bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–12–14
fifteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Neuronal fatty acid oxidation fuels memory after intensive learning in Drosophila.
  2. Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
  3. Fatal Presentation of Leigh Syndrome in a Neonate: Comprehensive Neuroimaging Findings With MT-ND5 Mutation.
  4. Activation of the integrated stress response contributes to developmental delay and seizures caused by mitochondrial prolyl-tRNA synthetase (PARS2) deficiency.
  5. Liver-directed base editing of ABCC6 prevents ectopic calcification in a variant-humanized mouse model of pseudoxanthoma elasticum.
  6. Cross-regulation of [2Fe-2S] cluster synthesis by ferredoxin-2 and frataxin.
  7. The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.
  8. Autophagy-NAD+ axis: emerging insights into neuronal homeostasis and neurodegenerative diseases.
  9. Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.
  10. Metformin Restores Mitochondrial Function and Neurogenesis in POLG Patient-Derived Brain Organoids.
  11. A direct role for a mitochondrial targeting sequence in signalling stress.
  12. An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.
  13. Kidney mitochondrial DNA contributes to systemic IL-6 release in sepsis-associated acute kidney injury.
  14. Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency.
  15. Combination of Cas9 and adeno-associated vectors enables efficient in vivo knockdown of precise miRNAs in the rodent and primate brain.
  1. Nat Metab. 2025 Dec 10.
    Neuronal fatty acid oxidation fuels memory after intensive learning in Drosophila.
    Alice Pavlowsky, Bryon Silva, Ruchira Basu, Amandine Correia Delecourt, David Geny, Lydia Danglot, Pierre-Yves Plaçais, Thomas Preat.
      Metabolic flexibility allows cells to adapt to different fuel sources, which is particularly important for cells with high metabolic demands1-3. In contrast, neurons, which are major energy consumers, are considered to rely essentially on glucose and its derivatives to support their metabolism. Here, using Drosophila melanogaster, we show that memory formed after intensive massed training is dependent on mitochondrial fatty acid (FA) β-oxidation to produce ATP in neurons of the mushroom body (MB), a major integrative centre in insect brains. We identify cortex glia as the provider of lipids to sustain the usage of FAs for this type of memory. Furthermore, we demonstrate that massed training is associated with mitochondria network remodelling in the soma of MB neurons, resulting in increased mitochondrial size. Artificially increasing mitochondria size in adult MB neurons increases ATP production in their soma and, at the behavioural level, strikingly results in improved memory performance after massed training. These findings challenge the prevailing view that neurons are unable to use FAs for energy production, revealing, on the contrary, that in vivo neuronal FA oxidation has an essential role in cognitive function, including memory formation.
    DOI:  https://doi.org/10.1038/s42255-025-01416-5
  2. Trends Biochem Sci. 2025 Dec 05. pii: S0968-0004(25)00266-X. [Epub ahead of print]
    Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
    Denis Lacabanne, Jonathan J Ruprecht, Maximilian Sichrovsky, Lucy R Forrest, Vanessa Leone, Sotiria Tavoulari, Edmund R S Kunji.
      The mitochondrial pyruvate carrier (MPC), of the SLC54 family of solute carriers, has a critical role in eukaryotic energy metabolism by transporting pyruvate, the end-product of glycolysis, into the mitochondrial matrix. Recently, structures of the human MPC1/MPC2 and MPC1L/MPC2 heterodimers in the outward-open, occluded, and inward-open states have been determined by cryo-electron microscopy (cryo-EM) and by AlphaFold modeling. In this review we discuss the membrane orientation, substrate binding site properties, and structural features of the alternating access mechanism of the carrier, as well as the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state. These structural studies will support drug development efforts for the treatment of diabetes mellitus, neurodegeneration, metabolic dysfunction-associated steatotic liver disease (MASLD), and some types of cancers.
    Keywords:  alternating access transport mechanism; membrane protein structure; mitochondrion; solute carrier family SLC54; structure-based drug design; sugar and energy metabolism
    DOI:  https://doi.org/10.1016/j.tibs.2025.11.002
  3. Cureus. 2025 Nov;17(11): e96098
    Fatal Presentation of Leigh Syndrome in a Neonate: Comprehensive Neuroimaging Findings With MT-ND5 Mutation.
