bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–02–08
twenty-one papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
  2. Mitochondrial superoxide signals shield the nucleus to delay ageing.
  3. Biomarking MELAS with neurofilament light chain and circulating cell free mitochondrial DNA.
  4. Expanding the cognitive spectrum of mitochondrial diseases.
  5. Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia.
  6. Suppression of interferon signaling via small-molecule modulation of TFAM.
  7. Mitochondrial SLC6A6 supports taurine transport.
  8. The Ketogenic Diet in the Neonatal Intensive Care Setting: The Case of a Preterm Newborn With Mitochondrial DNA Depletion Syndrome Type 13 (MTDPS13).
  9. Leigh Syndrome Pathomechanism Involves Region-Specific Innate Immune Activation in Ndufs4 Knockout Mice.
  10. Now is not the time to defund human fetal tissue research.
  11. Mesenchymal Stem Cell-derived Exosomes Alleviate Oxidative Stress and Brain Injuries Through Promoting OPA1 Mediated Mitochondrial Fusion After Intracerebral Hemorrhage.
  12. An in vivo and in vitro spatiotemporal profile of human midbrain development.
  13. Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice.
  14. Fahr Syndrome, Hypoparathyroidism and Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome.
  15. Mitochondrial superoxide regulates nuclear envelope integrity and ageing via redox-mediated lipid metabolism.
  16. Trophoblast-specific overexpression of Slc7a5 increases fetal amino acid availability and hepatic mTOR signalling and causes increased fetal growth.
  17. Nicotinamide counteracts Rotenone-induced mitochondrial and neuronal dysfunction in a translational early-life model.
  18. Mitochondrial specialization and signaling shape neuronal function.
  19. Proteostasis of organelles in aging and disease.
  20. Mitochondrial Complex I hyperactivation drives PET microplastic-induced intestinal bioenergetic collapse.
  21. Mitochondrial protein-enriched artificial nanovesicles: mitochondrial recovery and antioxidation for diabetic wound treatment.
  1. Brain. 2026 Feb 02. pii: awag037. [Epub ahead of print]
    Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
    Marton Szabo, Daniel Lagos, Emily Cross, Jack Collier, Rita Horvath.
      Primary mitochondrial diseases (PMDs) affect ∼1 in 4,300 individuals, yet mitochondrial dysfunction is also a hallmark of common inherited and acquired disorders. While advances in genomics now allow molecular diagnosis in 30-60% of mitochondrial diseases, treatment remains largely supportive, leading to progressive disability and early mortality. Despite progress in gene-modifying approaches, no approved therapies exist for the majority of mitochondrial diseases, and none of the recent trials have met their primary endpoints, underlining the urgent need for innovative therapeutic strategies. Patients with PMDs have very variable phenotypes, further complicated by increased susceptibility to infections, chronic inflammation and metabolic abnormalities. Recently, it has become evident that certain mitochondrial pathologies, including the loss of mitochondrial membrane integrity, impaired mtDNA maintenance, quality control defects, or respiratory chain defects, result in the release of mtDNA into the cytosol. Infections or metabolic changes also trigger the release of mtDNA, leading to the activation of a sterile innate immune response and interferon signalling. Free mtDNA acts as a pathogen-associated molecular pattern (PAMP), activating innate immune pathways such as the cGAS-STING axis, initiating a sterile inflammatory response. This can be followed by the extracellular release of mtDNA to convey the inflammatory response systemically to communicate between cells or across organs. However, it is unclear whether these pathways worsen the disease phenotype (hyperinflammatory reaction) or, in contrast, rescue the symptoms due to upregulation of compensatory pathways. In this review, we summarise recent advances in understanding the mechanism of mtDNA release and how it activates innate immune signalling in PMDs. We also discuss the implications for pathogenesis, clinical phenotypes, and therapeutic development. Defining the role of circulating mitochondrial material as a biomarker or therapeutic target is a critical step for precision medicine approaches in PMDs. These pathways may also have wider implications for common metabolic, inflammatory, and neurodegenerative disorders with mitochondrial dysfunction.
    Keywords:  mitochondria derived vesicles (MDVs); mtDNA; mtDNA release, primary mitochondrial diseases (PMD); pathogen-associated molecular patterns (PAMPs); sterile-inflammation
    DOI:  https://doi.org/10.1093/brain/awag037
  2. Nat Metab. 2026 Feb 03.
    Mitochondrial superoxide signals shield the nucleus to delay ageing.
