthetase Deficiency.
  15. Mitochondrial function regulates cell growth kinetics to maintain mitochondrial homeostasis.
  16. Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.
  17. Bilateral Sudden on Chronic Hearing Loss as an Auditory Manifestation of Mitochondrial DNA Mutations.
  18. Region-Specific Quantification of 2-Hydroxyglutarate Enantiomers in Murine Brain during Mitochondrial Complex I Deficiency.
  19. NAD+ precursor supplementation in human ageing: clinical evidence and challenges.
  20. Nanoengineered mitochondria for mitochondrial dysfunction and anti-aging interventions.
  21. Integrated multi-omics mapping of mitochondrial dysfunction and substrate preference in Barth syndrome cardiac tissue.
  22. Analyzing Endolysosome-Mitochondria Membrane Contact Sites by Thin Section TEM of Human Fibroblasts.
  23. Mitochondrial and psychosocial stress-related regulation of FGF21 in humans.
  24. The mitochondrial side of frailty.
  25. Substrate-dependent activation of LONP1 informs on proteolytic regulation and ATPase motor function.
  26. Systemic lipomatosis as a clue to mitochondrial myopathy.
  27. Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.
  28. Pearls and Oy-sters: Chronic Progressive External Ophthalmoplegia With Electrical Myotonia and Negative Initial Genetic Testing.
  29. FASTK post-transcriptional regulators - a 'FAST-tracK' in mitochondrial gene expression.
  30. Mitochondrial MFN2 integrates the function of multiple organelles to regulate metabolic dysfunction-associated steatotic liver disease: mechanisms and therapeutic insights.
  31. SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
  32. Polycomb Repressive Complex 1 and USP16 localize to the mitochondrion and influence its function.
  33. HMGB1 and mitochondrial dysfunction: a double-edged sword in ageing.
  34. Ethical challenges in extending mitochondrial replacement therapy (MRT) for overcoming poor egg quality in older women without mitochondrial diseases.
  35. Temporal Interactome Mapping of Human Tau in Drosophila Reveals Progressive Mitochondrial Engagement and Porin/VDAC1-Dependent Modulation of Toxicity.
  36. Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy.
  37. Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation.
  38. Ligase 3 prevents oxidative strand break-induced mitochondrial DNA loss but is not essential for replicative circularization.
  39. CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.
  40. MRI-based multi-organ clocks for healthy aging and disease assessment.
  41. Cardiac transplant outcomes in a pediatric patient with novel homozygous variants in TOP3Α causing mitochondrial dysfunction.
  42. Engineered 3D immuno-glial-neurovascular human miBrain model.
  43. Translational Remodeling of the Synaptic Proteome During Aging.
  44. Ferroptosis-related stress during aging and its relevance to disease.
  45. Molecular basis for noncanonical transcription initiation from Np4A alarmones.
  46. Towards a reference cell atlas of liver diversity over the human lifespan.
  47. Targeting mitochondrial transporters and metabolic reprogramming for disease treatment.
  48. SpIC3D imaging for spinal in situ contrast 3D visualization.
  49. EMito-Metrix enables automated evaluation of mitochondrial morphology across species.
  50. Genetic dissection of Huntington's disease modification by variation at RRM2B.
  51. Extracellular vesicles for the delivery of gene therapy.
  1. Biochim Biophys Acta Mol Basis Dis. 2025 Oct 10. pii: S0925-4439(25)00418-1. [Epub ahead of print]1872(2): 168070
    Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
    Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Marta Zaninello, Esther Barth, Matteo Veronese, Richard Rodenburg, Elena I Rugarli, Susanne Brodesser, Susanne Arnold, Ulrich Brandt.
      Inherited mitochondrial disorders are of multiple genetic origins and may lead to a broad range of frequently severe disease phenotypes. Yet, how molecular causes ultimately present as a clinical phenotype is poorly understood. To address this conundrum starting from the molecular defect, we thoroughly investigated the consequences of the well-known pathogenic mitochondrial DNA mutation m.10191T>C. The mutation changes serine-45 in subunit ND3 of respiratory chain complex I to proline and causes Leigh syndrome, which is one of the most devastating mitochondrial diseases. Human mitochondria carrying the mutation ND3S45P retained 30-40 % of complex I activity and oxidative phosphorylation capacity. In stark contrast, intact mutant cells exhibited only minimal oxygen consumption and a massively increased NADH/NAD+ ratio. Since the energy barrier for the Active/Deactive transition of complex I was reduced by ∼20 kJ∙mol-1 in mutant cells, we concluded that complex I was shut-off by malfunctioning of an as yet unknown regulatory pathway. Comprehensive analysis of the mitochondrial complexome of cybrids, patient fibroblasts and muscle biopsies rendered other causes for the accumulation of NADH unlikely. The complexome datasets provide a rich resource for further studies to discover possible additional factors involved in regulating complex I. We propose that the derailed regulation of complex I is the main culprit leading to NADH accumulation and eventually the severity of the disease phenotype caused by mutation ND3S45P.
    Keywords:  Active/deactive transition; Complex I; Complexome profiling; Mitochondria; Mitochondrial disease; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168070
  2. Mol Cell Biol. 2025 Oct 17. 1-27
    From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
    Phoebe J Leeming, Julia Mercuri-Svik, Diana Stojanovski.
      Mitochondria rely on the coordinated function of over 1000 proteins, most of which are nuclear-encoded, synthesized in the cytosol, and imported into distinct mitochondrial sub-compartments. Thirteen additional proteins are synthesized within the organelle itself, forming core components of the oxidative phosphorylation (OXPHOS) system. Once inside, mitochondrial precursors undergo precise maturation, folding, and assembly, supported by specialized factors that ensure their function. These processes are safeguarded by an intricate network of chaperones, proteases, and disaggregases that maintain proteome integrity. Protein biogenesis and quality control are deeply interconnected, operating continuously to preserve mitochondrial function. Disruption at any stage, whether in import, folding, assembly, or degradation, can lead to proteotoxic stress and mitochondrial dysfunction, underlying a wide spectrum of mitochondrial diseases. Despite progress in characterizing many of these pathways in human cells, large gaps in knowledge remain. A complete understanding of protein biogenesis and surveillance mechanisms is essential to uncover how their dysregulation drives disease. This knowledge will be foundational for interpreting pathogenic mutations, predicting disease mechanisms, and ultimately guiding therapeutic strategies aimed at restoring mitochondrial proteostasis and health.
    Keywords:  Mitochondria; mitochondrial disease; protein import; protein quality control
    DOI:  https://doi.org/10.1080/10985549.2025.2566671
  3. Life Sci Alliance. 2025 Dec;pii: e202302563. [Epub ahead of print]8(12):
    POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.
    Maria Miranda, Andrea Mesaros, Nathalie Scrima, Louise Pérard, Irina Kuznetsova, Martin Purrio, Ilian Atanassov, Aleksandra Filipovska, Arnaud Mourier, Nils-Göran Larsson, Inge Kühl.
      POLRMT is the sole RNA polymerase in human mitochondria, where it generates primers for mitochondrial DNA (mtDNA) replication and transcribes the mtDNA to express genes encoding essential components of the oxidative phosphorylation (OXPHOS) system. Elevated POLRMT levels are found in several cancers and in mouse models with severe mitochondrial dysfunction. Here, we generated and characterized mice overexpressing Polrmt to investigate the physiological and molecular consequences of elevated POLRMT levels. Increasing POLRMT levels did not result in any pathological phenotype but led to increased exercise performance in male mice under stress conditions. Polrmt overexpression increased mtDNA transcription initiation, resulting in higher steady-state levels of the promoter-proximal L-strand transcript 7S RNA. Surprisingly, the abundance of mature mitochondrial RNAs was not affected by the elevated POLRMT levels. Furthermore, ubiquitous simultaneous overexpression of Polrmt and Lrpprc, which stabilizes mitochondrial messenger RNAs, did not increase steady-state levels of mitochondrial transcripts in the mouse. Our data show that POLRMT levels regulate transcription initiation, but additional regulatory steps downstream of transcription initiation and transcript stability limit OXPHOS biogenesis.
    DOI:  https://doi.org/10.26508/lsa.202302563
  4. Front Cell Dev Biol. 2025 ;13 1650462
    Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.
    Karis B D'Alessandro, Enrico Zampese, Jenna L E Blum, Britta Kuusik, Alec Palmiotti, Shawn M Davidson, Colleen R Reczek, D James Surmeier, Navdeep S Chandel.
      Dysfunction of mitochondrial complex I (MCI) has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Here, we report the effect of expressing MitoLbNOX, a mitochondrial-targeted version of the bacterial enzyme LbNOX, which increases regeneration of NAD+ in the mitochondria to maintain the NAD+/NADH ratio, in dopaminergic neurons with impaired MCI (MCI-Park mice). MitoLbNOX expression did not ameliorate the cellular or behavioral deficits observed in MCI-Park mice, suggesting that alteration of the mitochondrial NAD+/NADH ratio alone is not sufficient to compensate for loss of MCI function in dopaminergic neurons.
    Keywords:  NAD+; Parkinson’s disease; dopaminergic neurons; mitochondrial complex I; neurodegeneration; neurometabolism
    DOI:  https://doi.org/10.3389/fcell.2025.1650462
  5. Adv Ophthalmol Pract Res. 2025 Nov-Dec;5(4):5(4): 278-284
    Exploring rare mitochondrial DNA in Leber hereditary optic neuropathy.
    Shanshan Cao, Yong Liu, Mingming Sun, Yuan Zhang, Yonghua Sun, Quangang Xu, Shihui Wei, Huanfen Zhou.
       Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder primarily caused by mutations in MT-ND1, MT-ND4, and MT-ND6, leading to retinal ganglion cell degeneration and severe vision loss. While 90%-95% of cases involve three common mutations (m.11778G ​> ​A, m.3460G ​> ​A, m.14484T ​> ​C), the genetic and clinical profiles of rare mutations remain poorly characterized, contributing to diagnostic challenges.
    Methods: This cohort study analyzed 26 genetically confirmed LHON patients harboring rare mitochondrial DNA (mtDNA) mutations. Patients underwent best-corrected visual acuity (BCVA), optical coherence tomography (OCT) measurements (peripapillary retinal nerve fiber layer [pRNFL] and macular ganglion cell layer [GCL] thickness), and neuroimaging findings. Prognostic outcomes were compared between pediatric (≤16 years) and adult (>16 years) subgroups.