    Shrinivas Radder, Nivedita Radder.
      Leigh syndrome represents a severe mitochondrial disorder characterized by progressive neurodegeneration, typically manifesting in infancy with devastating outcomes. We present a 30-day-old male infant who presented with acute neurological deterioration, including seizures, dystonia, and respiratory failure. Laboratory evaluation revealed elevated levels of lactate and pyruvate. Brain magnetic resonance imaging (MRI) demonstrated characteristic bilateral symmetric T2 hyperintensity with restricted diffusion involving the basal ganglia, thalami, brainstem structures, and multiple other regions. Single-voxel spectroscopy confirmed an elevated lactate peak in the basal ganglia. Genetic testing identified a 95% heteroplasmic pathogenic variant in MT-ND5, confirming mitochondrial DNA-associated Leigh syndrome. Despite intensive supportive care including mechanical ventilation and anticonvulsant therapy, the patient's condition progressively deteriorated, resulting in death 16 days after admission. This case highlights the fulminant presentation of neonatal Leigh syndrome and emphasizes the critical role of neuroimaging in establishing this diagnosis, particularly when combined with biochemical and genetic findings.
    Keywords:  leigh syndrome; mitochondrial disorder; mr spectroscopy; mt-nd5 mutation; neonatal encephalopathy; neuroimaging
    DOI:  https://doi.org/10.7759/cureus.96098
  4. Redox Biol. 2025 Dec 09. pii: S2213-2317(25)00479-3. [Epub ahead of print]89 103966
    Activation of the integrated stress response contributes to developmental delay and seizures caused by mitochondrial prolyl-tRNA synthetase (PARS2) deficiency.
    Man Xu, Yuxin Liu, Runhua Ma, Wenlu Fan, Jingwei Duan, Huan Deng, Yanbin Ma, Wanzhong Ge.
      Mutations in mitochondrial aminoacyl-tRNA synthetases (mtARSs) causes mitochondrial defects and serious, progressive and usually lethal diseases with exceptional heterogeneous and tissue-specific clinical manifestations. However, the pathogenic mechanisms for specific mtARS related diseases are largely unknown and currently there is no highly effective treatment or cure for these diseases. In the present study, we generate Drosophila models with human mitochondrial prolyl-tRNA synthetase (PARS2) deficiency by knocking out or knocking down dPARS2, the Drosophila ortholog of human PARS2, and further characterize the disease-associated defects and explore the molecular basis of these phenotypes. Inactivation of dPARS2 in Drosophila causes developmental delay and seizure, two main clinical features in human PARS2 deficiency-associated patients. Biochemical analysis demonstrates that loss of dPARS2 activity results in reduced mitochondrial tRNAPro aminoacylation, decreased levels of OXPHOS complex proteins, defective assembly and altered enzyme activities of OXPHOS complexes. Interestingly, we discover that dPARS2 deficiency activates the integrated stress response (ISR), which reduces global protein translation and increases activity of ATF4 in our neuronal dPARS2 knockdown model. Importantly, blockade of ISR activation by genetic suppression of GCN2 kinase prevents developmental delay and seizure phenotypes in dPARS2-deficient flies. Furthermore, the genetic suppression of ATF4, the ISR key effector, also reverses these developmental and behavioral abnormalities associated with dPARS2 deficiency. Furthermore, a disease-associated PARS2 V95I variant causes mitochondrial dysfunction and ISR activation in human cells, verifying the findings in the Drosophila models. Together, these results not only provide evidence for PARS2 deficiency associated mitochondrial dysfunction, but also reveal a novel pathogenic mechanism involved in ISR activation in the PARS2 deficiency related disease, indicating a novel disease treatment approach by targeting ISR.
    Keywords:  Developmental delay; Integrated stress response; Mitochondrial aminoacyl-tRNA synthetases; PARS2; Seizures
    DOI:  https://doi.org/10.1016/j.redox.2025.103966
  5. Mol Ther Nucleic Acids. 2025 Dec 09. 36(4): 102769
    Liver-directed base editing of ABCC6 prevents ectopic calcification in a variant-humanized mouse model of pseudoxanthoma elasticum.