      
    DOI:  https://doi.org/10.1038/s42255-026-01461-8
  3. Mol Genet Metab. 2026 Jan 27. pii: S1096-7192(26)00036-3. [Epub ahead of print]147(3): 109753
    Biomarking MELAS with neurofilament light chain and circulating cell free mitochondrial DNA.
    Alessandra Maresca, Monica Moresco, Giulia Amore, Chiara La Morgia, Maria Lucia Valentino, Giada Capirossi, Giulia Sacchetti, Valerio Carelli, Christian Vedeler, Laurence A Bindoff, Kristin N Varhaug.
      Mitochondrial diseases are genetic disorders caused either by nuclear or mitochondrial DNA (mtDNA) alterations and characterized by high genetic and phenotypic variability. The common mtDNA m.3243 A > G variant in the MT-TL1 gene leads to clinical manifestations ranging from the classical MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome to milder phenotypes such as MIDD (maternally inherited diabetes and deafness) or a spectrum of clinical features of intermediate severity defined as MELAS-Spectrum. The heterogeneous disease course makes the identification of biomarkers for monitoring disease progression challenging, particularly if we consider the occurrence of stroke-like episodes (SLEs), which remain unpredictable events. Here, we assessed two biomarkers, neurofilament light chain (NF-L) and circulating cell free-mtDNA (ccf-mtDNA), in a cross-sectional study in MELAS patients, including both patients in the interictal period and during SLEs, and MELAS-Spectrum patients. Both biomarkers were significantly elevated in MELAS patients during SLEs, compared to the other patients. In addition, we found significant correlation between NF-L and m.3243 A > G blood heteroplasmy in MELAS patients, as well as between NF-L and clinical severity in the whole patients cohort. Despite the limitations derived from the small sample size and the cross-sectional sample collection, our study confirms the value of NF-L and ccf-mtDNA as biomarkers efficiently hallmarking SLEs, highlighting their potential use to monitor the progression of MELAS.
    Keywords:  Blood biomarkers; Cell free mitochondrial DNA; Inflammation; Mitochondrial diseases; Neurodegeneration; Neurofilaments light chain
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109753
  4. Neurol Sci. 2026 Feb 04. 47(3): 228
    Expanding the cognitive spectrum of mitochondrial diseases.
    Anna Rita Giovagnoli, Costanza Lamperti, Ioana Raluca Mihai, Alessia Catania.
      
    Keywords:  Attention; Memory; Mitochondrial disease; Social cognition; Theory of mind
    DOI:  https://doi.org/10.1007/s10072-026-08827-6
  5. Mitochondrion. 2026 Feb 04. pii: S1567-7249(26)00010-3. [Epub ahead of print]88 102120
    Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia.
    Eunbin Jee, Maisha Medha, Hwayoung Baek, Jonghan Kim, Yuho Kim.
      Friedreich's ataxia (FRDA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein essential for iron-sulfur cluster assembly and iron homeostasis. In addition to neurological symptoms, cardiac dysfunction is common and represents a major cause of premature death in FRDA. Although iron overload has been suggested as a major player for FRDA-related cardiomyopathy, its underlying mechanisms remain unclear. Using heart-specific frataxin deficient mice, we observed that FRDA-related cardiac hypertrophy is accompanied by mitochondrial iron overload. Transmission electron microscopy (TEM) revealed iron aggregates within cardiac mitochondria, whose ultrastructure was severely altered. Along with the iron deposits and structural abnormalities, mitochondrial respiration was markedly impaired in FRDA hearts, despite the absence of increased oxidative stress. Notably, although dysfunctional mitochondria accumulate in parallel with enhanced mitochondrial biogenesis, the clearance of damaged or dysfunctional mitochondria (i.e., mitophagy) is disrupted, as evidenced by excessive accumulation of p62 and Parkin proteins. The lysosomal system, which plays a central role for mitochondrial turnover, appears to be dysregulated via the mTOR-TFEB axis. Hyperactivation mTOR inhibits lysosomal biogenesis and function, although lysosomal content remains unchanged. Collectively, our study provides mechanistic insight into the role of mitochondrial iron aggregates in the pathogenesis of FRDA-related cardiomyopathy and suggests a potential contribution of lysosomal dysfunction to impaired mitochondrial quality control in the context of cardiac frataxin deficiency.