    Results: The cohort (male:female ​= ​4.2:1) exhibited a median onset age of 17 years (range:4-42), with 30.77% unilateral involvement. Rare mutations were distributed in MT-ND4(34.62%,m.11696G ​> ​A), MT-ND1(34.62%,including m.3733G ​> ​A/m.3866T ​> ​C), and MT-ND6 (23.08%, m.14502T>C), with 26.92% harboring dual mutations. Younger patients showed significantly better visual recovery (59.09% vs. 22.73% achieving BCVA ≥ 0.3, P ​= ​0.014), despite comparable baseline vision and structural OCT parameters (pRNFL/GCL thickness, all P ​> ​0.05). T2 hyperintensity in the optic nerve magnetic resonance imaging (MRI) was present in 38.46% of cases.
    Conclusions: Our study probes into the clinical and genetic diversity of LHON with rare mtDNA mutations, revealing varied clinical presentations, such as more frequent unilateral involvement and enhanced optic nerve T2 MRI signals. Visual recovery was significantly better in the younger cohort. These results suggest the need for broader genetic testing in atypical LHON cases and offer insights into better prognostic strategies for new therapies.
    Keywords:  Leber's hereditary optic neuropathy; Maternal inheritance; Mitochondrial DNA; Rare mutation
    DOI:  https://doi.org/10.1016/j.aopr.2025.08.001
  6. Nat Cell Biol. 2025 Oct;27(10): 1708-1724
    MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
    Mai Nguyen, Jack J Collier, Olesia Ignatenko, Genevieve Morin, Vanessa Goyon, Alexandre Janer, Camila Tiefensee Ribeiro, Austen J Milnerwood, Sidong Huang, Michel Desjardins, Heidi M McBride.
      Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson's disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-lysosome pathway at the nexus of immune signalling and cell death.
    DOI:  https://doi.org/10.1038/s41556-025-01774-y
  7. JCI Insight. 2025 Oct 16. pii: e199443. [Epub ahead of print]
    Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders.
    Keaton J Solo, Yuxun Zhang, Sivakama S Bharathi, Bob B Zhang, Adam C Richert, Alexandra V Schmidt, Clinton Van't Land, Olivia D'Annibale, Timothy C Wood, Eric S Goetzman.
      Long chain fatty acid oxidation disorders (LC FAODs) cause energy deficits in heart and skeletal muscle that are only partially corrected by current medium chain lipid therapies such as triheptanoin. We find that heart and muscle lack medium chain acyl CoA synthetases, limiting the capacity for β-oxidation of medium-chain fatty acids. Instead, heart and muscle mitochondria robustly respire on medium-chain acylcarnitines. The mitochondrial matrix enzyme carnitine acetyltransferase (CrAT) efficiently converts orally delivered octanoylcarnitine (C8 carnitine) to octanoyl CoA for energy generation. C8-carnitine exhibits twice the oral bioavailability of triheptanoin and distributes to muscle and heart. A single oral dose significantly enhances grip strength and treadmill endurance while attenuating lactic acidosis in two mouse models of LC-FAODs. Thus, medium chain acylcarnitines overcome a previously unrecognized metabolic bottleneck in LC FAOD muscle and may represent an alternative to triglyceride based therapies for bioenergetic disorders.
    Keywords:  Bioenergetics; Genetics; Metabolism; Monogenic diseases; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.199443
  8. Med. 2025 Oct 13. pii: S2666-6340(25)00307-1. [Epub ahead of print] 100880
    The role of mitochondrial genetics in Parkinson's disease: Long-read sequencing as an emerging method.
    Ngan Le Kim Tran, Marka van Blitterswijk, Wolfdieter Springer, Pamela J McLean, Eddie G Martinez-Peña, Rodolfo Savica, Owen A Ross.
      Parkinson's disease (PD) is one of the most devastating neurodegenerative disorders, influenced by a complex interplay of genetic, epigenetic, and environmental factors. Genetic studies and neuropathological evidence suggest that there may be two main forms of early-onset PD driven centrally by either alpha-synuclein aggregation (Lewy bodies) or mitochondrial dysfunction. While numerous studies have utilized omics approaches to investigate the pathogenesis of PD, the role of mitochondrial DNA remains to be fully resolved, in part due to the finite resolution of short-read sequencing technologies. Integrating variations in nuclear and mitochondrial DNA is critical to understanding the etiology of PD and assessing the potential contribution of mitochondrial variation and age-related accumulation of mutations to disease risk. In this review, we explore the role of mitochondrial genetics in PD utilizing long-read sequencing, highlighting its unprecedented versatility in resolving difficult genomic regions and providing critical insights into complex cases of PD.
    Keywords:  Parkinson’s disease; genetics; long-read sequencing; mitochondria; mtDNA
    DOI:  https://doi.org/10.1016/j.medj.2025.100880
  9. Mol Genet Metab. 2025 Oct 06. pii: S1096-7192(25)00251-3. [Epub ahead of print]146(3): 109259
    Amino acid supplementation in patients affected by leukoencephalopathies associated with mitochondrial aminoacyl tRNA synthetase pathogenic variants: Pilot clinical trial in adults and review of literature.
    Alessia Catania, Silvia Marchet, Krisztina Einvag, Eleonora Lamantea, Ettore Salsano, Daniele Ghezzi, Costanza Lamperti.
       BACKGROUND: Mitochondrial aminoacyl tRNA synthetase (mt-ARS) related disorders represent a widely heterogeneous group of diseases affecting the efficiency of mitochondrial protein synthesis. AARS2 and DARS2 biallelic mutations are associated with clinical syndromes prominently characterized by diffuse leukoencephalopathy with a highly variable age of onset, ranging from early infancy to adulthood. Preliminary in vitro results on patients' fibroblasts and some anecdotal reports on patients affected by mt-ARS related disease have suggested a possible benefit of supplementation with the specific substrate amino acid of the defective mt-ARS.
    METHODS: We recruited 6 adult patients affected by AARS2 (n = 2) and DARS2 (n = 4) related leukoencephalopathies and started an oral supplementation with alanine and aspartate, respectively, for a total duration of 2 years. Therapeutic efficacy and safety were assessed through clinical examinations, standardized scales, functional tests, quality of life (QoL) scores, brain MRI, and laboratory analyses.
    RESULTS: Overall, the treatment was safe and well tolerated by all patients, but efficacy endpoints were not met as no significant improvements were observed in global, cognitive, or motor scores.; nonetheless, all patients but one remained clinically stable.
    CONCLUSIONS: Despite inherent limitations of this pivotal trial, our findings suggest that specific amino acid supplementation is a safe intervention but do not yield a clear symptomatic benefit; nevertheless, we cannot exclude a potential role in stabilizing the clinical condition in adult patients with DARS2-related disorders.
    Keywords:  Amino acid; Clinical trial; Leukoencephalopathies; Mitochondrial aminoacyl tRNA synthetase
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109259
  10. Nature. 2025 Oct;646(8085): 530-532
    Faulty mitochondria cause deadly diseases: fixing them is about to get a lot easier.
    Gemma Conroy.
      
    Keywords:  Biotechnology; CRISPR-Cas9 genome editing; Diseases; Gene therapy; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-03307-x
  11. Am J Physiol Cell Physiol. 2025 Oct 16.
    Postnatal Developmental Dynamics of Mitochondrial Complex I in Mouse Tissues.
    Max Siragusa, Belem Yoval-Sánchez, Ivan Guerrero, Alexander Galkin.
      Although the content of mitochondrial enzymes in different tissues can vary greatly, understanding the regulation behind these differences has been hampered by a lack of quantitative knowledge in relation to postnatal development. Here we report a quantitative analysis of developing brain, heart, kidneys, and muscle tissue of C57BL/6J mice, focusing on the content of mitochondrial complex I, a key component of the respiratory chain: We found that in all tissues except kidneys, complex I content gradually increases after birth, reaching a plateau level at around 25 days. Complex I content in muscles does not change significantly until postnatal day 7-10, and then also increases. The greatest increment was found in kidneys, where a 16-fold increase in complex I level after birth was observed. We also found that content of complex I in all postnatal tissues, but muscle, is higher in males than in females. These baseline dynamics of this key mitochondrial flavoprotein serve as a reference for evaluating genetic influences on development and provide a standard for assessing mitochondrial complex I function during postnatal growth.
    Keywords:  MItochondria; Postnatal Development; mitochondrial complex I; mouse; tissue specificity
    DOI:  https://doi.org/10.1152/ajpcell.00692.2025
  12. Mol Genet Metab. 2025 Oct 08. pii: S1096-7192(25)00252-5. [Epub ahead of print]146(3): 109260
    Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).
    Xueyang Pan, Yue Wang, Ning Liu, Xi Luo, V Reid Sutton, William J Craigen, Qin Sun.
      Large deletions in multi-copy mitochondrial DNA (mtDNA) are associated with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), and Pearson syndrome (PS), collectively referred to as single large-scale mtDNA deletion syndromes (SLSMDSs). These deletions are typically sporadic and heteroplasmic, yet the relationship between heteroplasmy levels and disease severity remains uncertain, particularly for low level deletions, making pathogenicity assessment challenging. To evaluate the functional impact of mtDNA deletions in muscle, we retrospectively analyzed 1104 consecutive clinical cases with both mtDNA sequencing and mitochondrial electron transport chain (ETC) enzyme assays performed on the same muscle specimen. Fifteen cases (1.4 %) carried a single large mtDNA deletion and exhibited clinical features consistent with the CPEO/KSS spectrum. Of these, seven showed ETC deficiencies despite low deletion heteroplasmy levels (<10 % in all cases). Four had enzyme deficiencies defined to a single complex, while three had deficiencies in multiple complexes. Complex IV was most frequently impaired, whereas nuclear-encoded complex II activity remained normal in all samples. Notably, the pattern of ETC impairment did not fully correlate with the specific mitochondrial genes disrupted by the deletions. These findings demonstrate that mitochondrial dysfunction can occur at mtDNA deletion heteroplasmy levels far below conventional pathogenic thresholds. This highlights the diagnostic relevance of low-level mtDNA deletions and supports the integration of molecular and functional testing in accurate SLSMDS diagnosis.
