bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–09–28
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
  2. A De Novo DNM1L Mutation in Twins with Variable Symptoms, Including Paraparesis and Optic Neuropathy.
  3. Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
  4. Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.
  5. Impact of age on neurofilament light chain in Friedreich ataxia: a 1-year longitudinal study.
  6. Widespread and progressive brain atrophy is a common feature in patients with mitochondrial disease.
  7. Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice.
  8. Cholesterol fuels microglia in chronic stroke.
  9. Mitochondria expel tainted DNA - spurring age-related inflammation.
  10. Mitochondria-driven inflammation: a new frontier in ovarian ageing.
  11. Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts.
  12. Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.
  13. Oxidative Stress and Antioxidant Therapies in Friedreich's Ataxia.
  14. Mitochondrial Acetoacetyl-CoA Thiolase Deficiency: Three New Cases Detected by Newborn Screening Confirming the Significance of C4OH Elevation.
  15. Huntington's disease treated for first time using gene therapy.
  16. Mitochondrial abnormalities in nondiabetic and nonhypertensive glomerular diseases: a comprehensive review.
  17. Inhibitory Infrared Light Attenuates Mitochondrial Hyperactivity and Accelerates Restoration of Mitochondrial Homeostasis in an Oxygen-Glucose Deprivation/Reoxygenation Model.
  18. Boosting Neurogenesis as a Strategy in Treating Alzheimer's Disease.
  19. Metabolic cardiomyopathies: untangling clinical heterogeneity with human stem-cell derived models.
  20. Regulation of mitochondrial dynamics in cardiomyocytes: implications for cardiac health and disease.
  21. The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases.
  22. Progress and challenges in sporadic late-onset cerebellar ataxias.
  1. Nat Aging. 2025 Sep 24.
    Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
    Gabriele Civiletto, Dario Brunetti, Giulia Lizzo, Kamila Muller, Guillaume E Jacot, Ioanna Daskalaki, Federico Sizzano, Minji Huh, Ivano Di Meo, Maria Nicol Colombo, José L Sanchez-Garcia, Bertrand J Bétrisey, Alix Zollinger, Patricia Lino, Christopher Neal, Anne-Laure Egesipe, Joy Richard, Myriam Chimen, Aurélie Hermant, Benjamin Brinon, Lorane Texari, Sylviane Metairon, Mohammed Adnan Qureshi, Dhaval S Patel, Siva A Vanapalli, Marco Malavolta, Arwen W Gao, Amelia Lalou, Mauro Provinciali, Fiorenza Orlando, Valeria Tiranti, Robert T Brooke, Steve Horvath, Johan Auwerx, Jerome N Feige, Philipp Gut.
      Small molecular food components contribute to the health benefits of diets rich in fruits, vegetables, herbs and spices. The cellular mechanisms by which noncaloric bioactives promote healthspan are not well understood, limiting their use in disease prevention. Here, we deploy a whole-organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism that promotes healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through a transient dampening of the mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mechanism originating from the mitochondrial membrane. Supplementation with thymol prevents excess liver fat accumulation in a mouse model of diet-induced obesity, improves pink-1-dependent heat stress resilience in Caenorhabditis elegans, and slows the decline of skeletal muscle performance while delaying epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive molecules for nutrition-based healthspan promotion.
    DOI:  https://doi.org/10.1038/s43587-025-00957-4
  2. Biomolecules. 2025 Aug 26. pii: 1230. [Epub ahead of print]15(9):
    A De Novo DNM1L Mutation in Twins with Variable Symptoms, Including Paraparesis and Optic Neuropathy.
    Alessia Nasca, Alessia Catania, Andrea Legati, Rossella Izzo, Carola D'onofrio, Teresa Ciavattini, Eleonora Lamantea, Costanza Lamperti, Daniele Ghezzi.
      Mitochondrial network dynamics, encompassing processes like fission, fusion, and mitophagy, are crucial for mitochondrial function and overall cellular health. Dysregulation of these processes has been linked to various human diseases. Particularly, pathogenic variants in the gene DNM1L can lead to a broad range of clinical phenotypes, ranging from isolated optic atrophy to severe neurological conditions. DNM1L encodes DRP1 (dynamin-1-like protein), which is a key player in mitochondrial and peroxisomal fission. This study describes two twin sisters with a de novo heterozygous variant in DNM1L, due to possible paternal germline mosaicism identified through clinical exome sequencing. The two twins showed a variable clinical presentation, including paraparesis and optic neuropathy. Functional studies of patient-derived fibroblasts revealed altered mitochondrial and peroxisomal morphology, along with dysregulated DNM1L transcript levels, indicating the deleterious effect of the variant. These findings allowed us to reclassify the identified variant from a variant of uncertain significance to a likely pathogenic variant. Our report provides insight into the phenotypic spectrum of DNM1L-related disorders and highlights the need to combine genetic and functional analyses to accurately diagnose rare mitochondrial diseases.