    Lauren C Testa, Dora Obiri-Yeboah, Hooda Said, Ping Qu, Michael A Levine, Mohamad-Gabriel Alameh, Kiran Musunuru, Qiaoli Li, Xiao Wang.
      Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disorder characterized by ectopic calcification of elastic fibers throughout the skin, retina, and arteries. It is caused by pathogenic variants in ABCC6, which encodes a transmembrane transporter that primarily localizes to hepatocytes. Loss of ABCC6 function in hepatocytes leads to systemic deficiency of inorganic pyrophosphate (PPi), a potent inhibitor of calcification; such depletion of PPi from the circulation is responsible for multisystemic ectopic calcification seen in PXE. Therefore, liver-targeted variant correction by genome editing and subsequent restoration of systemic PPi may offer a one-and-done therapeutic approach for PXE. The ABCC6 c.3490C>T (p.R1164X) variant is one of the most common variants found in PXE patients. Here, we show that liver-directed correction of the R1164X variant by adenine base editing restores plasma PPi and prevents ectopic skin calcification in mice fed a standard diet or an "acceleration diet" that exacerbates ectopic calcification. These results provide fundamental insight into the molecular etiology of PXE and provide a proof-of-principle that genetic correction of ABCC6 defects through adenine base editing may represent a novel, permanent therapy for the treatment of PXE.
    Keywords:  ABCC6; CRISPR; MT: RNA/DNA Editing; base editing; ectopic calcification; gene editing; genome editing; pseudoxanthoma elasticum; pyrophosphate; rare disease
    DOI:  https://doi.org/10.1016/j.omtn.2025.102769
  6. Nature. 2025 Dec 10.
    Cross-regulation of [2Fe-2S] cluster synthesis by ferredoxin-2 and frataxin.
    Kristian Want, Hubert Gorny, Ema Turki, Magali Noiray, Beata Monfort, Rémi Mor-Gautier, Thibault Tubiana, Estelle Jullian, Véronique Monnier, Benoit D'Autréaux.
      Iron-sulfur (Fe-S) clusters are essential metallocofactors that perform a multitude of biological functions1-7. Their synthesis is tightly regulated and defects in this process lead to severe diseases8-10, such as Friedreich's ataxia, which is caused by defective expression of frataxin (FXN)11. However, the underlying mechanisms that regulate this process remain unclear. Here we show that efficient Fe-S cluster assembly requires a fine-tuned balance in the ratio of FXN and ferredoxin-2 (FDX2). Fe-S clusters are assembled on the scaffold protein ISCU2; sulfur is provided as a persulfide by NFS1, and the persulfide is cleaved into sulfide by FDX2 (refs. 12,13). FXN stimulates the whole process by accelerating the transfer of persulfide to ISCU2 (refs. 12,14,15). Using an in-vitro-reconstituted human system, we show that any deviation from a close-to-equal amount of FXN and FDX2 downregulates Fe-S cluster synthesis. Structure-function investigation reveals that this is due to competition between FXN and FDX2 and their similar affinities for the same binding site on the NFS1-ISCU2 complex, with higher levels of FXN impairing the persulfide reductase activity of FDX2 and higher levels of FDX2 slowing the FXN-accelerated transfer of persulfide to ISCU2. We also find that FDX2 directly hinders persulfide generation and transfer to ISCU2 by interacting with the persulfide-carrying mobile loop of NFS1. We further show that knocking down the expression of FDX2 increases fly lifespan in a Drosophila model of Friedreich's ataxia. Together, this work highlights a direct regulation of Fe-S cluster biosynthesis through antagonistic binding of FXN and FDX2, and suggests that decreasing FDX2 in the context of FXN deficiency in Friedreich's ataxia might constitute a novel therapeutic axis.
    DOI:  https://doi.org/10.1038/s41586-025-09822-1
  7. FEBS J. 2025 Dec 07.
    The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.