    Keywords:  Chronic progressive external ophthalmoplegia (CPEO); ETC complex enzymatic assay; Heteroplasmy; Kearns-Sayre syndrome (KSS); Mitochondrial electron transport chain (ETC); Single large-scale mtDNA deletion syndrome (SLSMDS); mtDNA deletion; mtDNA next-generation sequencing (NGS)
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109260
  13. Biochem J. 2025 Oct 10. pii: BCJ20243016. [Epub ahead of print]
    Lon/Pim1 mediated degradation of presequence translocase-associated motor components Pam16 and Pam18 in Saccharomyces cerevisiae.
    Yerranna Boggula, Arpan Chatterjee, Gaurav Simaiya, Amita Pal, Akash Srinivasan, Naresh Babu Sepuri.
      Mitochondrial protein homeostasis depends mainly on the efficient import and folding of nuclear-encoded proteins, and defects in this process can lead to proteotoxicity, which is harmful to the cell. Mitochondrial chaperones and proteases are essential defense mechanisms that ensure dysfunctional proteins' proper concentration, folding, and degradation. Lon protease 1 (Pim1 in yeast) is the mitochondrial matrix protease known to prevent protein aggregation by degrading unfolded proteins. Here, we show that two essential components of ATP-dependent presequence translocase and associated motor (PAM complex)- Pam18 and Pam16 are specifically targeted for degradation by the proteolytically active Lon/Pim1, both in vitro and in vivo. Further, overexpression of Pam18 and Pam16 exacerbates the growth defect of the delta pim1 strain. Hence, our study reveals, for the first time, that components involved in protein import are substrates of Pim1, which could have potential implications for regulating mitochondrial protein import and proteostasis.
    Keywords:  Lon/Pim1 protease; Mitochondria; Protein turnover; Proteolysis; Proteostasis; Saccharomyces cerevisiae; mitochondrial protein import; presequence translocase-associated motor
    DOI:  https://doi.org/10.1042/BCJ20243016
  14. Int J Mol Sci. 2025 Sep 29. pii: 9525. [Epub ahead of print]26(19):
    Evaluation of Serum FGF21 Levels in Patients with Mitochondrial Aminoacyl-tRNA Synthetase Deficiency.
    Sebnem Tekin Neijmann, Dilek Gunes, Meryem Karaca, Volkan Karaman, Mehmet Cihan Balci, Gulden Fatma Gokcay, Asuman Gedikbasi.
      Fibroblast growth factor 21 (FGF21), a pleiotropic hormone, is a significant modulator of energy homeostasis. We evaluated serum FGF21 levels in patients with a deficiency of mitochondrial aminoacyl-tRNA synthetase (mt-aARSs). Six patients with mitochondrial aminoacyl tRNA synthetase deficiency and twelve healthy volunteers were included in this study. Whole-exome sequencing was used for molecular diagnosis. Serum FGF21 levels in the case group and healthy volunteers were analyzed using the enzyme-linked immunosorbent assay. Exome sequencing test revealed nine different pathogenic variants in the AARS2, EARS2, DARS2, SARS2, and WARS2 genes. A statistically significant difference was found between the serum FGF21 levels of the case and control groups: case group (n = 6), 882.49 ± 923.60 pg/mL; control group (n = 12), 20.89 ± 2.63 pg/mL (p < 0.001). The area under the ROC curve for FGF21 in the differential diagnosis of mitochondrial aminoacyl-tRNA synthetase deficiency was 1.000 (0.813-1.000). Sensitivity and specificity were 100%, and positive and negative predictive values were also 100% for an FGF21 cut-off value > 27.4 pg/mL. Assessment of FGF 21 levels as an indicator of mitochondrial damage in mt-aARSs deficiency may provide insight into the level of damage. Investigation of the biochemical mechanisms underlying the different levels of damage caused by different aminoacyl tRNA synthetases will be important in terms of elucidating clinical heterogeneity.
    Keywords:  AARS2; DARS2; EARS2; FGF21; SARS2; WARS2; mitochondrial aminoacyl tRNA synthetase deficiency; mitochondrial disease
    DOI:  https://doi.org/10.3390/ijms26199525
  15. Curr Biol. 2025 Oct 15. pii: S0960-9822(25)01246-1. [Epub ahead of print]
    Mitochondrial function regulates cell growth kinetics to maintain mitochondrial homeostasis.
    Leeba A Chacko, Hidenori Nakaoka, Richard G Morris, Wallace F Marshall, Vaishnavi Ananthanarayanan.
      Mitochondria are not produced de novo in newly divided daughter cells but are inherited from the mother cell during mitosis. While mitochondrial homeostasis is crucial for living cells, the feedback responses that maintain mitochondrial volume across generations of dividing cells remain elusive. Here, using a microfluidic yeast "mother machine," we tracked several generations of fission yeast cells and observed that cell size and mitochondrial volume grew exponentially during the cell cycle. We discovered that while mitochondrial homeostasis relied on the "sizer" mechanism of cell size maintenance, mitochondrial function was a critical determinant of the timing of cell division; cells born with lower-than-average amounts of mitochondria grew slower and thus added more mitochondria before they divided. Thus, mitochondrial addition during the cell cycle was tailored to the volume of mitochondria at birth, such that all cells ultimately contained the same mitochondrial volume at cell division. Quantitative modeling and experiments with mitochondrial DNA-deficient rho0 cells additionally revealed that mitochondrial function was essential for driving the exponential growth of cells. Altogether, we demonstrate a central role for mitochondrial activity in dictating cellular growth rates and ensuring mitochondrial volume homeostasis.
    Keywords:  S. pombe; fission yeast; growth kinetics; homeostasis; microfluidics; mitochondria; yeast mother machine
    DOI:  https://doi.org/10.1016/j.cub.2025.09.046
  16. Cell Metab. 2025 Oct 10. pii: S1550-4131(25)00434-6. [Epub ahead of print]
    Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.
    Artem Khan, Frederick S Yen, Gokhan Unlu, Nicole L DelGaudio, Ranya Erdal, Michael Xiao, Khando Wangdu, Kevin Cho, Eric R Gamazon, Gary J Patti, Kıvanç Birsoy.
      Solute carriers (SLCs) regulate cellular and organismal metabolism by transporting small molecules and ions across membranes, yet the physiological substrates of ∼20% remain elusive. To address this, we developed a machine-learning platform to predict gene-metabolite associations. This approach identifies UNC93A and SLC45A4 as candidate plasma membrane transporters for acetylglucosamine and polyamines, respectively. Additionally, we uncover SLC25A45 as a mitochondrial transporter linked to serum levels of methylated basic amino acids, products of protein catabolism. Mechanistically, SLC25A45 is necessary for the mitochondrial import of methylated basic amino acids, including ADMA and TML, the latter serving as a precursor for carnitine synthesis. In line with this observation, SLC25A45 loss impairs carnitine synthesis and blunts upregulation of carnitine-containing metabolites under fasted conditions. By facilitating mitochondrial TML import, SLC25A45 connects protein catabolism to carnitine production, sustaining β-oxidation during fasting. Altogether, our study identifies putative substrates for three SLCs and provides a resource for transporter deorphanization.
    Keywords:  SLC25A45; SLC45A4; UNC93A; acetylglucosamine; carnitine synthesis; fasting; metabolomic GWAS; mitochondrial metabolism; polyamines; solute carrier transporters
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.015
  17. Laryngoscope. 2025 Oct 17.
    Bilateral Sudden on Chronic Hearing Loss as an Auditory Manifestation of Mitochondrial DNA Mutations.
    Chin-Nung Liu, Hong-Yu Yan, Steven Chun-Kang Liao, Cheng-Yu Tsai, Li-Huei Tseng, Pei-Hsuan Lin, Ni-Chung Lee, Chen-Chi Wu.
      We presented a series of patients with a mitochondrial DNA mutation who presented to our clinic with sudden bilateral sudden on chronic sensorineural hearing loss; these patients responded well to cochlear implantation. In cases of sudden sensorineural hearing loss-particularly when clinical features raise suspicion for an underlying mitochondrial disorder-genetic testing may offer valuable diagnostic insight and assist in guiding appropriate management strategies.
    Keywords:  genetic testing; mitochondrial DNA mutations; sudden hearing loss
    DOI:  https://doi.org/10.1002/lary.70208
  18. ACS Chem Neurosci. 2025 Oct 16.
    Region-Specific Quantification of 2-Hydroxyglutarate Enantiomers in Murine Brain during Mitochondrial Complex I Deficiency.
    Richard S McCain, Gerardo G Piroli, Holland H Smith, Aman S Sumal, Paul A Grimsrud, William E Cotham, Michael D Walla, Norma Frizzell.
      The Ndufs4-/- mouse is a model of mitochondrial Complex I deficiency that contributes to altered production of the tricarboxylic acid cycle metabolites. We hypothesized that l-2-hydroxyglutarate (l-2-HG) levels would be elevated in the pathologically affected regions of the Ndufs4-/- mouse brain in parallel with metabolic acidosis. We employed a stable isotope dilution method for the concurrent quantification of l-lactate and the distinct 2-HG enantiomers in isolated mouse brain regions. While lactate levels were elevated, as expected in the Ndufs4-/- brain, the levels of l-2-HG and the enantiomer d-2-HG were markedly reduced in a region-specific manner, and this decrease was also reproduced in the Ndufs4-/- serum. The specific and reproducible decreases in 2-HG quantified in Complex I deficiency may have utility as a unique disease biomarker. Quantitative analysis of the mitochondrial proteome of the Ndufs4-/- mouse brainstem indicated an increased abundance of l-2-HG dehydrogenase, suggesting that 2-HG enantiomers are metabolized in the Ndufs4-/- mouse yielding FADH2 to alleviate the bioenergetic deficit.
    Keywords:  2-hydroxyglutarate; brainstem; lactate; mass spectrometry; mitochondrial disease; neurometabolic
    DOI:  https://doi.org/10.1021/acschemneuro.5c00628
  19. Nat Metab. 2025 Oct 13.
    NAD+ precursor supplementation in human ageing: clinical evidence and challenges.
    Kasper T Vinten, Maria M Trętowicz, Evrim Coskun, Michel van Weeghel, Carles Cantó, Rubén Zapata-Pérez, Georges E Janssens, Riekelt H Houtkooper.
      Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01387-7
  20. Front Aging. 2025 ;6 1688482
    Nanoengineered mitochondria for mitochondrial dysfunction and anti-aging interventions.