    Keywords:  DNM1L; mitochondrial and peroxisomes fission; mitochondrial disorders; mitochondrial dynamics; variant reclassification
    DOI:  https://doi.org/10.3390/biom15091230
  3. Nature. 2025 Sep 24.
    Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
    Amir Bahat, Dusanka Milenkovic, Eileen Cors, Mabel Barnett, Sadig Niftullayev, Athanasios Katsalifis, Marc Schwill, Petra Kirschner, Thomas MacVicar, Patrick Giavalisco, Louise Jenninger, Anders R Clausen, Vincent Paupe, Julien Prudent, Nils-Göran Larsson, Manuel Rogg, Christoph Schell, Isabella Muylaert, Erik Lekholm, Hendrik Nolte, Maria Falkenberg, Thomas Langer.
      Metabolic dysregulation can lead to inflammatory responses1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling3. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME14, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.
    DOI:  https://doi.org/10.1038/s41586-025-09541-7
  4. J Cell Sci. 2025 Sep 15. pii: jcs263691. [Epub ahead of print]138(18):
    Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.
    Mariana Joaquim, Maria-Bianca Bulimaga, Marie A Mohn, Solenn Plouzennec, Leon Osinski, Selver Altin, Esther Mahabir, Arnaud Chevrollier, Mafalda Escobar-Henriques.
      The neuropathy Charcot-Marie-Tooth (CMT) is an incurable disease with a lack of genotype-phenotype correlation. Variants of the mitochondrial protein mitofusin 2 (MFN2), a large GTPase that mediates mitochondrial fusion, are responsible for the subtype CMT type 2A (CMT2A). Interestingly, beyond membrane remodelling, additional roles of MFN2 have been identified, expanding the possibilities to explore its involvement in disease. Here, we investigated how cellular functions of MFN2 are associated with variants present in individuals with CMT2A. Using human cellular models, we observed that cells expressing CMT2A variants display increased endoplasmic reticulum (ER) stress and apoptotic cell death. Increased cleavage of PARP1, caspase 9, caspase 7 and caspase 3, alongside BAX translocation to mitochondria, pointed towards effects on intrinsic apoptosis. Moreover, although disruption of fusion and fission dynamics per se did not correlate with cell death markers, expression of MFN1 or MFN2 alleviated the apoptosis markers of CMT2A variant cell lines. In sum, our results highlight excessive cell death by intrinsic apoptosis as a potential target in CMT2A disease.
    Keywords:  Apoptosis; CMT2A; Cell death; Charcot–Marie–Tooth; Fusion; MFN2; Mitochondria
    DOI:  https://doi.org/10.1242/jcs.263691
  5. Brain Commun. 2025 ;7(5): fcaf331
    Impact of age on neurofilament light chain in Friedreich ataxia: a 1-year longitudinal study.
    Sara Petrillo, Alessia Mongelli, Anna Castaldo, Lidia Sarro, Samuele Azzarelli, Riccardo Ronco, Barbara Castellotti, Cinzia Gellera, Fiorella Piemonte, Caterina Mariotti.
      Friedreich's ataxia (FRDA) is a recessive inherited ataxia caused by intronic GAA repeat expansions in FXN gene. The repeat length is the major determinant of age at onset, usually occurring in adolescence. Clinical manifestations include progressive gait and limb ataxia, sensory loss, cardiomyopathy, and scoliosis. Neurofilament light chain protein (NfL) has been recently studied as a potential plasma biomarker for the disease. We performed a longitudinal study in 62 patients with FRDA, including 12 children (age 12-17 years) and 50 adult patients (age 18-45). The characteristics of our patient cohort largely matched those of a population mostly recruited in therapeutical clinical trials, with a mean age of 25.1 ± 8.5 years, age at onset 13.1 ± 4.8 years, and disease duration 12 ± 7 years. We found higher NfL levels in children in comparison with adult patients. Plasma concentrations remained stable at 1-year follow-up. We observed a significantly inverse correlation between plasma NfL levels and patient ages, while no correlations were found with other clinical or genetic variables. Our study confirms the typical NfL profile in FRDA patients. Our data further support the role of NfL as early indicator of axonal damage and as potential pharmacodynamic biomarker of therapeutical response especially valuable in pediatric populations.