    Jiaxin Qian, Annika Nutz, Katja Hansen, Lea Bertgen, Mirita Franz-Wachtel, Boris Macek, Johannes M Herrmann, Doron Rapaport.
      The biogenesis of mitochondria relies on the import of newly synthesized precursor proteins from the cytosol. Tom70 is a mitochondrial surface receptor which recognizes precursors and serves as an interface between mitochondrial protein import and the cytosolic proteostasis network. Mitochondrial import defects trigger a complex stress response, in which compromised protein synthesis rates are a characteristic element. The molecular interplay that connects mitochondrial (dys)function to cytosolic translation rates in yeast cells is however poorly understood. Here, we show that the deletion of the two Tom70 paralogs of yeast (TOM70 and TOM71) leads to defects in mitochondrial biogenesis and slow cell growth. Surprisingly, upon heat stress, the deletion of ZUO1, a chaperone of the ribosome-associated complex (RAC), largely prevented the slow growth and the reduced translation rates in the tom70Δ/tom71Δ double deletion mutant. In contrast, the mitochondrial defects were not cured but even enhanced by ZUO1 deletion. Our study shows that Zuo1 is a critical component in the signaling pathway that mutes protein synthesis upon mitochondrial dysfunction. We propose a novel paradigm according to which RAC serves as a stress-controlled regulatory element of the cytosolic translation machinery.
    Keywords:  Tom70; mitochondria; protein import; proteostasis; ribosome‐associated complex
    DOI:  https://doi.org/10.1111/febs.70356
  8. Front Mol Biosci. 2025 ;12 1695486
    Autophagy-NAD+ axis: emerging insights into neuronal homeostasis and neurodegenerative diseases.
    Gamze Kocak, Mylla M Dimas, Luiz F S E Silva, Danyelle Silva-Amaral, Congxin Sun, Sophie Cruddas, Timothy Barrett, Daniel Martins-de-Souza, Edecio Cunha-Neto, Patricia S Brocardo, Tetsushi Kataura, Viktor I Korolchuk, Sovan Sarkar.
      Autophagy is an evolutionarily conserved catabolic process that plays a central role in maintaining cellular homeostasis by degrading and recycling damaged or surplus proteins, organelles, and other cellular macromolecules and components. A growing body of evidence highlights a bidirectional relationship between autophagy and nicotinamide adenine dinucleotide (NAD+), a vital metabolic cofactor involved in numerous cellular processes, including energy metabolism, genomic maintenance, stress resistance, and cell survival. Autophagy supports NAD+ homeostasis by recycling metabolic precursors, while NAD+-dependent enzymes such as sirtuins and PARPs regulate autophagy initiation and lysosomal function. Disruption of this autophagy-NAD+ axis has emerged as a common feature in several neurodegenerative diseases, where impaired cellular clearance and metabolic dysfunction contribute to neuronal vulnerability. In this review, we summarize the advances of the molecular links between autophagy and NAD+ metabolism, with a particular focus on their roles in mitochondrial quality control, bioenergetic regulation, and cellular resilience. We also discuss the therapeutic potential of targeting the autophagy-NAD+ axis to promote neuroprotection in neurodegenerative disease.
    Keywords:  NAD+; NAD+ precursor; NAD+ supplementation; NAD+-dependent enzyme; autophagy; autophagy inducer; neuronal cell death; neuroprotection
    DOI:  https://doi.org/10.3389/fmolb.2025.1695486
  9. Nat Cardiovasc Res. 2025 Dec 11.
    Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.
    Abigail V Giles, Raul Covian, Hiran A Prag, Nils Burger, Bertrand Lucotte, Chak Shun Yu, Junhui Sun, Elizabeth Murphy, Thomas Krieg, Michael P Murphy, Robert S Balaban.