    Keywords:  Cardiomyopathy; Frataxin; Iron overload; Lysosome; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2026.102120
  6. Elife. 2026 Feb 06. pii: RP108742. [Epub ahead of print]14
    Suppression of interferon signaling via small-molecule modulation of TFAM.
    Dionisia Sideris, Husan Lee, Lyndsay Olson, Kalyan Nallaparaju, Keiichiro Okuyama, Jeffrey Ciavarri, Robert Lafyatis, Mads Larsen, Bo Lin, Irene Alfaras, Jason Kennerdell, Toren Finkel, Yuan Liu, Bill Chen, Lin Lyu.
      The mitochondrial transcription factor A (TFAM) is essential for mitochondrial genome maintenance. It binds to mitochondrial DNA (mtDNA) and determines the abundance, packaging, and stability of the mitochondrial genome. Because its function is tightly associated with mtDNA, TFAM has a protective role in mitochondrial diseases, and supportive studies demonstrate reversal of disease phenotypes by TFAM overexpression. In addition, TFAM deficiency has been shown to cause release of mtDNA into the cytosol and activation of the cGAS/STING innate immune response pathway. As such, TFAM presents as a unique target for therapeutic intervention, but limited efforts for activators have been reported. Herein, we disclose novel TFAM small-molecule modulators with sub-micromolar activity. Our results demonstrate that these compounds result in an increase of TFAM protein levels and mtDNA copy number. This results in inhibition of a mtDNA stress-mediated inflammatory response by preventing mtDNA escape into the cytosol. Furthermore, we see beneficial effects in cellular disease models in which boosting TFAM activity has been advanced as a disease-modifying strategy including improved energetics in MELAS cybrid cells and a decrease of fibrotic markers in systemic sclerosis fibroblasts. These results highlight the therapeutic potential of using small-molecule TFAM activators in indications characterized by mitochondrial dysfunction.
    Keywords:  TFAM; cGAS-STING pathway; cell biology; human; interferon sinaling; mitochondria; mitochondrial DNA; small molecule
    DOI:  https://doi.org/10.7554/eLife.108742
  7. Nat Metab. 2026 Feb 06.
    Mitochondrial SLC6A6 supports taurine transport.
    Katsuhisa Inoue.
      
    DOI:  https://doi.org/10.1038/s42255-026-01471-6
  8. Case Rep Genet. 2026 ;2026 6492770
    The Ketogenic Diet in the Neonatal Intensive Care Setting: The Case of a Preterm Newborn With Mitochondrial DNA Depletion Syndrome Type 13 (MTDPS13).
    Gabriele D'Amato, Mattia Gentile, Rossella Carella, Antonio Giannini, Maria Felicia Faienza, Albina Tummolo.
       Background: Mitochondrial DNA depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder presenting in early infancy with encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Patient-derived cells typically exhibit impaired mitochondrial oxidative phosphorylation and a marked reduction in mitochondrial DNA (mtDNA) copy number.
    Case Report: We report the case of a male preterm neonate born at 31 + 3 weeks of gestation following a pregnancy marked by severe polyhydramnios. At birth, his weight was 1400 g. Physical examination revealed dysmorphic features, redundant and lax skin, and generalized muscular hypotonia. Laboratory investigations showed marked lactic acidosis associated with lactic aciduria, ketonuria, and urinary biomarkers indicating activation of preoxidative phosphorylation biochemical pathways to sustain ATP production. Echocardiography demonstrated mild, early-onset hypertrophic cardiomyopathy. The Exome Analysis Clinical and Biochemical Markers: The exome analysis, performed within the first week of life, highlighted a pathogenic variant in homozygous state of FBXL4 gene (c.1648_1649delGA), which led to the diagnosis of MTDPS13. In this clinical contest, a ketogenic diet (KD) was started with a daily caloric intake of 120 kcal/kg and an initial ketogenic ratio of 1:1. These intakes were administered both with a parenteral nutrition and continuous nasogastric tube feeding and were gradually increased and adapted on a day-by-day basis according to lactic acidosis, growth increase, and common metabolic parameters such as glucose, electrolytes, creatinine, and blood urea nitrogen. After 3 days of this treatment approach, a significant reduction in lactate levels and improvement in acid-base balance and growth trend were observed along with clinical and cardiovascular parameters. At discharge from neonatal intensive care unit, the KD was continued at home and during follow-up. The infant showed stability in the clinical and biochemical markers.