    Keywords:  Friedreich ataxia; longitudinal study; neurofilament light chain; pediatric population
    DOI:  https://doi.org/10.1093/braincomms/fcaf331
  6. J Neurol. 2025 Sep 23. 272(10): 648
    Widespread and progressive brain atrophy is a common feature in patients with mitochondrial disease.
    Nora Mickelsson, Jussi Hirvonen, Mika H Martikainen.
       BACKGROUND: Primary mitochondrial diseases comprise a group of inherited disorders that frequently affect the central nervous system. Previous studies have reported brain imaging findings commonly associated with mitochondrial disease. However, longitudinal data on volumetric brain abnormalities, their progression in time, and associations with clinical features of the disease remain limited.
    METHODS: We conducted a retrospective observational study of 36 patients with genetically confirmed mitochondrial disease at Turku University Hospital (Turku, Finland). A total of 73 brain magnetic resonance scans (1-8 per patient) were analysed using the cNeuro® image quantification tool to assess lobar and regional cortical atrophy. Associations with clinical features, including stroke-like episodes (SLEs), sex, and genetic subtype, were investigated.
    RESULTS: Cerebral atrophy was present in all patients and was most pronounced in the temporal and occipital lobes. Patients with a history of SLEs exhibited significantly greater atrophy in both temporal lobes and the right occipital and parietal lobes. Follow-up imaging (available for 15 patients) revealed progressive atrophy, particularly in the occipital lobes, in patients with SLEs. No significant differences in atrophy severity or progression were found between patients with the m.3243A > G variant and those with other genetic causes.
    CONCLUSIONS: Cerebral atrophy is a common and often progressive feature of mitochondrial disease, even in patients without clinical brain symptoms. Atrophy predominantly affects posterior brain regions, and its progression is particularly evident in patients with SLEs. These findings underline the neurodegenerative nature of mitochondrial disease and highlight the need to develop neuroprotective therapies.
    Keywords:  Cerebral atrophy; Longitudinal imaging; Magnetic resonance imaging; Mitochondrial disease; Neurodegeneration; Stroke-like episodes
    DOI:  https://doi.org/10.1007/s00415-025-13354-z
  7. Mol Metab. 2025 Sep 22. pii: S2212-8778(25)00163-2. [Epub ahead of print] 102256
    Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice.
    Lorenzo Da Dalt, Francesca Fantini, Giulia Giancane, Annalisa Moregola, Silvia Roda, Monika Svecla, Silvia Pedretti, Giovanni Battista Vingiani, Jiangming Sun, Andreas Edsfeldt, Isabel Goncalves, Patrizia Uboldi, Elena Donetti, Andrea Baragetti, Nico Mitro, Luca Scorrano, Giuseppe Danilo Norata.
       AIMS: Mitochondria are involved in cellular metabolism, energy production, calcium homeostasis, and the synthesis of sterols and bile acids (BAs). Emerging evidence suggests that mitochondrial dynamics including biogenesis, fusion, fission, and mitophagy critically influence cardiometabolic diseases, yet their role in atherogenesis remain poorly understood. Mitochondrial fusion ensures metabolic flexibility and stress adaptation, processes highly relevant to lipid handling and vascular cell plasticity. OPA1, a key regulator of inner mitochondrial membrane fusion, has been implicated in metabolic remodeling and cellular stress responses. We therefore investigated whether modulation of OPA1 expression affects lipid homeostasis and plaque formation in LDL receptor-deficient (LDLR KO) mice and in human carotid atherosclerosis.
    METHODS: OPA1TG/LDLR KO and OPA1ΔHep /LDLR KO were fed with a Western-type diet (WTD) for 12 weeks. The development of atherosclerosis was compared to that of LDLR KO mice. In humans, the impact of OPA1 was investigated in asymptomatic and symptomatic subjects from the Carotid Plaque Imaging Project (CPIP) biobank.
    RESULTS: OPA1TG/LDLR KO mice showed a significant increase in plasma cholesterol levels mainly in VLDL and LDL fractions. OPA1TG/LDLR KO display a reduction of unconjugated bile acids and higher percentage of conjugated bile acids leading to an increased lipid adsorption. This phenotype was associated with increased atherosclerosis in the aortic root. OPA1 overexpression also resulted in an altered vascular smooth muscle cell (VSMC) cellular metabolism and differentiation, promoting a shift from a contractile/synthetic phenotype toward a more proliferative and metabolically active state. Concordantly, the deletion of OPA1 in hepatocytes improved systemic lipoprotein metabolism protecting from atherosclerosis. Concordantly in humans, plaque OPA1 mRNA levels are associated with metabolic and smooth muscle cell related pathways.