      The mitochondrial membrane potential (ΔΨm) drives oxidative phosphorylation and alterations contribute to cardiac pathologies, but real-time assessment of ΔΨm has not been possible. Here we describe noninvasive measurements using mitochondrial heme bL and bH absorbances, which rapidly respond to ΔΨm. Multi-wavelength absorbance spectroscopy enabled their continuous monitoring in isolated mitochondria and the perfused heart. Calibration of heme b absorbance in isolated mitochondria revealed that reduced heme bL relative to total reduced heme b (fbL = bL/(bL + bH)) exhibits a sigmoidal relationship with ΔΨm. Extrapolating this relationship to the heart enabled estimation of ΔΨm as 166 ± 18 mV (n = 25, mean ± s.d.). We used this approach to assess how ΔΨm changes during ischemia-reperfusion injury, an unknown limiting the understanding of ischemia-reperfusion injury. In perfused hearts, ΔΨm declined during ischemia and rapidly reestablished upon reperfusion, supported by oxidation of the succinate accumulated during ischemia. These findings expand our understanding of ischemia-reperfusion injury.
    DOI:  https://doi.org/10.1038/s44161-025-00752-9
  10. Adv Sci (Weinh). 2025 Dec 08. e17721
    Metformin Restores Mitochondrial Function and Neurogenesis in POLG Patient-Derived Brain Organoids.
    Zhuoyuan Zhang, Tsering Yangzom, Ning Lu, Shenglong Deng, Xianglu Xiao, Guang Yang, Kristina Xiao Liang.
      Mitochondrial dysfunction and impaired neurogenesis are central to mitochondrial DNA polymerase (POLG)-related disorders, yet therapeutic options remain limited. Here, patient-derived induced pluripotent stem cell (iPSC)-based cortical organoids are used to model POLG-associated neurodegeneration and assess the therapeutic potential of metformin. Single-cell RNA-seq reveals distinct vulnerabilities in dopaminergic, glutamatergic, and GABAergic neuronal subtypes, with dopaminergic neurons exhibiting the most severe loss and mitochondrial transcriptomic deficits. Metformin treatment (250 µm, 2 months) significantly restores neuronal identity, subtype-specific gene expression, and mitochondrial function. Functional assays demonstrate improved mitochondrial membrane potential (TMRE), increased mitochondrial mass (MTG, MTDR), and reduced oxidative stress (MitoSOX, BAX/cleaved caspase 3). Notably, mitochondrial DNA (mtDNA) copy number and the expression of mitochondrial replisome proteins (POLG, POLG2) are upregulated, indicating enhanced mitochondrial genome maintenance. Calcium measurement confirms improved neuronal excitability. Untargeted metabolomics further reveals metformin-induced metabolic reprogramming, including enrichment of the tricarboxylic acid (TCA) cycle, amino acid metabolism, and redox-related pathways. Together, these findings demonstrate that metformin enhances mitochondrial integrity and neural function across multiple neuronal subtypes and offer mechanistic insights into its potential as a treatment for POLG-related disorders.
    Keywords:  POLG‐related disorders; cortical organoids; iPSCs; mitochondrial dysfunction; neurogenesis impairment
    DOI:  https://doi.org/10.1002/advs.202417721
  11. Nature. 2025 Dec 10.
    A direct role for a mitochondrial targeting sequence in signalling stress.
    Zixuan Yuan, Megan Balzarini, Marina Volpe, Madeleine Goldstein, Tony Shengzhe Peng, Elizabeth Hui, Nancy Neng Fang, Waleed S Albihlal, Melika Hajimohammadi, Kevin Wei, Calvin K Yip, Folkert J van Werven, Thibault Mayor, Hilla Weidberg.
      Mitochondrial protein import is required for maintaining organellar function1. Perturbations in this process are associated with various physiological and disease conditions2. Several stress responses, including the mitochondrial compromised protein import response (mitoCPR), combat damage caused by mitochondrial protein import defects2. However, how this defect is sensed remains largely unknown. Here we reveal that the conserved mitochondrial Hsp70 co-chaperone, Mge1, acts as a stress messenger in budding yeast. During mitochondrial stress, unimported Mge1 entered the nucleus and triggered the transcription of mitoCPR target genes. This was mediated by the interaction of Mge1 with the transcription factor Pdr3 on DNA regulatory elements. The mitochondrial targeting sequence of Mge1 was both sufficient and essential for mitoCPR induction, demonstrating that in addition to their roles in mitochondrial protein import, targeting sequences can also function as signalling molecules. As protein import defects are a common consequence of various types of mitochondrial damage3,4, these findings suggest a novel function for the targeting sequence of Mge1 as an indicator of mitochondrial health.