    Conclusions: This is the first documented report of the use of a KD in a preterm neonate with this mitochondrial disorder during the early days of life. Prompt genetic confirmation and early initiation of KD may enable a more targeted and effective management of MTDPS within the neonatal intensive care setting.
    DOI:  https://doi.org/10.1155/crig/6492770
  9. Cell Mol Neurobiol. 2026 Feb 04.
    Leigh Syndrome Pathomechanism Involves Region-Specific Innate Immune Activation in Ndufs4 Knockout Mice.
    Belinda R Fouché, Sibonelo G Khumalo, Werner J H Koopman, Marianne Venter.
      
    Keywords:   Ndufs4 knockout mouse model; Neuroinflammation; Olfactory bulb; RIG-I like signalling; Transcriptomics
    DOI:  https://doi.org/10.1007/s10571-026-01681-2
  10. Nature. 2026 Feb;650(8100): 8
    Now is not the time to defund human fetal tissue research.
      
    Keywords:  Developmental biology; Policy; Politics; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-00308-2
  11. Mol Neurobiol. 2026 Feb 07. 63(1): 426
    Mesenchymal Stem Cell-derived Exosomes Alleviate Oxidative Stress and Brain Injuries Through Promoting OPA1 Mediated Mitochondrial Fusion After Intracerebral Hemorrhage.
    Yanni Xu, Yong Du, Qing Hu, Ping Wang, Yaning Cai, Gaoyang Zhou, Haixiao Liu, Wei Guo.
      Oxidative stress (OS) is a hallmark of secondary brain damage after intracerebral hemorrhage (ICH), contributing to the progression of neurological damage and poor clinical outcomes. While mesenchymal stem cell-derived exosomes (MSC-Exo) demonstrate antioxidative potential, the specific mechanisms underlying their protective effects, particularly concerning mitochondrial dynamics, remain unclear. This study identifies OPA1-mediated mitochondrial fusion as a novel mechanism through which MSC-Exo alleviates oxidative stress and brain injury after ICH. In vivo fluorescence imaging and immunofluorescence assay revealed that intravenously injected MSC-Exo could be effectively internalized by neuronal cells in ICH mice. MRI assay indicated that although MSC-Exo had little effect on the volume of hematoma, it significantly relieved brain edema and improved the neurological outcomes. MSC-Exo effectively reduced oxidative stress and neuronal apoptosis in the peri-hematoma tissues. Notably, both in vivo and in vitro studies showed that MSC-Exo significantly alleviated mitochondrial morphological damage following ICH. MSC-Exo substantially reversed the downregulation of OPA1 after ICH but showed no significant impact on other proteins associated with mitochondrial dynamics. Neuron-specific knockout of OPA1 (Opa1cko) aggravated the impairment of mitochondrial morphology, the accumulation of superoxide production, and the deficits of mitochondrial respiratory capacities following ICH. Moreover, MSC-Exo failed to restore mitochondrial morphology and functionality, alleviate oxidative stress-induced damage, enhance neuronal viability, and facilitate functional recovery subsequent to ICH in Opa1cko mice models.
    Keywords:  Exosome; Intracerebral hemorrhage; Mesenchymal stem cells; Mitochondrial fusion; OPA1; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-026-05703-4
  12. Nat Commun. 2026 Feb 03. 17(1): 1354
    An in vivo and in vitro spatiotemporal profile of human midbrain development.
    Dimitri Budinger, Pau Puigdevall, George T Hall, Charlotte Roth, Theodoros Xenakis, Elena Marrosu, Julie Jerber, Alessandro Di Domenico, Francesca Picco, Helena Kilpinen, Sergi Castellano, Manju A Kurian, Serena Barral.