    CONCLUSION: Mitochondrial fusion mediated by OPA1 plays a key role in atherosclerosis by affecting lipoprotein metabolism and vascular smooth muscle cell biology.
    Keywords:  Atherosclerosis; Lipoprotein; Liver; OPA1; VSMCs
    DOI:  https://doi.org/10.1016/j.molmet.2025.102256
  8. Nat Metab. 2025 Sep 23.
    Cholesterol fuels microglia in chronic stroke.
    Stefano Pluchino, Cory M Willis.
      
    DOI:  https://doi.org/10.1038/s42255-025-01362-2
  9. Nature. 2025 Sep 26.
    Mitochondria expel tainted DNA - spurring age-related inflammation.
    Gemma Conroy.
      
    Keywords:  Ageing; Cell biology; Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-03064-x
  10. J Transl Med. 2025 Sep 24. 23(1): 1005
    Mitochondria-driven inflammation: a new frontier in ovarian ageing.
    Wenhan Ju, Binghan Yan, Danping Li, Fang Lian, Shan Xiang.
      Ovarian ageing is a key factor in the decline of female fertility. It is primarily characterised by diminished oocyte quality, follicular depletion, and dysregulated hormone levels. In recent years, mitochondria-driven inflammation has emerged as a potential mechanism in ovarian ageing. Mitochondrial dysfunction results in the accumulation of reactive oxygen species (ROS) and the release of mitochondrial DNA (mtDNA), as well as the leakage of mitochondrial components and metabolites into the cytosol or extracellular space. These elements act as damage-associated molecular patterns (DAMPs), activating inflammasomes like NLRP3, thereby initiating and amplifying innate immune responses and contributing to sustained inflammation. Furthermore, an imbalance in mitochondrial quality control mechanisms can worsen the spread and persistence of inflammatory responses. In this study, we present a comprehensive overview of the signalling origins, molecular mechanisms of amplification, and key regulatory nodes involved in mitochondria-driven inflammation during ovarian ageing. Finally, we summarise potential therapeutic strategies targeting mitochondria-driven inflammation, offering novel perspectives and targets for delaying ovarian ageing and enhancing female reproductive health.
    Keywords:  Damage-associated molecular patterns; Inflammation; Mitochondria; Mitochondrial dysfunction; Ovarian ageing
    DOI:  https://doi.org/10.1186/s12967-025-06966-6
  11. Life Sci. 2025 Sep 23. pii: S0024-3205(25)00631-9. [Epub ahead of print] 123995
    Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts.
    Paola Zanfardino, Alessandro Amati, Stefano Doccini, Francesco Girolamo, Apollonia Tullo, Giovanna Longo, Filippo M Santorelli, Vittoria Petruzzella.
       AIMS: Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is a rare autosomal recessive neuropathy caused by biallelic MTMR5/SBF1 variants, which encode a catalytically inactive myotubularin involved in phosphoinositide metabolism and autophagy regulation. This study investigates the impact of MTMR5/SBF1 dysfunction on autophagy and mitophagy in patient-derived fibroblasts and examines the relationship between protein aggregates and autophagic machinery.
    MATERIALS AND METHODS: Fibroblasts from a CMT4B3 patient with compound heterozygous MTMR5/SBF1 mutations were compared with a healthy control. Autophagic flux was analyzed via LC3B and SQSTM1; mitophagy was assessed through PINK1 and PRKN recruitment and by quantifying mitophagosomes and autolysosomes under mitochondrial stress. Protein aggregates were visualized using Proteostat and tested for colocalisation with autophagic structures.
    KEY FINDINGS: CMT4B3 fibroblasts showed normal basal macroautophagy but failed to increase autophagy in response to mitochondrial stress or protein aggregates. Conversely, mitophagy was strongly activated via the PINK1-PRKN pathway.
    SIGNIFICANCE: These results reveal an uncoupling between mitophagy and macroautophagy, indicating that MTMR5/SBF1 mutations modify autophagic selectivity. Our findings provide new mechanistic insights into the pathogenesis of CMT4B3 and highlight the value of patient-derived fibroblasts for studying selective autophagy defects.