    DOI:  https://doi.org/10.1038/s41586-025-09834-x
  12. Int J Mol Sci. 2025 Nov 24. pii: 11349. [Epub ahead of print]26(23):
    An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.
    Roman Abrosimov, Ankush Borlepawar, Parvana Hajieva, Bernd Moosmann.
      Inhibition of respiratory chain complex I (NADH dehydrogenase) is a widely encountered biochemical consequence of drug intoxication and a primary consequence of mtDNA mutations and other mitochondrial defects. In an organ-selective form, it is also deployed as antidiabetic pharmacological treatment. Complex I inhibition evokes a pronounced metabolic reprogramming of uncertain purposefulness, as in several cases, anabolism appears to be fostered in a state of bioenergetic shortage. A hallmark of complex I inhibition is the enhanced biosynthesis of serine, usually accompanied by an induction of folate-converting enzymes. Here, we have revisited the differential transcriptional induction of these metabolic pathways in three published models of selective complex I inhibition: MPP-treated neuronal cells, methionine-restricted rats, and patient fibroblasts harboring an NDUFS2 mutation. We find that in a coupled fashion, serinogenesis and circular folate cycling provide an unrecognized alternative pathway of complete glucose oxidation that is mostly dependent on NADP instead of the canonic NAD cofactor (NADP:NAD ≈ 2:1) and thus evades the shortage of oxidized NAD produced by complex I inhibition. In contrast, serine utilization for anabolic purposes and C1-folate provision for S-adenosyl-methionine production and transsulfuration cannot explain the observed transcriptional patterns, while C1-folate provision for purine biosynthesis did occur in some models, albeit not universally. We conclude that catabolic glucose oxidation to CO2, linked with NADPH production for indirect downstream respiration through fatty acid cycling, is the general purpose of the remarkably strong induction of serinogenesis after complex I inhibition.
    Keywords:  NADPH-FADH2 axis; Parkinson’s disease; fatty acid cycling; futile cycle; glycolytic inhibition; metabolic reprogramming; metformin; mitochondrial disease; oxidative stress
    DOI:  https://doi.org/10.3390/ijms262311349
  13. JCI Insight. 2025 Dec 08. pii: e177004. [Epub ahead of print]10(23):
    Kidney mitochondrial DNA contributes to systemic IL-6 release in sepsis-associated acute kidney injury.
    Avnee J Kumar, Katharine Epler, Jing Wang, Alice Shen, Negin Samandari, Mark L Rolfsen, Laura A Barnes, Gerald S Shadel, Alexandra G Moyzis, Alva G Sainz, Karlen Ulubabyan, Kefeng Li, Kristen Jepsen, Xinrui Li, Mark M Fuster, Roger G Spragg, Roman Sasik, Volker Vallon, Helen Goodluck, Joachim H Ix, Prabhleen Singh, Mark L Hepokoski.
      Mitochondrial dysfunction is a major mechanism of acute kidney injury (AKI), and increased circulating interleukin 6 (IL-6) is associated with systemic inflammation and death due to sepsis. We tested whether kidney mitochondrial DNA (mtDNA) contributes to IL-6 release in sepsis-associated AKI via Toll-like receptor 9 (TLR9). In a murine model of sepsis via cecal ligation and puncture (CLP), we used next-generation sequencing of plasma mtDNA to inform the design of optimal target sequences for quantification by droplet digital PCR, and to identify single-nucleotide polymorphisms (SNPs) to infer tissue origin. We found significantly higher concentrations of plasma mtDNA after CLP versus shams and that plasma mtDNA SNPs matched kidney SNPs more than other organs. Kidney mtDNA contributed directly to IL-6 and mtDNA release from dendritic cells in vitro and kidney mitochondria solution led to higher IL-6 concentrations in vivo. IL-6 release was mitigated by a TLR9 inhibitor. Finally, plasma mtDNA was significantly higher in septic patients with AKI compared with those without AKI and correlated significantly with plasma IL-6. We conclude that AKI contributes to increased circulating IL-6 in sepsis via mtDNA release. Targeting kidney mitochondria and mtDNA release are potential translational avenues to decrease mortality from sepsis-associated AKI.