      The dopaminergic system has key roles in human physiology and is implicated in a broad range of neurological and neuropsychiatric conditions that are increasingly investigated using induced pluripotent stem cell-derived midbrain models. To determine similarities of such models to human systems, here we undertake single-cell and spatial profiling of first and second trimester fetal midbrain and compare it to in vitro midbrain models. Histological examination reveals that, by the second trimester, fetal midbrain tissue exhibits structural complexity comparable to that of adults. At the molecular level, single-cell profiling uncovers differences in cellular composition across models, with brain organoids most closely resembling late first trimester tissue - an observation supported by meta-integration of existing midbrain datasets. By reconstructing developmental trajectories of neuronal and astrocytic lineages, we map gene expression dynamics associated with maturation. Importantly, integration of spatial transcriptomics provides critical context for aligning organoid models, revealing that their spatial organization and intercellular signaling resemble the architecture and microenvironment of the second trimester midbrain. Ultimately, we leverage our findings to study Dopamine Transporter Deficiency Syndrome progression in patient-derived midbrain organoids, validating their relevance. Understanding the extent of human tissue recapitulation in midbrain laboratory models is essential to justify their use as biological proxies.
    DOI:  https://doi.org/10.1038/s41467-025-67779-1
  13. FASEB Bioadv. 2026 Feb;8(2): e70088
    Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice.
    Takanaga Shirai, Hideto Hanakita, Kohei Takeda, Yu Kitaoka, Kaori Ishikawa, Kazuto Nakada, Tohru Takemasa.
      Mitochondrial function is essential for skeletal muscle health, and its disruption leads to atrophy and functional decline. This study examines the impact of denervation on skeletal muscle mitochondria in polymerase gamma (PolG)(+/mut) mice, which accumulate mitochondrial DNA (mtDNA) mutations due to a partial deficiency in polymerase gamma proofreading. Using a 14-day denervation protocol, we assessed muscle mass, mtDNA copy number, oxidative stress and mitochondrial dynamics in wild-type (WT) and PolG(+/mut) mice. Our findings reveal that while denervation significantly reduced muscle wet weight and mitochondrial enzyme activity, no genotype-specific differences in muscle atrophy were observed. However, PolG(+/mut) mice displayed more disorganized mitochondrial cristae and elevated oxidative stress markers, indicating greater mitochondrial vulnerability. Despite these changes, the lack of significant differences in mitochondrial proteins and gene expression between genotypes may reflect an adaptive antioxidant response, including increased catalase expression, although the compensatory nature of this response cannot be conclusively determined. These results suggest that oxidative stress-related responses are involved in mitochondrial adaptations during denervation-induced muscle atrophy. The increased expression of antioxidant enzymes, such as catalase, in PolG(+/mut) mice suggests that antioxidant mechanisms are activated in response to increased oxidative stress. These findings underscore the importance of controlling oxidative stress for maintaining muscle health.
    Keywords:  atrophy; mitochondria; mtDNA; oxidative stress; polymerase gamma; skeletal muscle
    DOI:  https://doi.org/10.1096/fba.2025-00072
  14. AACE Endocrinol Diabetes. 2026 Jan-Feb;13(1):13(1): 102-106
    Fahr Syndrome, Hypoparathyroidism and Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome.
    Jing Li, Xiaodi Wang, Yanmei Guo, Wenwen Wang, Shujuan Wu, Jingmin Sun.
       Background/Objective: We describe a 5-year-old boy with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome presenting with epilepsy, refractory hyperlactatemia, and profound hypoparathyroidism accompanied by Fahr syndrome-like brain calcifications. This case expands the known phenotypic spectrum of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome by demonstrating concurrent parathyroid dysfunction and basal ganglia calcifications. The objective of this report is to characterize this unique neuroendocrine presentation and highlight diagnostic considerations for similar cases.
    Case Presentation: A previously healthy 5-year-old boy presented with 2 days of vomiting, diarrhea, and 1 generalized tonic-clonic seizure. Examination revealed lethargy, positive Chvostek sign, and positive Trousseau sign. Laboratory results showed plasma-free calcium 0.98 mmol/L (reference range, 1.15-1.33), lactate 6.0 mmol/L (reference, 0.7-2.1), and parathyroid hormone 6.62 pg/mL (reference, 12-65). Brain imaging demonstrated symmetrical basal ganglia calcifications. Treatment included levetiracetam, calcium and vitamin D supplementation. Genetic testing confirmed mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome with m.3243A>G mutation. Follow-up showed persistent hyperlactatemia (peak 8.4 mmol/L) and worsening hypoparathyroidism (parathyroid hormone <3 pg/mL).