    Keywords:  CMT4B3; Charcot-Marie-Tooth disease; Macroautophagy; PINK1–PRKN pathway; Phosphoinositide metabolism; Proteasome
    DOI:  https://doi.org/10.1016/j.lfs.2025.123995
  12. Sci Adv. 2025 Sep 26. 11(39): eadt6366
    Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.
    Ashutosh Kumar, Yonghui Zhao, Litao Xie, Rahul Chadda, John D Tranter, Ryan T Mikami, Nihil Abraham, Juan Hong, Ethan Feng, David R Rawnsley, Haiyan Liu, Kayla M Henry, Gretchen Meyer, Meiqin Hu, Haoxing Xu, Antentor Hinton, Chad E Grueter, E Dale Abel, Andrew W Norris, Abhinav Diwan, Rajan Sah.
      The lysosome integrates anabolic signaling and nutrient sensing to regulate intracellular growth pathways. The leucine-rich repeat-containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signaling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show that LRRC8A affects leucine-stimulated mTOR; lysosome size; number; pH; expression of lysosomal proteins LAMP2, P62, and LC3B; and lysosomal function. Mutating an LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signaling and altered lysosomal morphology and pH observed in LRRC8A knockout cells. In vivo, LRRC8A-L706A;L707A knock-in mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance associated with reduced skeletal muscle PI3K-AKT-mTOR signaling, glucose uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8-mediated metabolic signaling function regulating lysosomal function, systemic glucose homeostasis, and insulin sensitivity.
    DOI:  https://doi.org/10.1126/sciadv.adt6366
  13. Cells. 2025 Sep 09. pii: 1406. [Epub ahead of print]14(18):
    Oxidative Stress and Antioxidant Therapies in Friedreich's Ataxia.
    Félix Javier Jiménez-Jiménez, Hortensia Alonso-Navarro, Elena García-Martín, Alba Cárcamo-Fonfría, Miguel Angel Martín-Gómez, José A G Agúndez.
      The pathogenesis of Friedreich's ataxia (FRDA) remains poorly understood. The most important event is the deficiency of frataxin, a protein related to iron metabolism and, therefore, involved in oxidative stress. Studies on oxidative stress markers and gene expression in FRDA patients have yielded inconclusive results. This is largely due to the limited number of studies, small sample sizes, and methodological differences. A notable finding is the decreased activity of mitochondrial respiratory chain complexes I, II, and III, as well as aconitase, in endomyocardial tissue. In contrast, numerous studies in experimental models of FRDA (characterized by frataxin deficiency) have shown evidence of the involvement of oxidative stress in cellular degeneration. These findings include increased iron concentration, mitochondrial dysfunction (with reduced respiratory chain complex activity and membrane potential), and decreased aconitase activity. Additionally, there is the induction of antioxidant enzymes, reduced glutathione levels, elevated markers of lipoperoxidation, and DNA and carbonyl protein oxidation. The expression of NRF2 is decreased, along with the downregulation of PGC-1α. Therefore, it is plausible that antioxidant treatment may help improve symptoms and slow the progression of FRDA. Among the antioxidant treatments tested in FRDA patients, only omaveloxolone and, to a lesser extent, idebenone (particularly for cardiac hypertrophy) have shown some efficacy. However, many antioxidant drugs have shown the ability to reduce oxidative stress in experimental models of FRDA. Therefore, these drugs may be useful in treating FRDA and are likely candidates for future clinical trials. Future studies investigating oxidative stress and antioxidant therapies in FRDA should adopt a prospective, multicenter, long-term, double-blind design.
    Keywords:  Friedreich’s ataxia; animal models; biological markers; frataxin; oxidative stress; pathogenesis
    DOI:  https://doi.org/10.3390/cells14181406
  14. Int J Neonatal Screen. 2025 Sep 06. pii: 76. [Epub ahead of print]11(3):
    Mitochondrial Acetoacetyl-CoA Thiolase Deficiency: Three New Cases Detected by Newborn Screening Confirming the Significance of C4OH Elevation.
    Alessandra Vasco, Clarissa Berardo, Simona Lucchi, Laura Cappelletti, Giulio Tamburello, Salvatore Fazzone, Alessia Mauri, Francesca Fiumani, Diana Postorivo, Luisella Alberti, Michela Perrone Donnorso, Serena Gasperini, Francesca Furlan, Laura Fiori, Stephana Carelli, Laura Assunta Saielli, Cristina Montrasio, Cristina Cereda.