    Keywords:  Inflammation; Innate immunity; Mitochondria; Nephrology
    DOI:  https://doi.org/10.1172/jci.insight.177004
  14. Nature. 2025 Dec 10.
    Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency.
    Joshua D Meisel, Pallavi R Joshi, Amy N Spelbring, Hong Wang, Sandra M Wellner, Presli P Wiesenthal, Maria Miranda, Jason G McCoy, David P Barondeau, Gary Ruvkun, Vamsi K Mootha.
      Frataxin is a key component of an ancient, mitochondrial iron-sulfur cluster biosynthetic machinery, serving as an allosteric activator of the cysteine desulfurase NFS1 (refs. 1-5). Loss of frataxin levels underlies Friedreich's ataxia6, the most common inherited ataxia. Yeast, Caenorhabditis elegans and human cells can tolerate loss of frataxin when grown in 'permissive' low oxygen tensions7. Here we conducted an unbiased, genome-scale forward genetic screen in C. elegans leveraging permissive and non-permissive oxygen tensions to discover suppressor mutations that bypass the need for frataxin. All mutations act dominantly and are in the ferredoxin FDX2/fdx-2 or in the cysteine desulfurase NFS1/nfs-1 genes, resulting in amino-acid substitutions at the FDX2-NFS1 binding interface. Our genetic and biochemical analyses show that the suppressor mutations boost iron-sulfur cluster levels in the absence of frataxin. We also demonstrate that an excess of FDX2 inhibits frataxin-stimulated NFS1 activity in vitro and blocks the synthesis of iron-sulfur clusters in mammalian cell culture. These findings are consistent with structural and biochemical evidence that frataxin and FDX2 compete for occupancy at the same site on NFS1 (refs. 8,9). We show that lowering levels of wild-type FDX2 through loss of one gene copy can ameliorate the growth of frataxin mutant C. elegans or the ataxia phenotype of a mouse model of Friedreich's ataxia under normoxic conditions. These genetic and biochemical studies indicate that restoring the stoichiometric balance of frataxin and FDX2 through partial knockdown of FDX2 may be a potential therapy for Friedreich's ataxia.
    DOI:  https://doi.org/10.1038/s41586-025-09821-2
  15. Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2513076122
    Combination of Cas9 and adeno-associated vectors enables efficient in vivo knockdown of precise miRNAs in the rodent and primate brain.
    David Roura-Martinez, Natalia Popa, Florence Jaouen, Cynthia Rombaut, Catherine Lepolard, Dipankar Bachar, Ana Borges, Maxime Cazorla, Maxime Villet, Sebastien Moreno, Hélène Marie, Eduardo Gascon.
      microRNAs (miRNAs) are key regulators of multiple biological functions. Although intensively studied, inactivating miRNAs in vivo is particularly challenging, especially in the brain. Here, we designed cell-specific tools aiming at downregulating defined miRNA species in vivo and investigating their function in discrete neuronal networks. Focusing on miR-124, a miRNA highly expressed in the mammalian brain and transcribed from three independent chromosomal loci, we designed and validated different guide RNAs. In vivo, our CRISPR-Cas9 designs strongly downregulate miR-124 levels without affecting the expression of other miRNAs. As a result, levels of endogenous miR-124 targets exhibit a significant increase supporting the release of its silencing activity. We provide evidence that specific deletion of miR-124 in neural stem cells of the subventricular zone altered migration of newly generated neurons into the olfactory bulb. We also showed that our vectors modified the Ca2+ permeability of AMPA receptors, a robust functional output downstream of miR-124. We also extended our approach to other miRNAs, mammalian species, and Cas9 proteins, confirming the versatility of CRISPR-Cas9. These tool properties support their potential for elucidating miRNA functions in complex experimental in vivo settings such as brain networks.
    Keywords:  Cas9; brain; microRNA; nonhuman primate; rodent
    DOI:  https://doi.org/10.1073/pnas.2513076122
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