    Discussion: The severity and persistence of parathyroid hormone suppression in this case contrasts with typical mitochondrial disorder presentations. The concurrence of Fahr-type calcifications and profound hypoparathyroidism suggests potential mitochondrial dysfunction in calcium-regulating tissues.
    Conclusion: This case illustrates a severe neuroendocrine phenotype of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome. Unexplained hypoparathyroidism with basal ganglia calcifications should prompt consideration of mitochondrial disorders, even without classic stroke-like episodes.
    Keywords:  Fahr syndrome; MELAS syndrome; hypoparathyroidism; mitochondrial disorders; neuroendocrine disorders; pediatric endocrinology
    DOI:  https://doi.org/10.1016/j.aed.2025.09.007
  15. Nat Metab. 2026 Feb 03.
    Mitochondrial superoxide regulates nuclear envelope integrity and ageing via redox-mediated lipid metabolism.
    Peng X Chen, Leyuan Zhang, Xueying Wu, Zhiqiang Liang, Xusheng Hao, Qingyuan Zhu, Ying Liu, Jinrou Zheng, Qian Zhang, Qinmeng Yang, Fan Zhou, Chunbao Zhou, Ye Tian.
      The nuclear envelope (NE) is essential for cellular homeostasis, yet its integrity declines with age, accelerating functional deterioration. Here we report a mitochondria-to-NE signalling pathway that safeguards NE integrity through redox-dependent lipid metabolism. In Caenorhabditis elegans, reducing mitochondrial ETC activity preserves NE morphology during ageing. This effect requires developmental mitochondrial superoxide, which downregulates SBP-1 (SREBP orthologue) and suppresses unsaturated fatty acid biosynthesis. The resulting reduction in unsaturated fatty acid levels limits lipid peroxidation, thereby preserving NE structure. Interventions targeting lipid peroxidation preserve NE integrity, extend lifespan in worms and ameliorate senescence-associated phenotypes in human fibroblasts and monkey cells mimicking Hutchinson-Gilford progeria syndrome disease. Our findings reveal a previously unrecognized role for mitochondrial superoxide as a protective developmental signal that programs long-term NE integrity. This work establishes lipid peroxidation control as a conserved strategy to delay nuclear ageing and highlights redox-lipid cross-talk as a therapeutic axis for healthy ageing.
    DOI:  https://doi.org/10.1038/s42255-026-01452-9
  16. J Physiol. 2026 Jan 31.
    Trophoblast-specific overexpression of Slc7a5 increases fetal amino acid availability and hepatic mTOR signalling and causes increased fetal growth.
    Fredrick J Rosario, Hiroshi Shimada, Sam Blessen J Fredrick, Kenneth Barentsen, Theresa L Powell, Johann Urschitz, Thomas L Brown, Laura Brown, Thomas Jansson.
      Abnormal fetal growth is linked to perinatal complications and increased risk of metabolic and cardiovascular diseases, yet the underlying mechanisms remain unclear. Placental System L amino acid transport is decreased in human pregnancies complicated by fetal growth restriction and increased in fetal overgrowth. We previously demonstrated that trophoblast-specific overexpression (OX) of Slc7a5/LAT1 enhances transplacental leucine transport and fetal growth. However, the mechanistic link between increased placental transfer of leucine and stimulation of fetal growth remains unclear. We hypothesized that trophoblast-specific Slc7a5 OX in mice increases fetal plasma levels of essential amino acids, which are associated with elevated fetal circulating levels of insulin and IGF-1 and activation of fetal liver insulin/IGF-1 and mTOR signalling. Trophoblast-specific Slc7a5 OX in mice was generated by lentiviral transduction of embryonic day (E) 3.5 mouse blastocysts followed by embryo transfer. Maternal and pooled fetal plasma samples and fetal livers were collected at E18.5. Slc7a5 OX significantly increased fetal weight and fetal plasma levels of essential amino acids, including leucine, phenylalanine, tryptophan, lysine, histidine, valine, methionine and isoleucine. Insulin and IGF-1 concentrations were elevated in fetal plasma, and fetal liver showed an increased phosphorylation of p70S6K1-Threonine-389, S6-Serine-235/236 and Akt-Serine-473, indicating activation of insulin/IGF-1 and mTORC1 and mTORC2 pathways. These results support the hypothesis that placental LAT1 overexpression enhances fetal amino acid supply, driving endocrine responses and anabolic signalling that promote accelerated fetal growth. We speculate that targeting placental LAT1 may represent a novel intervention in cases of pathological fetal growth. KEY POINTS: Placental amino acid transport is critical for fetal growth and serves as a link between maternal nutrition, placental function and fetal development. Trophoblast-specific overexpression of Slc7a5 (LAT1) in mice increases placental transport of essential amino acids, including leucine and lysine. Fetal plasma amino acids, insulin and IGF-1 concentrations were elevated following LAT1 overexpression. Fetal hepatic signalling was activated, with increased mTORC1 (p-S6 Ser235/236) and mTORC2 (p-Akt Ser473) phosphorylation, while Akt Thr308 phosphorylation was unaffected. Fetuses exposed to LAT1 overexpression were larger, with increased fetal and placental weights, consistent with a fetal overgrowth phenotype. These findings demonstrate that placental LAT1 functions as a nutrient-sensing regulator of fetal growth via endocrine and metabolic signalling pathways.