      Acetoacetyl-CoA thiolase deficiency, also known as Beta-ketothiolase deficiency (BKTD), is an autosomal recessive organic aciduria included in the Italian newborn screening (NBS) panel. It is caused by mutations in the ACAT1 gene, which encodes the mitochondrial acetyl-CoA acetyltransferase. Its deficiency impairs the degradation of isoleucine and acetoacetyl-CoA, leading to the accumulation of toxic metabolites. We describe three cases of BKTD. The first newborn showed increase in C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. Urinary organic acids (uOAs) revealed marked excretion of 2-methyl-3-hydroxybutyrate. Tiglylglycine was absent. Genetic testing identified the compound heterozygosity for two pathogenic ACAT1 variants. The second patient showed increased levels of C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. uOAs revealed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous VUS in ACAT1 was identified. The third case showed elevation of C4DC/C5OH, C3DC/C4OH in the NBS, with a slight increase in C5:1. uOAs showed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous missense VUS was identified in the ACAT1 gene. BKTD exhibited variable NBS biochemical phenotypes across the three cases. While C5OH and C5:1, the primary markers, were not consistently elevated in all our cases, C4OH strongly increased in all three. Our findings support the use of C4OH in a combined marker strategy to improve BKTD NBS.
    Keywords:  beta-ketothiolase deficiency; inborn errors of metabolism (IEMs); mitochondrial acetoacetyl-CoA thiolase deficiency; newborn screening (NBS); organic acidemias (OAs); organic acids; rare diseases
    DOI:  https://doi.org/10.3390/ijns11030076
  15. Nature. 2025 Sep 25.
    Huntington's disease treated for first time using gene therapy.
    Elie Dolgin.
      
    Keywords:  Brain; Gene therapy; Medical research; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41586-025-03139-9
  16. Mol Cell Biochem. 2025 Sep 23.
    Mitochondrial abnormalities in nondiabetic and nonhypertensive glomerular diseases: a comprehensive review.
    Baris Afsar, Rengin Elsurer, Krista L Lentine.
      Glomerulonephritis (GN) is a general term which encompasses various types of glomerular disorders characterized by damage to the capillary endothelium, basement membrane, podocytes, mesangium, or parietal epithelial cells with different combinations leading to proteinuria, hematuria, and azotemia. Although disease process begins in the cells of mentioned above, there is cross-talk with tubular cells leading to tubular atrophy and interstitial fibrosis in the final stages of most GN. Recent developments in genetic, molecular, serologic methods enhances understanding of the pathophysiology and management of GN although more work is needed. The recent ultra-structural studies demonstrated various subcellular disorders present in the context of GN. Mitochondria are one of the most studied subcellular organelles, and various mitochondrial structural and functional alterations have been identified in GNs, including focal segmental glomerulosclerosis, IgA nephropathy, lupus nephritis and anti-glomerular basement membrane disease. However, these studies are still at an early stage and currently the impacts of mitochondrial dysfunction on the development and progression of glomerular disease are not well defined. In the current review article, we examine how mitochondrial dysfunction associates with GN, and discuss the unknowns, conflicting issues and potential treatment options regarding mitochondrial dysfunction and GN.
    Keywords:  Focal segmental glomerulosclerosis mitochondria; Glomerulonephritis; Nephropathy; Podocyte
    DOI:  https://doi.org/10.1007/s11010-025-05393-x
  17. Antioxidants (Basel). 2025 Sep 15. pii: 1119. [Epub ahead of print]14(9):
    Inhibitory Infrared Light Attenuates Mitochondrial Hyperactivity and Accelerates Restoration of Mitochondrial Homeostasis in an Oxygen-Glucose Deprivation/Reoxygenation Model.
    Lucynda Pham, Tasnim Arroum, Paul T Morse, Jamie Bell, Moh H Malek, Thomas H Sanderson, Maik Hüttemann.
      Ischemia/reperfusion (I/R) injury following stroke results in increased neuronal cell death due to mitochondrial hyperactivity. Ischemia results in loss of regulatory phosphorylations on cytochrome c oxidase (COX) and cytochrome c of the electron transport chain (ETC), priming COX for hyperactivity. During reperfusion, the ETC operates at maximal speed, resulting in hyperpolarization of the mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) production. We have shown that COX-inhibitory near-infrared light (IRL) provides neuroprotection in small and large animal models of brain I/R injury. IRL therapy is non-invasive and non-pharmacological and does not rely on blood flow. We identified specific wavelengths of IRL, 750 and 950 nm, that inhibit COX activity. To model the mitochondrial effects following neuronal I/R, SH-SY5Y cells underwent oxygen-glucose deprivation/reoxygenation (OGD/R) ± IRL applied at the time of reoxygenation. Untreated cells exhibited ΔΨm hyperpolarization, whereas IRL treated cells showed no significant difference compared to control. IRL treatment suppressed ROS production, decreased the level of cell death, and reduced the time to normalize mitochondrial activity to baseline levels from 4-5 to 2.5 h of reperfusion time. We show that IRL treatment is protective by limiting ΔΨm hyperpolarization and ROS production, and by speeding up cellular recovery.