    Siqi Deng, Yingying Ren, Qian Zhang, Qinling Liu, Jiaxin Long, Kelsey Picard, Miguel Martin, Thomas Miller, Chaofan Yuan, Yunxiang He, Junling Guo.
      Aging is a multifactorial process and a major risk factor for chronic disease. Among its hallmarks, mitochondrial dysfunction plays a central role, driven by impaired respiration and accumulated mitochondrial DNA mutations that disrupt energy metabolism and redox balance. Conventional mitochondrial transplantation has been explored as a therapeutic strategy, but its emphasis on increasing mitochondrial quantity without restoring function has limited success. Recent advances in nanoengineered mitochondria that integrate isolated mitochondria with functional nanomaterials, offer new opportunities to enhance organelle quality, boost metabolic activity, and achieve targeted delivery. Preclinical studies highlight their promise in cardiovascular, neurodegenerative, and other age-related disorders. In this mini-review, mitochondrial dysfunction in aging is first introduced, followed by the summary of rational designed strategies for engineering mitochondrial biohybrids and their emerging applications, and finally translational challenges are further discussed. By bridging materials science and mitochondrial therapy, nanoengineered mitochondria may represent a next-generation approach to anti-aging interventions.
    Keywords:  age-related diseases; anti-aging; mitochondrial function restoration; nanoengineered mitochondrial biohybrids; surface functionalization
    DOI:  https://doi.org/10.3389/fragi.2025.1688482
  21. EMBO Mol Med. 2025 Oct 13.
    Integrated multi-omics mapping of mitochondrial dysfunction and substrate preference in Barth syndrome cardiac tissue.
    Bauke V Schomakers, Adriana S Passadouro, Maria M Trętowicz, Pelle J Simpson, Yorrick R J Jaspers, Michel van Weeghel, Iman Man Hu, Cathelijne M E Lamboo, Denise Cloutier, Barry J Byrne, Jan Bert van Klinken, Paul M L Janssen, Sander R Piersma, Connie R Jimenez, Frédéric M Vaz, Gajja S Salomons, Jolanda van der Velden, Riekelt H Houtkooper, Signe Mosegaard.
      Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. This study describes a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.
    Keywords:  Barth Syndrome; Cardiac Tissue; Integrated Multi-omics; Mitochondrial Dysfunction
    DOI:  https://doi.org/10.1038/s44321-025-00320-5
  22. Methods Mol Biol. 2026 ;2976 119-134
    Analyzing Endolysosome-Mitochondria Membrane Contact Sites by Thin Section TEM of Human Fibroblasts.
    Claudia Parra-Ruiz, Carlos Enrich, Silvana Zanlungo.
      Membrane contact sites (MCS) are dynamic nanoregions of close apposition between two different organelles, functioning as discrete lipid or ion transfer sites. This new concept in cell biology involves unique proteins at both membrane sites, named tethers, and emerges in early observations by transmission electron microscopy (TEM). Currently, this technique still constitutes a valuable tool for MCS visualization and quantification. In the last decade, Lysosomal Storage Diseases (LSD) have been instrumental in studying the MCS between lysosomes (Ly), or endolysosomes (EL), and other organelles in close proximity such as mitochondria or the endoplasmic reticulum (ER). At present, the analysis of composition, functioning, and alterations/rewiring of MCS in health and disease represents an innovative area of research for designing therapeutic strategies in a variety of pathologies. Here, we describe procedures for chemical fixation using the Flat Embedding technique to characterize and quantify the MCS between LE/Lys and mitochondria in human fibroblasts by thin-section TEM.
    Keywords:  Flat embedding; Image analysis; Lysosomal storage diseases; Lysosomes; Membrane contact sites; Mitochondria; Transmission electron microscopy-chemical fixation
    DOI:  https://doi.org/10.1007/978-1-0716-4844-5_10
  23. Nat Metab. 2025 Oct 14.
    Mitochondrial and psychosocial stress-related regulation of FGF21 in humans.
    Mangesh Kurade, Natalia Bobba-Alves, Catherine Kelly, Alexander Behnke, Quinn Conklin, Robert-Paul Juster, Michio Hirano, Caroline Trumpff, Martin Picard.
      Fibroblast growth factor 21 (FGF21) is a metabolic hormone induced by fasting, metabolic stress and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (P < 0.0001) in healthy controls, but increases FGF21 by 32% (P < 0.0001) in people with MitoD, pointing to a functional FGF21 interaction between the stress response and OxPhos capacity. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report associations between FGF21 and psychosocial factors related to stress and wellbeing. Overall, these results highlight a potential role for FGF21 as a stress hormone involved in meeting the energetic needs of psychosocial stress.
    DOI:  https://doi.org/10.1038/s42255-025-01388-6
  24. Curr Opin Clin Nutr Metab Care. 2025 Oct 06.
    The mitochondrial side of frailty.
    Emanuele Marzetti, Rosa Di Lorenzo, Anna Picca.
       PURPOSE OF REVIEW: Frailty, a prevalent geriatric condition marked by reduced physiological reserve and greater vulnerability to stressors, is increasingly linked to mitochondrial dysfunction. This review summarizes current evidence on mitochondrial quality control, bioenergetics, and signaling in frailty, with emphasis on biomarker discovery and translational potential.
    RECENT FINDINGS: Preclinical and human studies have shown that impaired mitochondrial biogenesis, altered dynamics, and defective mitophagy contribute to frailty, sarcopenia, and immune dysregulation. Frail older adults exhibit reduced mitochondrial DNA content, diminished mitochondrial respiratory capacity, elevated reactive oxygen species generation, and distinctive metabolomic changes. Potential biomarkers include mitochondria-derived vesicles, circulating metabolites, and measures of peripheral blood mononuclear cell respiration, which may enable early detection of functional decline. Multivariate profiling approaches have identified sex-specific and shared molecular signatures converging on mitochondrial pathways. Interventions promoting mitochondrial health, including resistance training and targeted immunomodulation, hold promise in slowing frailty progression.
    SUMMARY: Mitochondrial dysfunction lies at the intersection of musculoskeletal, metabolic, and immune changes underpinning frailty. While integrative biomarker panels have defined metabolic signatures, early diagnosis and personalized therapies remain unmet needs. Longitudinal studies are required to establish causality, refine biomarker utility, and guide precision medicine strategies to preserve mitochondrial function, extend healthspan, and improve quality of life in aging populations.
    Keywords:  inflammaging; metabolic dysregulation; mitochondrial quality control; oxidative capacity; physical frailty
    DOI:  https://doi.org/10.1097/MCO.0000000000001175
  25. Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2415153122
    Substrate-dependent activation of LONP1 informs on proteolytic regulation and ATPase motor function.
    Jeffrey T Mindrebo, Gabriel C Lander.
      AAA+ enzymes use energy from ATP hydrolysis to remodel diverse cellular targets. Structures of substrate-bound AAA+ complexes suggest that these enzymes employ a conserved hand-over-hand mechanism to thread substrates through their central pore. However, the fundamental aspects of the mechanisms governing motor function and substrate processing within specific AAA+ families remain unresolved. We used cryoelectron microscopy to structurally interrogate reaction intermediates from in vitro biochemical assays to inform the underlying regulatory mechanisms of the human mitochondrial AAA+ protease, LONP1. Our results demonstrate that substrate binding, rather than nucleotide binding, activates the assembly and allosterically regulates proteolytic activity. The N-terminal domain plays a critical role in this process and facilitates the initial stages of substrate selection and engagement. Moreover, structures of LONP1 actively degrading a substrate in the presence of ATP provide important context to the conventional understanding of the hand-over-hand translocation mechanism, suggesting that ATP hydrolysis is likely not limited to a single position in the right-handed spiral during the hand-over-hand translocation mechanism.
    Keywords:  AAA+ motors; ATP hydrolysis; LONP1; allostery; cryo-EM
    DOI:  https://doi.org/10.1073/pnas.2415153122
  26. Pract Neurol. 2025 Oct 15. pii: pn-2025-004808. [Epub ahead of print]
    Systemic lipomatosis as a clue to mitochondrial myopathy.
    Julia F B Cavalcanti, Ahmed Haydar, Gabriel Keller, Cristiane Araujo Martins Moreno, Andre Macedo-Silva, Edmar Zanoteli.
      
    Keywords:  MITOCHONDRIAL DISORDERS; MYOPATHY; NEUROMUSCULAR
    DOI:  https://doi.org/10.1136/pn-2025-004808
  27. EMBO Mol Med. 2025 Oct 15.
    Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.
    Ang Li, Sen Huang, Shu-Qin Cao, Jinyi Lin, Linping Zhao, Feng Yu, Miaodan Huang, Lele Yang, Jiaqi Xin, Jing Wen, Lingli Yan, Ke Zhang, Maoyuan Jiang, Weidong Le, Peng Li, Yong U Liu, Dajiang Qin, Jiahong Lu, Guang Lu, Hanming Shen, Xiaoli Yao, Evandro F Fang, Huanxing Su.
      Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.
    Keywords:  Amyotrophic Lateral Sclerosis; Drug Screening; Isoginkgetin; Mitophagy; PINK1-Parkin
    DOI:  https://doi.org/10.1038/s44321-025-00323-2
  28. Neurology. 2025 Nov 11. 105(9): e214313
    Pearls and Oy-sters: Chronic Progressive External Ophthalmoplegia With Electrical Myotonia and Negative Initial Genetic Testing.
    Brian Y Li, Julia H Greenberg, Connolly Steigerwald, Renkui Bai, Kurenai Tanji, Elina Zakin, Nicolas J Abreu.
      Chronic progressive external ophthalmoplegia (CPEO), a genetic syndrome characterized by slowly progressive paresis of extraocular muscles, is often due to single large-scale deletions of the mitochondrial genome (mtDNA). Owing to heteroplasmy, mtDNA variants are often not uniformly expressed across tissues. This genetic variability affects clinical presentation and diagnostic testing. We report a case of a 34-year-old woman who presented with symptoms suspicious for a genetic myopathy: chronic asymmetric ptosis, slowly progressive asymmetric weakness, and external ophthalmoplegia. After initial nondiagnostic peripheral genetic testing, whole-exome and mitochondrial genome sequencing of muscle revealed a single large-scale mtDNA deletion, consistent with a diagnosis of mtDNA deletion-associated CPEO. Of interest, electrophysiologic studies showed myotonia in select muscles, a rarely reported finding. We discuss the clinical presentation and diagnostic approach in suspected CPEO, with an emphasis on common pitfalls in genetic testing for mitochondrial myopathies and the need for appropriate tissue and genetic testing modality selection.