    Keywords:  fetal development; leucine; maternal–fetal exchange; mechanistic target of rapamycin; placenta; pregnancy complications
    DOI:  https://doi.org/10.1113/JP289970
  17. Sci Rep. 2026 Feb 04.
    Nicotinamide counteracts Rotenone-induced mitochondrial and neuronal dysfunction in a translational early-life model.
    Amanda Siena, E Silva Luiz Felipe Souza, Vitória Cristina Araujo, Martina Raissa Ribeiro, Larissa de Sá Lima, Diana Zukas Andreotti, Ana Maria Orellana, Elisa Mitiko Kawamoto, Silva Junior Pedro Ismael, Cristoforo Scavone, Tatiana Rosado Rosenstock.
      
    Keywords:  Cell respiration; Dendritic spines; Mitochondrial dynamics; Neurodevelopmental disorders; Schizophrenia
    DOI:  https://doi.org/10.1038/s41598-026-36651-7
  18. Trends Neurosci. 2026 Feb 03. pii: S0166-2236(25)00263-2. [Epub ahead of print]
    Mitochondrial specialization and signaling shape neuronal function.
    Benjamin Chun-Kit Tong, Francesco Gubinelli, Lena F Burbulla, Angelika B Harbauer.
      Neurons are specialized cells designed to process information and transmit it, often across long distances. In many neurons, the axonal volume far exceeds the somato-dendritic volume, creating a need for long-range transport and local polarization mechanisms. In addition, action potential firing and restoration of ionic gradients, as well as dynamic changes in synaptic plasticity, further increase the energetic demands of neurons. In this review, we highlight the roles mitochondria play in vertebrate neuronal biology and how mitochondrial functionality is tuned to support the unique demands of neurons. We cover the influence of mitochondrial positioning, ATP generation and Ca2+ buffering on neuronal function, and explore the role of mitochondria in neurotransmitter metabolism and local protein translation.
    Keywords:  Ca(2+) signaling; local translation; neuronal cell biology; neurotransmitter metabolism; respiration; transport
    DOI:  https://doi.org/10.1016/j.tins.2025.12.006
  19. FEBS J. 2026 Feb 04.
    Proteostasis of organelles in aging and disease.
    Yara Nabawi, Cansu Doğan, Dunja Petrović, Gülce Perçin, Seda Koyuncu, David Vilchez.
      To maintain proteome integrity within distinct subcellular compartments, cells rely on tightly regulated proteostasis mechanisms, including protein synthesis, folding, trafficking, and degradation. Disruption of these processes leads to the accumulation of damaged proteins and structural changes that progressively compromise organelle function, contributing to aging and age-associated disorders, such as neurodegeneration, cancer, and metabolic dysfunction. Here, we discuss recent insights into how proteostasis influences the integrity and function of specific organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes, as well as membraneless organelles, such as stress granules, processing bodies, the nucleolus, and nuclear speckles. We further discuss how dysfunction in these systems contributes to different hallmarks of aging and disease progression, highlighting potential therapeutic strategies aimed at maintaining organelle homeostasis to promote healthy aging.
    Keywords:  aging; cellular stress responses; membraneless organelles; membrane‐bound organelles; neurodegenerative diseases; organelle dysfunction; protein aggregation; proteostasis; stress granules
    DOI:  https://doi.org/10.1111/febs.70439
  20. J Hazard Mater. 2026 Jan 31. pii: S0304-3894(26)00292-X. [Epub ahead of print]504 141314
    Mitochondrial Complex I hyperactivation drives PET microplastic-induced intestinal bioenergetic collapse.