    Keywords:  cytochrome c oxidase; ischemia/reperfusion injury; mitochondria; mitochondrial membrane potential; near-infrared light; phosphorylations; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox14091119
  18. Int J Mol Sci. 2025 Sep 13. pii: 8926. [Epub ahead of print]26(18):
    Boosting Neurogenesis as a Strategy in Treating Alzheimer's Disease.
    Abena Dwamena, Rashini Beragama-Arachchi, Hongmin Wang.
      Alzheimer's disease (AD) causes progressive cognitive decline and neuronal loss, partly due to the buildup of amyloid-β (Aβ) plaques and tau tangles. Despite years of research, treatments targeting these hallmark pathologies have yielded only modest clinical success, prompting interest in regenerative approaches to restore the brain's ability to repair itself. One such approach focuses on adult hippocampal neurogenesis, the process by which neural stem cells (NSCs) produce new neurons throughout life. In AD, this process is impaired, worsening cognitive deficits. In this review, we examine the molecular pathways that control adult neurogenesis, including transcriptional, epigenetic, inflammatory, and metabolic mechanisms, and how they become dysregulated in AD. We also highlight various therapeutic strategies aimed at boosting neurogenesis, such as pharmacological treatments, stem cell therapy, gene therapy, and epigenetic modulation. Preclinical studies indicate that enhancing neurogenesis can improve cognition and reduce brain pathology in AD models. Several of these treatments are now being tested in clinical trials. Ultimately, promoting neurogenesis may offer a promising avenue to complement current AD therapies and help restore lost neural function.
    Keywords:  Alzheimer’s disease; adult hippocampal neurogenesis; cognitive decline; dementia treatment; epigenetic regulation; neural stem cells; neurogenesis enhancement; neurotrophic factors; regenerative therapy; stem-cell therapy
    DOI:  https://doi.org/10.3390/ijms26188926
  19. EMBO Mol Med. 2025 Sep 22.
    Metabolic cardiomyopathies: untangling clinical heterogeneity with human stem-cell derived models.
    Adriana S Passadouro, Berith M Balfoort, Mirjam Langeveld, Clara D M van Karnebeek, Jolanda van der Velden, Riekelt H Houtkooper, Signe Mosegaard.
      Inherited metabolic diseases are rare monogenic conditions that disrupt biochemical pathways, affecting energy production and homeostasis, often leading to damaging metabolite accumulation. These disorders are clinically heterogeneous and can impact all organs, including the heart. Metabolic cardiomyopathies present with varying severity and unpredictable prognosis, complicating patient care. Pre-clinical research aims to model these cardiomyopathies to understand their pathophysiological mechanisms and develop personalised treatments. Animal models have provided insights into cardiac pathology and treatment, but species differences limit data translation. Human induced pluripotent stem cells (hiPSC) offer a valuable tool for establishing disease models using reprogrammed somatic cells from patients and healthy donors, differentiated into disease-relevant cell types. Cardiomyocytes generated in significant numbers are crucial for investigating cardiac mechanisms and assessing patient-specific drug responses. This review summarises literature on metabolic cardiomyopathies, focusing on long-chain fatty acid oxidation disorders and Barth syndrome. We highlight cardiac readouts from various models and discuss the potential of hiPSC technologies as clinically relevant disease models.
    Keywords:  Inherited Metabolic Diseases (IMD); Metabolic Cardiomyopathy; Personalized Medicine; Pre-clinical Models
    DOI:  https://doi.org/10.1038/s44321-025-00313-4
  20. Front Cell Dev Biol. 2025 ;13 1652683
    Regulation of mitochondrial dynamics in cardiomyocytes: implications for cardiac health and disease.
    Tengxu Zhang, Ziwei Li, Ying Xu, Chaoqun Xu, Hao Wang, Tao Rui.