    DOI:  https://doi.org/10.1212/WNL.0000000000214313
  29. Biochem Soc Trans. 2025 Oct 16. pii: BST20253089. [Epub ahead of print]
    FASTK post-transcriptional regulators - a 'FAST-tracK' in mitochondrial gene expression.
    Justin Van Riper, Bridget J Corsaro, Monica C Pillon.
      Fas-activated serine/threonine kinase (FASTK) proteins comprise one of the largest families of mitochondrial post-transcriptional regulators. Members are classified based on their conserved C-terminus, which shows homology with the PD-(D/E)XK superfamily of endoribonucleases. However, it is still uncertain which of these FASTK members are catalytic. The six human FASTK homologs rely on their RNA-binding activity to regulate distinct stages of mitochondrial gene expression, including early processing of nascent RNA, 3'-end messenger RNA (mRNA) maturation, ribosomal RNA (rRNA) modification, mRNA stability, and translation. Genetic and genomic studies have highlighted the crucial role of FASTK proteins in balancing the mitochondrial transcriptome and controlling oxidative phosphorylation. However, until recently, the molecular mechanisms governing their RNA metabolic activities have remained elusive. New biochemical and structural advances have provided molecular insights into the architecture and regulation of FASTK proteins. Here, we summarize the current understanding of the FASTK family's specialized roles in gene regulation, with an emphasis on mitochondrial mRNA metabolism by the proteins FASTK, FASTK domain-containing protein 4 (FASTKD4), and FASTKD5. Additionally, we leverage recent experimental structures and artificial intelligence-based prediction models to explore the molecular organization of FASTK proteins and highlight the family's signature C-terminus, a region essential for their RNA-binding activity.
    Keywords:  FASTK; RAP domain; RNA; gene regulation; helix-turn-helix; mitochondria; nuclease
    DOI:  https://doi.org/10.1042/BST20253089
  30. Biochem Pharmacol. 2025 Oct 12. pii: S0006-2952(25)00688-4. [Epub ahead of print] 117423
    Mitochondrial MFN2 integrates the function of multiple organelles to regulate metabolic dysfunction-associated steatotic liver disease: mechanisms and therapeutic insights.
    Yibing Wang, Sitong Wan.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a wide spectrum of liver diseases with increasing global prevalence. Its hallmarks include aberrant lipid accumulation, inflammation, which leads to liver fibrosis. The efficacious therapies for treating MASLD are limited, and the response rates to antifibrotic drugs are moderate. Understanding the novel mechanisms that regulate the progression of MASLD enables the discovery of drugs with higher response rates and safety. Besides the canonical pathogenic pathways, the dysfunctions in the contact and communication between mitochondria, endoplasmic reticulum (ER) and lipid droplet (LD) causatively drive and promote MASLD. Mitofusin-2 (MFN2) is a mitochondria-bound GTPase that stimulates mitochondrial fusion and is an emerging key factor that suppresses the progression of MASLD and liver fibrosis by maintaining the contact between mitochondria, ER and LD. MFN2 interacts with distinct binding proteins in the ER to facilitate the ER-to-mitochondria transfer of Ca2+ and phosphatidylserine. Moreover, MFN2 is essential for mitochondria-LD contact, which facilitates the lipid transfer and maintains homeostasis. Our analyses indicate that MFN2 is a validated therapeutic target, and exercise elevates the expression of mitochondrial MFN2 to enhance fatty acid oxidation. Regarding translational potential, the advantages and limitations of small-molecule- and peptide-based MFN2 agonists are critically discussed. They effectively induce conformational change and activation of MFN2. We demonstrate that echinacoside and compound 5 are the most promising lead compounds for future development. Evaluation of their anti-MASLD and antifibrotic activities and the combination of them with current therapies and exercise to combat MASLD is warranted in the future.
    Keywords:  Agonist; Endoplasmic reticulum; Lipid droplet; MASLD; MFN2; Mitochondria
    DOI:  https://doi.org/10.1016/j.bcp.2025.117423
  31. Mol Cell. 2025 Oct 10. pii: S1097-2765(25)00703-8. [Epub ahead of print]
    SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
    Marilia M Dias, Martin S King, Engy Shokry, Sergio Lilla, Nikki Paul, Peter Thomason, Sara Zanivan, David Sumpton, Edmund R S Kunji, Thomas MacVicar.
      Methylated amino acids accumulate upon the degradation of methylated proteins and are implicated in diverse metabolic and signaling pathways. Disturbed methylated amino acid homeostasis is associated with cardiovascular disease and renal failure. Mitochondria are core processing hubs in conventional amino acid metabolism, but how they interact with methylated amino acids is unclear. Here, we reveal that the orphan mitochondrial solute carrier 25A45 (SLC25A45) is required for the mitochondrial uptake of methylated amino acids. SLC25A45 binds with dimethylarginine and trimethyllysine but has no affinity for unmethylated arginine and lysine. A non-synonymous mutation of human SLC25A45 (R285C) stabilizes the carrier by limiting its proteolytic degradation and associates with altered methylated amino acids in human plasma. Metabolic tracing of trimethyllysine in cancer cells demonstrates that SLC25A45 drives the biosynthesis of the key amino acid derivative, carnitine. SLC25A45 is therefore an essential mediator of compartmentalized methylated amino acid metabolism.
    Keywords:  SLC25; carnitine; metabolism; metabolite transport; methylated amino acids; mitochondria; solute carriers
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.018
  32. Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2508812122
    Polycomb Repressive Complex 1 and USP16 localize to the mitochondrion and influence its function.
    Lei Shi, Chunxu Chen, Xiaokun Jian, Qiushi Wang, Yuan Shen, Asmaa Alajmi, Hao Zhang, Lisa S Shock, Louise T Chow, Hengbin Wang.
      Polycomb Repressive Complex 1 (PRC1) represses gene expression by ubiquitinating histone H2A or physically compacting chromatin. USP16, one of the histone H2A deubiquitinases, antagonizes PRC1-mediated H2A ubiquitination (H2Aub). Here, we report that both PRC1 and USP16 are also localized in mitochondria and influence mitochondrial function directly. Our findings are based on immunofluorescence and proximity ligation assays, cell fractionation, and biochemical analyses of isolated or affinity-purified mitochondria. We further showed that PRC1 and USP16 function with the ubiquitin pathway. Auxin-induced, mitochondria-specific depletion of the PRC1 subunit RING2 altered the ubiquitination status of mitochondrial proteins, including H2Aub. Disruption of PRC1, either through double knockout (KO) of RING1 and RING2 or through mitochondria-specific deletion of RING2 in the RING1 KO background, caused profound alterations in mitochondrial proteome and led to disturbances in mitochondrial integrity and impaired respiratory function. Thus, in addition to their canonical functions in the nucleus, PRC1 and USP16 also translocate into mitochondria and directly impact mitochondrial integrity and function.
    Keywords:  PRC1; USP16; mitochondria; respiratory function; ubiquitin
    DOI:  https://doi.org/10.1073/pnas.2508812122
  33. Open Biol. 2025 Oct;15(10): 240376
    HMGB1 and mitochondrial dysfunction: a double-edged sword in ageing.
    Maheen Wahid, Margaret Cunningham.
      Ageing is an intricate and progressive decline across all biological systems, marked by various molecular and cellular processes termed as the hallmarks of ageing. One of the hallmarks is mitochondrial dysfunction, which is brought about through several pathways: mutations in mitochondrial DNA, elevated reactive oxygen species production, disrupted mitochondrial dynamics and impaired mitophagy. Here, we explore the role of high mobility group box 1 (HMGB1) as a potential contributor to mitochondrial dysfunction, examining how it may influence these pathways through its dual roles as both a protector of mitochondrial integrity and a promoter of inflammatory damage. Furthermore, we consider how mitochondrial dysfunction, possibly mediated by HMGB1, could link to other hallmarks of ageing, positioning HMGB1 as a possible central regulator in the ageing process.
    Keywords:  HMGB1; ageing; mitochondrial dysfunction
    DOI:  https://doi.org/10.1098/rsob.240376
  34. J Assist Reprod Genet. 2025 Oct 18.
    Ethical challenges in extending mitochondrial replacement therapy (MRT) for overcoming poor egg quality in older women without mitochondrial diseases.
    Alexis Heng Boon Chin, Adrian Villalba, Ido Alon, Ningyu Sun, Jiao Yang.
      Recently, eight healthy human offspring were born through mitochondrial replacement therapy (MRT) with pronuclear transfer (PNT), aimed at preventing the transmission of pathological mitochondrial DNA (mtDNA) mutations. These encouraging preliminary results on the safety of MRT, accompanied by some early neonatal findings and ongoing follow-ups, open up the possibility for its broader application in addressing age-related female infertility by enhancing oocyte quality in older women, commonly referred to as ooplasmic donation or ooplasmic transfer. Because female fertility declines sharply with age, and not all women choose to undergo elective egg freezing (oocyte cryopreservation), there will always be a substantial number of older female IVF patients who are unable to conceive with their own oocytes. For such patients, enabling them to conceive genetically related offspring via MRT would be a far more preferable alternative to conventional egg donation, which disrupts the continuity of maternal genetic lineage. However, extending the use of MRT from the prevention of mitochondrial diseases to the treatment of age-related infertility raises numerous ethical issues. A significant challenge lies in balancing the aspirations of infertile older women to have genetically related offspring with the medical risks and ethical concerns associated with the MRT procedure. To navigate these ethical challenges, some policy recommendations are proposed, including (i) MRT should be conducted in clinical trials until its long-term safety is validated, (ii) rigorous patient counseling to ensure informed consent, (iii) stringent regulations to govern egg donation for MRT, and (iv) implementation of an internationally recognized ethical and regulatory framework for MRT.
    Keywords:  Advanced reproductive age; Female infertility; Genome; Mitochondrial donation; Mitochondrial replacement techniques; Ooplasm
    DOI:  https://doi.org/10.1007/s10815-025-03713-0
  35. Int J Mol Sci. 2025 Oct 07. pii: 9741. [Epub ahead of print]26(19):
    Temporal Interactome Mapping of Human Tau in Drosophila Reveals Progressive Mitochondrial Engagement and Porin/VDAC1-Dependent Modulation of Toxicity.