    Chuxin Zhang, Wenjing Li, Jiaxing An, Guodong Cao, Yitao Yan, Hao Chen, Huimei Yu, Chao Zhang, Juan Shao, Haitao Zhou, Zhifang Wu, Sijin Li, Zhongyuan Guo.
      Polyethylene terephthalate (PET) microplastics (MPs) are pervasive environmental contaminants with documented human exposure, transporting across intestinal epithelium into the circulatory system and accumulating in multiple organs. This study demonstrates that digestive transformation confers a surface modification on PET MPs, altering their bio-identity and initiating a multilevel pathogenic cascade leading to intestinal dysfunction. Using physiologically relevant particles derived from commercial bottles and a simulated gastrointestinal tract, digested PET MPs inhibit the GLUT2 causing intracellular glucose accumulation and glycolytic disruption, leading to a functional glycolytic blockade, where paradoxical enzyme upregulation results in severely inhibited flux and loss of glucose homeostasis. High-resolution respirometry reveals dysfunctional hyperactivation of mitochondrial Complex I (13.46 ± 7.65 fold, p < 0.0001) as a novel toxic mechanism, driving paradoxical electron transport chain overactivity that culminates in rampant ROS generation (1.89 ± 0.14 fold, p < 0.0001), ATP synthesis shutdown (1.90 ± 0.29 fold, p < 0.01), and decompensated oxidative stress, as evidenced by a significant rise in lipid peroxidation (1.23 ± 0.12 fold, p < 0.01). These disruptions critically impair mitochondrial bioenergetics, initiating a maladaptive metabolic reprogramming that culminates in systemic collapse of mitochondrial metabolism. Integrated multi-omics profiling delineates a self-amplifying mitochondrial metabolic trap, linking proteomic stress to irreversible energetic deficit. These findings establish digestively transformed PET MPs as drivers of metabolic toxicity and provide a mechanistic framework for assessing the health risks of dietary microplastic exposure.
    Keywords:  Complex I hyperactivation; Digestive transformation; Intestinal Dysfunction; Mitochondrial metabolic reprogramming; PET microplastics
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.141314
  21. J Nanobiotechnology. 2026 Feb 05.
    Mitochondrial protein-enriched artificial nanovesicles: mitochondrial recovery and antioxidation for diabetic wound treatment.
    Junhao Xia, Lizhi Wang, Yang Song, Mengru Zhu, Yu Xu, Jia Liu, Xin Guan, Qingwen Zhang, Keman He, Fengya Wang, Lukuan Liu, Jing Liu.
      Oxidative stress and mitochondrial dysfunction are major barriers to the healing of diabetic wounds (DW). Eliminating reactive oxygen species (ROS) and restoring mitochondrial function are considered effective strategies to accelerate DW healing. Although extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have shown therapeutic potential, the quality and yield of mitochondrial components in naturally secreted EVs are limited. Thus, we employed a top-down approach, using the self-assembly properties of membrane components to develop artificial nanovesicles enriched with mitochondria-associated proteins derived from human umbilical cord MSCs. These cell-derived nanovesicles (CNVs) selectively encapsulate mitochondrial proteins, effectively reducing intracellular ROS levels and specifically restoring mitochondrial membrane potential (∆Ψm) and morphology. Furthermore, the CNVs demonstrate remarkable antioxidant and mitochondrial functional restoration capacity, involving the restoration of mitochondrial complexes I, Ⅲ, V and the uncoupling process, as well as multiple mitochondrial function-associated pathways, such as the ALDH2/HADHA/HADHB axis, the IDH2/GSR/GSH axis, and the Ca2+/VDAC1 axis. In vivo experiments further validated the therapeutic potential of CNVs, which significantly promoted wound healing in diabetic mice. In conclusion, our study emphasizes the potential of artificial nanovesicles containing organelle-associated proteins in DW therapy, providing a novel and promising strategy for organelle-based disease treatment.
    Keywords:  Cell-derived nanovesicles; Diabetic wounds; Mesenchymal stem cells; Mitochondrion; Oxidative stress
    DOI:  https://doi.org/10.1186/s12951-026-04100-2
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