      Mitochondrial dynamics, involving fission and fusion, are vital for maintaining mitochondrial quality, shape, and function in heart cells. This review explores how key regulators-Dynamin-related protein 1 (Drp1), mitofusins 1 and 2 (Mfn1/2), and Optic Atrophy 1 (OPA1)-control these processes in the heart. Drp1 facilitates fission, while Mfn1/2 and OPA1 mediate outer and inner membrane fusion. Their activities are finely tuned by modifications, gene regulation, and stress pathways. Disruptions in these dynamics can impair functions like energy production, calcium balance, ROS management, and mitophagy, contributing to heart diseases. Abnormal fission and fusion are also linked to conditions such as sepsis, ischemia/reperfusion injury, and diabetic cardiomyopathy. This review aims to offer a thorough analysis of recent advancements in the understanding of dysregulated mitochondrial dynamics and their contribution to cardiac pathology. Additionally, it evaluates emerging therapeutic strategies that target the balance between mitochondrial division and fusion. We posit that precise modulation of the activities of Drp1, Mfn1/2, and OPA1 presents significant potential for the treatment of cardiac diseases. However, achieving tissue specificity and temporal control remains a critical challenge for clinical translation.
    Keywords:  DRP1; I/R injury; MFN2; Mfn1; OPA1; diabetic cardiomyopathy; mitochondrial dynamics; sepsis
    DOI:  https://doi.org/10.3389/fcell.2025.1652683
  21. Nat Metab. 2025 Sep 22.
    The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases.
    Femke M Feringa, Sascha J Koppes-den Hertog, Lian Y Wang, Rico J E Derks, Iris Kruijff, Lena Erlebach, Jorin Heijneman, Ricardo Miramontes, Nadine Pömpner, Niek Blomberg, Damien Olivier-Jimenez, Lill Eva Johansen, Alexander J Cammack, Ashling Giblin, Christina E Toomey, Indigo V L Rose, Hebao Yuan, Michael E Ward, Adrian M Isaacs, Martin Kampmann, Deborah Kronenberg-Versteeg, Tammaryn Lashley, Leslie M Thompson, Alessandro Ori, Yassene Mohammed, Martin Giera, Rik van der Kant.
      Lipid alterations in the brain have been implicated in many neurodegenerative diseases. To facilitate comparative lipidomic research across brain diseases, we establish a data common named the Neurolipid Atlas that we prepopulated with isogenic induced pluripotent stem cell (iPS cell)-derived lipidomics data for different brain diseases. Additionally, the resource contains lipidomics data of human and mouse brain tissue. Leveraging multiple datasets, we demonstrate that iPS cell-derived neurons, microglia and astrocytes exhibit distinct lipid profiles that recapitulate in vivo lipotypes. Notably, the Alzheimer disease (AD) risk gene ApoE4 drives cholesterol ester (CE) accumulation specifically in human astrocytes and we also observe CE accumulation in whole-brain lipidomics from persons with AD. Multiomics interrogation of iPS cell-derived astrocytes revealed that altered cholesterol metabolism has a major role in astrocyte immune pathways such as the immunoproteasome and major histocompatibility complex class I antigen presentation. Our data commons, available online ( https://neurolipidatlas.com/ ), allows for data deposition by the community and provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s42255-025-01365-z
  22. Nat Rev Neurol. 2025 Sep 22.
    Progress and challenges in sporadic late-onset cerebellar ataxias.
    Thomas Wirth, Jennifer Faber, Christel Depienne, Emmanuel Roze, Jérôme Honnorat, Wassilios G Meissner, Paola Giunti, Christine Tranchant, Thomas Klockgether, Mathieu Anheim.
      Sporadic late-onset cerebellar ataxia (SLOCA) is a syndrome defined by subacute or chronic and progressive ataxia occurring after the age of 40 years in individuals without a family history of ataxia. The 2022 publication of revised consensus diagnostic criteria for multiple system atrophy and the emergence of promising biomarkers provides a thorough diagnostic framework that now enables the diagnosis of numerous acquired causes of SLOCA, including autoimmune disorders and neurodegenerative diseases. The ongoing development and increased availability of DNA sequencing technology have uncovered several molecular causes of SLOCA besides spastic paraplegia type 7 and very late-onset Friedreich ataxia. These additional causes include sporadic genetic disorders, such as spinocerebellar atrophy type 27B, caused by GAA expansion in the FGF14 gene, and cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS), caused by biallelic expansions in the RFC1 gene. This Review presents an updated clinical approach to the diagnosis and management of SLOCA that focuses on the most important developments in this field. Future challenges are also discussed, including the identification of additional missing genetic causes of SLOCA, especially via the use of long-read genome sequencing, improvements in SLOCA prognostication and the implementation of clinical trials of neuroprotective interventions.
    DOI:  https://doi.org/10.1038/s41582-025-01136-0
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