    Eleni Tsakiri, Martina Samiotaki, Efthimios M C Skoulakis, Katerina Papanikolopoulou.
      Tau protein misfolding and aggregation are central to Tauopathies, yet the temporal dynamics of Tau interactions in vivo remain poorly understood. Here, we applied quantitative proteomics to demonstrate that the interactome of human Tau in adult Drosophila brains changes dynamically over a 12-day time course, revealing a progressive shift from early cytosolic and ribosomal associations to late enrichment of mitochondrial and synaptic partners. Notably, the mitochondrial pore protein Porin/VDAC1 was identified as a late-stage interactor and functional analyses demonstrated that Tau overexpression impairs mitochondrial respiration, elevates oxidative damage, and disrupts carbohydrate homeostasis. To validate this temporally specific interaction, Porin was downregulated, resulting in reduced Tau mitochondrial association, phosphorylation and aggregation. Paradoxically, however, Porin attenuation exacerbated Tau-induced toxicity, including shortened lifespan, locomotor deficits, and impaired learning. These findings indicate that while Porin facilitates pathological Tau modifications, it is also essential for neuronal resilience, highlighting a complex role in modulating Tau toxicity. Our study provides a temporal map of Tau-associated proteome changes in vivo and identifies mitochondria as critical mediators of Tau-driven neurodegeneration.
    Keywords:  Drosophila; Tau protein; mitochondria; porin; proteomics
    DOI:  https://doi.org/10.3390/ijms26199741
  36. J Clin Invest. 2025 Oct 14. pii: e184474. [Epub ahead of print]
    Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy.
    Natalia Dominik, Stephanie Efthymiou, Christopher J Record, Xinyu Miao, Renee Q Lin, Jevin M Parmar, Annarita Scardamaglia, Reza Maroofian, Simon A Lowe, Gabriel N Aughey, Abigail D Wilson, Riccardo Curro, Ricardo P Schnekenberg, Shahryar Alavi, Leif Leclaire, Yi He, Kristina Zhelcheska, Yohanns Bellaiche, Isabelle Gaugué, Mariola Skorupinska, Liedewei Van de Vondel, Sahar I Da'as, Valentina Turchetti, Serdal Güngör, Gavin V Monahan, Ehsan Ghayoor Karimiani, Yalda Jamshidi, Phillipa J Lamont, Camila Armirola-Ricaurte, Haluk Topaloglu, Albena Jordanova, Mashaya Zaman, Selina H Banu, Wilson Marques, Pedro J Tomaselli, Busra Aynekin, Ali Cansu, Huseyin Per, Ayten Güleç, Javeria Raza Alvi, Tipu Sultan, Arif Khan, Giovanni Zifarelli, Shahnaz Ibrahim, Grazia M S Mancini, M M Motazacker, Esther Brusse, Vincenzo Lupo, Teresa Sevilla, A Nazli Başak, Seyma Tekgul, Robin J Palvadeau, Jonathan Baets, Yesim Parman, Arman Çakar, Rita Horvath, Tobias B Haack, Jan-Hendrik Stahl, Kathrin Grundmann-Hauser, Joohyun Park, Stephan Zuchner, Nigel G Laing, Lindsay A Wilson, Alexander M Rossor, James Polke, Fernanda Barbosa Figueiredo, André Pessoa, Fernando Kok, Antônio Rodrigues Coimbra-Neto, Marcondes C Franca, Gianina Ravenscroft, Sherifa A Hamed, Wendy K Chung, Alan M Pittman, Daniel P Osborn, Michael Hanna, Andrea Cortese, Mary M Reilly, James Ec Jepson, Nathalie Lamarche-Vane, Henry Houlden.
      Charcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies. Despite progress in genetic sequencing, around a quarter of patients remain unsolved. Here, we identify 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families. The ARHGAP19 protein acts as a negative regulator of the RhoA GTPase. In vitro biochemical and cellular assays revealed that patient variants impair the GTPase-activating protein (GAP) activity of ARHGAP19 and reduce ARHGAP19 protein levels. Combined in vitro and in vivo studies reveal that human ARHGAP19, and conserved ARHGAP19 orthologs in Drosophila and Zebrafish, influence motoneuron morphology and promote locomotor capacity. Transcriptomic studies further demonstrate that ARHGAP19 regulates cellular pathways associated with motor proteins and the cell cycle. Taken together, our findings establish ARHGAP19 variants as a cause of inherited neuropathy acting through a loss-of-function mechanism.
    Keywords:  Genetics; Neuromuscular disease; Neuroscience
    DOI:  https://doi.org/10.1172/JCI184474
  37. Circ Res. 2025 Oct 15.
    Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation.
    Julius Ryan D Pronto, Fleur E Mason, Eva A Rog-Zielinska, Funsho E Fakuade, Donata Bülow, Marcell Tóth, Khaled Machwart, Paulina Brandes, Felix Wiedmann, Michael Kohlhaas, Alexander Nickel, Matthias Wolf, Julian Mustroph, Kim-Chi Vu, Sören Brandenburg, Tri Q Do, Peter Joshua Siedler, Katharina Ritzenhoff, Zongqian Xue, Xiaobo Zhou, Stefanie Kestel, Olga Dschun, Oksana Kyshynska, George Kensah, Robyn T Rebbeck, Aschraf El-Essawi, Ahmad Fawad Jebran, Bernhard C Danner, Hassina Baraki, Johann Schredelseker, Ivan Bogeski, Bianca J J M Brundel, Stephan E Lehnart, Constanze Bening, Ingo Kutschka, Felix Bremmer, Stefan Kallenberger, Silvio O Rizzoli, Björn C Knollmann, Stefan Neef, Katrin Streckfuss-Bömeke, Constanze Schmidt, Christoph Maack, Niels Voigt.
       BACKGROUND: Mitochondrial calcium (Ca2+) is a key regulator of cardiac energetics by stimulating the tricarboxylic acid cycle during elevated workload. Atrial fibrillation (AF) is associated with a reduction in cytosolic Ca2+ transient amplitude, but its effect on mitochondrial Ca2+ handling and cellular redox state has not been explored in AF.
    METHODS: Cardiac myocytes isolated from patient-derived right atrial biopsies were subjected to workload transitions using patch-clamp stimulation and β-adrenergic stimulation (isoproterenol). In conjunction, NAD(P)H/flavin adenine dinucleotide autofluorescence, cytosolic and mitochondrial [Ca2+] were monitored using epifluorescence microscopy. Sarcoplasmic reticulum and mitochondria were imaged using electron tomography and stimulated emission depletion microscopy. The effects of the mitochondrial Ca2+ uptake enhancer ezetimibe on proarrhythmic activity in atrial myocytes and on AF burden in patients were investigated.
    RESULTS: Mitochondrial Ca2+ accumulation during increased workload was blunted in AF, and was associated with impaired regeneration of nicotinamide adenine dinucleotide and flavin adenine dinucleotide. Nanoscale imaging revealed spatial disorganization of sarcoplasmic reticulum and mitochondria, associated with microtubule destabilization. This was confirmed in human induced pluripotent stem cell-derived myocytes, where nocodazole treatment displaces mitochondria and increases proarrhythmic Ca2+ sparks, which were rescued by MitoTEMPO. Ezetimibe also reduced the occurrence of arrhythmogenic Ca2+ release events both in AF myocytes and nocodazole-treated human induced pluripotent stem cell-derived cardiac myocytes. Retrospective patient analysis also revealed a reduced AF burden in patients on ezetimibe treatment.
    CONCLUSIONS: Mitochondrial Ca2+ uptake and accumulation are impaired in atrial myocytes from patients with AF. The disturbed spatial association between sarcoplasmic reticulum and mitochondria driven by destabilized microtubules may underlie impaired Ca2+ transfer in AF. Enhancing mitochondrial Ca2+ uptake potentially protects against arrhythmogenic events.
    Keywords:  atrial fibrillation; calcium; ezetimibe; microtubules; mitochondria
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325658
  38. Nucleic Acids Res. 2025 Oct 14. pii: gkaf1000. [Epub ahead of print]53(19):
    Ligase 3 prevents oxidative strand break-induced mitochondrial DNA loss but is not essential for replicative circularization.
    Genevieve Trombly, Afaf Milad Said, Alexei P Kudin, Kerstin Hallmann, Anano Kakabadze, Viktoriya Peeva, Kerstin Becker, Karl Köhrer, Gábor Zsurka, Wolfram S Kunz.
      The mitochondrial isoform of LIG3 is proposed to catalyze both circularization of newly replicated mitochondrial DNA (mtDNA) and rejoining of free mtDNA strands in base excision and single-strand break repair. Inactivation of LIG3 has been reported to cause embryonic lethality in mice due to loss of mtDNA. Here, we applied genome editing to inactivate LIG3 in HEK 293 cells and observed only a moderate decrease of mtDNA copy numbers. BrdU incorporation experiments confirmed ongoing synthesis of intact supercoiled mtDNA. Using ultra-deep long-read sequencing of isolated mtDNA, we detected increased frequencies of single-strand and double-strand breaks clustering at sites with high GC-content, as well as hallmarks of accelerated degradation of linear mtDNA. This is likely due to the missing repair of intrinsic oxidative single-strand breaks, since the frequency of detected single-strand breaks was dependent on oxygen tension and on expression levels of enzymes involved in ROS (reactive oxygen species) defense. Exogenous oxidative challenge, that resulted in transient mtDNA damage in wild-type cells, caused dramatic mtDNA loss in LIG3-/- cell lines. Thus, our data provide evidence for the pivotal role of LIG3 in preventing mtDNA loss after oxidative damage and corroborate the hypothesis that oxidative strand break-induced mtDNA degradation is highly relevant for mtDNA turnover in vivo.
    DOI:  https://doi.org/10.1093/nar/gkaf1000
  39. Cell Rep. 2025 Oct 13. pii: S2211-1247(25)01183-0. [Epub ahead of print]44(10): 116412
    CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.
    Alison Galloway, Katarzyna Knop, Carolina Gomez-Moreira, Vanessa Xavier, Sarah Thomson, Harunori Yoshikawa, Olga Suska, Radoslaw Lukoszek, Aneesa Kaskar, Angus I Lamond, Thomas MacVicar, Victoria H Cowling.
      During T cell activation, mitochondrial biogenesis and cellular metabolism are altered to meet the elevated energy demands of protein synthesis, rapid proliferation, and effector T cell function. The mechanisms coupling mitochondrial dynamics to T cell status are unclear. Here, we report that RNA cap methyltransferase 1 (CMTR1) is induced in activated T cells, methylating the first nucleotide on mRNA and U2 small nuclear RNA (snRNA), a component of the spliceosome. Using transcriptomic analyses, we identify a functional splicing module regulating mitochondrial dynamics in T cells, which alters the isoforms of proteins controlling mitochondrial fission and fusion. Through epitranscriptomic control of U2 snRNA and splicing, CMTR1 directs protein isoform selection during T cell activation to promote the development of longer mitochondria with increased respiratory capacity. Thus, CMTR1 upregulation supports the energetic demands of T cell activation, survival, and immune responses.
    Keywords:  CMTR1; CP: Immunology; CP: Metabolism; MFF; RNA cap; RNA methylation; T cell; T lymphocyte; metabolism; mitochondria; snRNA; splicing
    DOI:  https://doi.org/10.1016/j.celrep.2025.116412
  40. Nat Med. 2025 Oct 16.
    MRI-based multi-organ clocks for healthy aging and disease assessment.
    MULTI Consortium
      Biological aging clocks across organ systems and tissues have advanced understanding of human aging and disease. In this study, we expand this framework to develop seven magnetic resonance imaging-based multi-organ biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney and pancreas. Using data from 313,645 individuals curated by the MULTI Consortium, we link the seven MRIBAGs to 2,923 plasma proteins, 327 metabolites and 6,477,810 common genetic variants. Genome-wide associations identify 53 MRIBAG-locus pairs (P < 5 × 10-8). Genetic correlation and Mendelian randomization analyses support organ-specific and cross-organ interconnection, including 24 non-MRI biological aging clocks and 525 disease endpoints. Through functional gene mapping and Bayesian co-localization multi-omics evidence, we prioritize nine druggable genes as targets for future anti-aging treatments. Furthermore, the seven MRIBAGs are linked to future risk of systemic disease endpoints (for example, diabetes mellitus) and all-cause mortality. Finally, participants with more youthful versus more aged brain profiles exhibited distinct cognitive decline trajectories over 240 weeks of treatment with the Alzheimer's disease drug solanezumab, although this heterogeneity cannot be fully attributed to the drug. In summary, we developed seven MRIBAGs that enhance the existing multi-organ biological aging framework, and we demonstrate their clinical potential to advance aging research.
    DOI:  https://doi.org/10.1038/s41591-025-03999-8
  41. Mol Genet Metab. 2025 Sep 22. pii: S1096-7192(25)00227-6. [Epub ahead of print]146(3): 109236
    Cardiac transplant outcomes in a pediatric patient with novel homozygous variants in TOP3Α causing mitochondrial dysfunction.
    J Ganesh, C Donnelly, A Ligezka, G Preston, E Morava, M Breilyn, I Marin-Valencia, H Raynes, N Bansal, J Lamour, C Mintz, T Kozicz.
      Pathogenic variants TOP3A gene have been recently described to cause a multisystem disorder associated with mitochondrial dysfunction in adults (Nicholls et al., 2018 [1]) and with a Bloom syndrome-like disorder in children (Martin et al., 2018 [2]). We present the case of an 11-year-old male with homozygosity for a novel variant in TOP3A with myopathy, ataxia, and atrioventricular conduction defect similar to the adult cases described in the literature. He developed dilated cardiomyopathy and presented in acute decompensated heart failure requiring left ventricular assist device support as a bridge to heart transplantation. Clinical and laboratory features showed mitochondrial dysfunction confirming pathogenicity of the TOP3A variants. However, unlike the other pediatric cases of TOP3A related disease reported so far, the features of Bloom syndrome were not evident in this patient.
    Keywords:  Cardiac transplant; Mitochondrial disease; TOP3A
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109236
  42. Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2511596122
    Engineered 3D immuno-glial-neurovascular human miBrain model.
    Alice E Stanton, Adele Bubnys, Emre Agbas, Benjamin James, Dong Shin Park, Alan Jiang, Rebecca L Pinals, Liwang Liu, Nhat Truong, Anjanet Loon, Colin Staab, Oyku Cerit, Hsin-Lan Wen, David Mankus, Margaret E Bisher, Abigail K R Lytton-Jean, Manolis Kellis, Joel W Blanchard, Robert Langer, Li-Huei Tsai.
      Patient-specific, human-based cellular models integrating a biomimetic blood-brain barrier, immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. To construct a human cell-based model that includes these features and all six major brain cell types needed to mimic disease and dissect pathological mechanisms, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model by engineering a brain-inspired 3D hydrogel and identifying conditions to coculture these six brain cell types, all differentiated from patient induced pluripotent stem cells. miBrains recapitulate in vivo-like hallmarks inclusive of neuronal activity, functional connectivity, barrier function, myelin-producing oligodendrocyte engagement with neurons, multicellular interactions, and transcriptomic profiles. We implemented the model to study Alzheimer's Disease pathologies associated with APOE4 genetic risk. APOE4 miBrains differentially exhibit amyloid aggregation, tau phosphorylation, and astrocytic glial fibrillary acidic protein. Unlike the coemergent fate specification of glia and neurons in other organoid approaches, miBrains integrate independently differentiated cell types, a feature we harnessed to identify that APOE4 in astrocytes promotes neuronal tau pathogenesis and dysregulation through crosstalk with microglia.
    Keywords:  biomaterials; brain organoid; microphysiological system; neuro-immune; neurovascular
    DOI:  https://doi.org/10.1073/pnas.2511596122
  43. Aging Cell. 2025 Oct 16. e70262
    Translational Remodeling of the Synaptic Proteome During Aging.
    Cinzia Caterino, Martino Ugolini, William Durso, Kristina Jevdokimenko, Marco Groth, Konstantin Riege, Matthias Görlach, Eugenio Fornasiero, Alessandro Ori, Steve Hoffmann, Alessandro Cellerino.
      An important hallmark of aging is the loss of proteostasis, which can lead to the formation of protein aggregates and mitochondrial dysfunction in neurons. Although it is well known that protein synthesis is finely regulated in the brain, especially at synapses, where mRNAs are locally translated in an activity-dependent manner, little is known as to the changes in the synaptic proteome and transcriptome during aging. Therefore, this work aims to elucidate the relationship between the transcriptome and proteome at the soma and synaptic levels during aging. Proteomic and transcriptomic data analysis reveal that, in young animals, proteins and transcripts are correlated and synaptic regulation is driven by changes in the soma. During aging, there is a decoupling between transcripts and proteins and between somatic and synaptic compartments. Furthermore, the soma-synapse gradient of ribosomal genes changes upon aging, that is, ribosomal transcripts are less abundant and ribosomal proteins are more abundant in the synaptic compartment of old mice with respect to younglings. Additionally, transcriptomics data highlight a difference in the splicing of certain synaptic mRNA with aging. Taken together, our data provide a valuable resource for the study of the aging synapse.
    Keywords:  RNA‐Seq; aging; alternative splicing; bioinformatics; synaptosomes
    DOI:  https://doi.org/10.1111/acel.70262
  44. Geroscience. 2025 Oct 13.
    Ferroptosis-related stress during aging and its relevance to disease.
    Pamela Maher, David Soriano-Castell, Nawab John Dar, Salvador Soriano, Antonio Currais.
      Aging is a progressive and complex process of physiological changes that accumulate over time and end up undermining organismal performance. In many cases, this leads to the development of age-related diseases. Therefore, the identification of the exact mechanisms connecting aging to disease will be critical for the advancement of biomedical research in the field. Recently, a growing number of reports have linked ferroptosis, a form of non-apoptotic regulated cell death, to numerous age-related human pathologies. Although key molecular events associated with ferroptosis have been consistently observed with aging in various tissues, the interaction between ferroptosis and aging remains mostly unexplored. In this review, we investigate this interplay by examining reported findings from three different perspectives: (1) the manifestation of ferroptosis with age; (2) the acceleration of aging when ferroptosis is experimentally enhanced; and (3) the potential to slow, stop, or reverse aging through ferroptosis-targeted therapeutic interventions. Based on this analysis, we hypothesize that, although ferroptosis is defined as a cell death pathway, ferroptosis-related processes can operate at a chronic, sublethal level during aging. Importantly, the persistence of this stress might increase the susceptibility of organisms to age-associated diseases by undermining fundamental cellular functions that are critical to their healthspan, even in the absence of overt cell death. The implications for the design and development of new treatments for a broad range of age-related diseases where ferroptosis-related stress could play a central role is discussed.
    Keywords:  Age-related diseases; Ferroptosis; Glutathione; Iron; Lipid peroxidation; Mitochondrial disfunction
    DOI:  https://doi.org/10.1007/s11357-025-01929-7
  45. Nat Chem Biol. 2025 Oct 15.
    Molecular basis for noncanonical transcription initiation from Np4A alarmones.
    Wenqian Duan, Abhishek Kaushik, Ilona C Unarta, Yue Wu, Mengjie M J Liu, Jacob W Weaver, Bing Wang, William J Rice, Daniel J Luciano, Joel G Belasco, Xuhui Huang, Evgeny Nudler, Alexander Serganov.
      Stress-induced dinucleoside tetraphosphates (Np4Ns, where N is adenosine, guanosine, cytosine or uridine) are ubiquitous in living organisms, yet their function has been largely elusive for over 50 years. Recent studies have revealed that RNA polymerase can influence the cellular lifetime of transcripts by incorporating these alarmones into RNA as 5'-terminal caps. Here we present structural and biochemical data that reveal the molecular basis of noncanonical transcription initiation from Np4As by Escherichia coli and Thermus thermophilus RNA polymerases. Our results show the influence of the first two nucleotide incorporation steps on capping efficiency and the different interactions of Np4As with transcription initiation complexes. These data provide critical insights into the substrate selectivity that dictates levels of Np4 capping in bacterial cells.
    DOI:  https://doi.org/10.1038/s41589-025-02044-6
  46. Nat Rev Gastroenterol Hepatol. 2025 Oct 13.
    Towards a reference cell atlas of liver diversity over the human lifespan.
    Sarah A Taylor, Gary D Bader, Sonya MacParland, Alan C Mullen, Tallulah Andrews, Alex G Cuenca, Ramanuj DasGupta, Adam J Gehring, Dominic Grün, Martin Guilliams, Aliya Gulamhusein, Neil C Henderson, Gideon Hirschfield, Stacey S Huppert, Shalev Itzkovitz, Z Gordon Jiang, Georg M Lauer, Ian McGilvray, Krupa R Mysore, Carlos J Pirola, Gerald Quon, Mohammad Rahbari, Aviv Regev, Amanda Ricciuto, Charlotte L Scott, Ankur Sharma, Silvia Sookoian, Michelle M Tana, Sarah A Teichmann, Ludovic Vallier, Ioannis S Vlachos, Bruce Wang, Mei Zhen.
      The goal of the Human Liver Cell Atlas (HLiCA) is to create a comprehensive map that defines the normal functions of diverse liver cell types and their spatial relationships over the human lifespan. This project fits within the goals of the Human Cell Atlas to create comprehensive reference maps of all human cells as a basis for both understanding human health and diagnosing, monitoring and treating disease. Through collection of samples from diverse individuals, data integration across technologies and overcoming liver-specific challenges for experimental methods, the HLiCA will map as many cell types and states as possible in healthy human livers from individuals across all ages and many ancestries. Establishing this HLiCA of healthy livers is a critical step to begin to understand perturbations in disease. The HLiCA will be available on an open-access platform to facilitate data sharing and dissemination. We expect that creation of the HLiCA will help to lay the foundation for new research initiatives to advance our understanding of liver disease, improve methods of tissue engineering, and identify novel prognostic biomarkers and therapies to improve patient outcomes. We describe key experimental and computational challenges to overcome in building the atlas and the potential impact of the atlas on disease research.
    DOI:  https://doi.org/10.1038/s41575-025-01114-3
  47. J Transl Med. 2025 Oct 16. 23(1): 1111
    Targeting mitochondrial transporters and metabolic reprogramming for disease treatment.
    Mboneye Anselme, Huafeng He, Chengyang Lai, Wenwei Luo, Shilong Zhong.
      In the realm of cellular biochemistry, mitochondria have been increasingly recognized for their critical role in both cellular metabolism and the etiology of various diseases. Mitochondrial transporters (MTs) are essential for maintaining cellular energy dynamics and metabolic fluxes by facilitating the bidirectional transfer of metabolites across mitochondrial membranes. Dysregulation of these transporters, such as the mitochondrial pyruvate carrier (MPC), citrate carrier (SLC25A1), and voltage-dependent anion channel (VDAC), disrupts energy metabolism, redox balance, and cellular signaling, contributing to the pathogenesis of neurodegenerative diseases (NDDs), cardiovascular diseases (CVDs), type 2 diabetes (T2D), and cancer. In NDDs, impaired transporters exacerbate oxidative stress and neuronal death, while in CVDs, they lead to energy deficits and heart failure. In T2D, dysfunctional transporters like MPC and carnitine palmitoyltransferase (CPT) systems drive insulin resistance and metabolic dysregulation. In cancer, upregulated transporters such as citrate carrier (SLC25A1), and dicarboxylate carrier (SLC25A10) as well as metabolic shifts like the Warburg effect support tumor growth and survival. Targeting MTs and metabolic reprogramming (MR) offers significant therapeutic potential. Preclinical studies have demonstrated the efficacy of mitochondrial-targeted therapies (MTT), such as adenosine monophosphate-activated protein kinase (AMPK) activators and antioxidants, in restoring metabolic homeostasis and reducing disease pathology. In cancer, inhibitors of glutamine transporters and VDAC1 are being explored to disrupt tumor metabolism. Several therapies are advancing to clinical trials, including mitochondrial-targeted drugs for NDDs and metabolic modulators for T2D and cancer, highlighting their translational potential. Despite notable individual achievements and isolated reviews in this field, there remains a lack of comprehensive syntheses that integrate these advancements. This review seeks to combine the prevailing scientific evidence and outline prospective research trajectories. The gathered data robustly support the significant potential of targeting MTs as a groundbreaking approach in the treatment of complex diseases, with the potential to significantly improve health outcomes and mitigate disease progression.
    Keywords:  Cellular metabolism; Disease treatment; Metabolic reprogramming; Mitochondria; Mitochondrial transporters
    DOI:  https://doi.org/10.1186/s12967-025-06976-4
  48. Cell Rep Methods. 2025 Oct 14. pii: S2667-2375(25)00238-3. [Epub ahead of print] 101202
    SpIC3D imaging for spinal in situ contrast 3D visualization.
    Lucy Liang, Alessandro Fasse, Arianna Damiani, Maria K Jantz, Uzoma Agbor, Matteo Del Brocco, Rachel Monney, Cecelia Rowland, Taylor Newton, Chaitanya Gopinath, David J Schaeffer, Christi L Kolarcik, John G Pagiazitis, George Z Mentis, Lee E Fisher, Esra Neufeld, Marco Capogrosso, Robert A Gaunt, T Kevin Hitchens, Elvira Pirondini.
      High-definition visualization techniques are critical for understanding the neuroanatomy of the spinal cord, an essential structure for sensorimotor and autonomic functions, in both healthy and pathological conditions. Magnetic resonance imaging (MRI) is a common method for visualizing neural structures in 3D. However, techniques for spinal cord MRI have historically achieved limited visualization of rootlets and nerves, especially at lower spinal levels, due to their highly complex and compact organization. Here, we developed a spinal in situ contrast 3D imaging (SpIC3D) method that allows visualization of spinal compartments in fixed animal and human specimens with high resolution (50 μm) at various spinal levels. Using SpIC3D, we achieved quantification of neuronal cell density in dorsal root ganglia, multi-segment identification of individual rootlets and roots, and volumetric reconstruction of multiple spinal structures for computational modeling. SpIC3D provides a basis for accelerated spinal pathology characterization and personalized spinal cord stimulation treatments.
    Keywords:  CP: Imaging; CP: Neuroscience; computational modeling; dorsal root entry zone; dorsal root ganglion; fiber tractography; in situ; multi-segment; multi-species; multi-tissue; spinal cord; volumetric imaging
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101202
  49. Nat Metab. 2025 Oct 15.
    EMito-Metrix enables automated evaluation of mitochondrial morphology across species.
    Eléna Morin, Emmanuel Doumard, Lisa M Hartnell, Beñat Salegi Ansa, Jean-Philippe Leduc-Gaudet, Aurélie Quillien, Jean Nakhle, Séverine Ethuin, Dominique Goudounèche, Bruno Payré, Vanessa Soldan, Stéphanie Balor, Anna Mattout, Jacques Rouquette, Laurence Dubois, Coralie Sengenès, Valérie Planat, Louis Casteilla, Armelle Yart, Cédric Dray, Julien Aligon, Luigi Ferrucci, Élise Duchesne, Sabah N A Hussain, Gilles Gouspillou, Laura Formentini, Arnaud Mourier, Olivier R Baris, Philippe Valet, Harold Parpex, Paul Monsarrat, Mathieu Vigneau, Jean-Philippe Pradère.
      
    DOI:  https://doi.org/10.1038/s42255-025-01400-z
  50. Hum Mol Genet. 2025 Oct 15. pii: ddaf150. [Epub ahead of print]
    Genetic dissection of Huntington's disease modification by variation at RRM2B.
    Kiuk Lee, Baehyun Shin, Mingyu Kim, Seong Won Lee, Young Mi Oh, Kyung-Hee Kim, Andrew Jiang, Kwanyoung Ko, Tammy Gillis, Diane Lucente, Ramee Lee, Seung Kwak, Jong-Min Lee, Vanessa C Wheeler, Andrew S Yoo, James F Gusella, Marcy E MacDonald, Ihn Sik Seong.
      Huntington's disease (HD) is driven by somatic expansion of the HTT CAG repeat, with onset modified by genetic factors. One such modifier, 8AM1, maps to chromosome 8 near RRM2B, a gene not directly involved in the machinery that lengthens the repeat. To investigate this locus, we performed capture sequencing and identified variants at both the 5' and 3' ends of RRM2B with expected minor allele frequencies. A polymorphic frameshift variant (rs1037699) in an alternate exon 1 disrupts expression of a previously uncharacterized RRM2B isoform 2, but not isoform 1. Functional analyses in RRM2B knock-out cells and 8AM1 heterozygous LCLs suggest that isoform 2 may function at mitochondria. Several 3' variants, including a 21 bp 3'UTR deletion (rs200678743) and peak tag-SNV (rs79136984), act as cis expression quantitative trait loci. Analysis of HD onset data (n = 12,982) revealed that 5' and 3' variants contribute independently to the 8AM1 modifier effect, with full impact observed only in the absence of the frameshift variant. Knockdown of both isoforms increased neurodegeneration in HD neurons derived from pre-symptomatic patient fibroblasts, supporting an intersection of RRM2B biology and HD pathogenesis. We conclude that the 8AM1 haplotype, present in ~ 14% of Europeans, modifies RRM2B expression in a cell- and context-dependent manner, thereby accelerating HD onset in mutation carriers.
    Keywords:  Expression quantitative trait loci; Genetic Modifier; Neurodegeneration; mitochondrial DNA maintenance; ribonucleotide reductase
    DOI:  https://doi.org/10.1093/hmg/ddaf150
  51. Nat Rev Bioeng. 2025 May;3(5): 360-373
    Extracellular vesicles for the delivery of gene therapy.
    Emilio Di Ianni, Wataru Obuchi, Koen Breyne, Xandra O Breakefield.
      Gene therapy has brought hope for the treatment of previously incurable diseases, such as genetic disorders, cancers and autoimmune diseases. However, gene therapy requires efficient delivery with cell and tissue specificity, which remains challenging owing to the limited targeting and cargo-loading capacity of viral delivery vehicles, as well as immunogenicity and toxicity concerns. Extracellular vesicles can be designed as non-viral carriers for gene therapy owing to their ability to deliver multiple cargo types, including transgenes, small encoding or non-coding RNA, DNA and functional proteins. Importantly, extracellular vesicles are immunologically neutral and can cross biological barriers. In this Review, we discuss the application of extracellular vesicles in gene therapy. We outline how the inherent content of extracellular vesicles can facilitate different gene-therapy approaches and examine the design of extracellular vesicles for the loading of gene-therapy tools, targeted delivery and cargo release. Finally, we survey clinical applications of extracellular vesicles and highlight important engineering and translational challenges.
    DOI:  https://doi.org/10.1038/s44222-025-00277-7
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