bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–07–06
thirty-one papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. The role of NAD+ metabolism and its modulation of mitochondria in aging and disease.
  2. Selfish mutations promote age-associated erosion of mtDNA integrity in mammals.
  3. A constricted mitochondrial morphology formed during respiration.
  4. Mitochondrial DNA genotypes modify m.3243A>G-associated mitochondrial disease via the 15-HETE/Akt/FoxO1 pathway.
  5. Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice.
  6. Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
  7. The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
  8. Role of mitochondrial dynamics in mouse preimplantation embryonic development and its molecular mechanisms.
  9. Modulating mitochondrial dynamics in CMT2A: a multifaceted platform for drug discovery and evaluation.
  10. A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.
  11. Endometriosis-related infertility focusing on mitochondrial DNA damage and its repair mechanism: Considering treatment strategies.
  12. Molecular machineries and pathways of mitochondrial protein transport.
  13. MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction.
  14. Cell-specific mitoproteomics reveals mitochondrial plasticity and applications.
  15. Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.
  16. Muscle-specific AXIN1 and AXIN2 double knockout does not alter AMPK/mTORC1 signalling or glucose metabolism.
  17. Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
  18. Muscle needs NAD, but how much?
  19. Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
  20. Triglycerides are an important fuel reserve for synapse function in the brain.
  21. Disruption of Lrpprc affects B cell development and proliferation in a mouse model of Leigh Syndrome French Canadian type.
  22. Mitochondrial transplantation: adaptive bio-enhancement.
  23. Impaired AMPK control of alveolar epithelial cell metabolism promotes pulmonary fibrosis.
  24. Small molecule OPA1 inhibitors amplify cytochrome c release and reverse cancer cells resistance to Bcl-2 inhibitors.
  25. Structural-functional characterization of the MIRO1-TRAK1 complex.
  26. Reduction of neuronal activity mediated by blood-vessel regression in the adult brain.
  27. Newborn mitochondrial DNA copy number is associated with changes to DNA methylation that persist into childhood and are associated with cognitive development.
  28. The ability of SAMHD1-deficient monocytes to trigger the type I IFN response depends on cGAS and mitochondrial DNA.
  29. In utero ASO therapy for spinal muscular atrophy.
  30. Rare presentation of dandy-walker variant syndrome associated with leigh syndrome: a promising therapeutic approach for prognosis in children related in a case report.
  31. An ex vivo uterine system captures implantation, embryogenesis, and trophoblast invasion via maternal-embryonic signaling.
  1. npj metabolic health and disease... 2025 Jun 18. 3(1): 26
    The role of NAD+ metabolism and its modulation of mitochondria in aging and disease.
    Khalishah Yusri, Sandra Jose, Karen S Vermeulen, Trina Chia Min Tan, Vincenzo Sorrentino.
      Nicotinamide adenine dinucleotide (NAD+) is a coenzyme involved in a plethora of physiological reactions, with a key relevance in supporting mitochondrial function. Due to its critical role in these cellular processes, declining levels of NAD+ are associated with general aging and chronic disorders, including cognitive decline, sarcopenia, and metabolic diseases. These conditions are also typified by loss of mitochondrial health through dysfunction of homeostatic components such as mitophagy, unfolded protein response, and the antioxidant system. Therefore, raising cellular NAD+ through vitamin B3 family precursors or via drug-based interventions has become a broadly used strategy to restore mitochondrial and organismal homeostasis, with NAD+ precursors becoming a popular supplementation approach. As increasing components of the NAD+ biology are unraveled, this comprehensive review summarizes the advances in mechanisms of NAD+ metabolism and its modulation via compound-based strategies. Furthermore, it highlights the role of NAD+ in mitochondrial homeostasis in aging and disease conditions, the latest results of NAD+-boosting therapeutics in clinical trials, and areas of further translational development.
    DOI:  https://doi.org/10.1038/s44324-025-00067-0
  2. Nat Commun. 2025 Jul 01. 16(1): 5435
    Selfish mutations promote age-associated erosion of mtDNA integrity in mammals.
    Ekaterina Korotkevich, Daniel N Conrad, Zev J Gartner, Patrick H O'Farrell.
      Mutations in mitochondrial DNA (mtDNA) accumulate during aging and contribute to age-related conditions. High mtDNA copy number masks newly emerged recessive mutations; however, phenotypes develop when cellular levels of a mutant mtDNA rise above a critical threshold. The process driving this increase is unknown. Single-cell DNA sequencing of mouse and human hepatocytes detected increases in abundance of mutant alleles in sequences governing mtDNA replication. These alleles provided a replication advantage (drive) leading to accumulation of the affected genome along with a wide variety of associated passenger mutations, some of which are detrimental. The most prevalent human mtDNA disease variant, the 3243A>G allele, behaved as a driver, suggesting that drive underlies prevalence. We conclude that replicative drive amplifies linked mtDNA mutations to a threshold at which phenotypes are seen thereby promoting age-associated erosion of the mtDNA and influencing the transmission and progression of mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60477-y
  3. Nat Commun. 2025 Jul 01. 16(1): 5314
    A constricted mitochondrial morphology formed during respiration.
    Manish K Singh, Laetitia Cavellini, Maria Angeles Morcillo-Parra, Christina Kunz, Mickaël Lelek, Perrine Bomme, Aurélia Barascu, Cynthia Alsayyah, Maria Teresa Teixeira, Naïma Belgareh-Touzé, Adeline Mallet, Lea Dietrich, Christophe Zimmer, Mickael M Cohen.
      Mitochondria assemble in a dynamic tubular network. Their morphology is governed by mitochondrial fusion and fission, which regulate most mitochondrial functions including oxidative phosphorylation. Yet, the link between mitochondrial morphology and respiratgion remains unclear. Here, we uncover a mitochondrial morphology dedicated to respiratory growth of Saccharomyces cerevisiae, which we refer to as "Ringo". The Ringo morphology is characterized by stable constrictions of mitochondrial tubules. Ringo constrictions are mediated by the yeast dynamin Dnm1 and, unlike mitochondrial fission, occur in the absence of contacts with the endoplasmic reticulum. Our data show that blocking formation of the Ringo morphology correlates with decreased respiration, decreased expression of OXPHOS subunits and perturbed mitochondrial DNA distribution. These results open important perspectives about the link between mitochondrial form and function.
    DOI:  https://doi.org/10.1038/s41467-025-60658-9
  4. Biochim Biophys Acta Mol Cell Res. 2025 Jun 30. pii: S0167-4889(25)00117-X. [Epub ahead of print]1872(7): 120012
    Mitochondrial DNA genotypes modify m.3243A>G-associated mitochondrial disease via the 15-HETE/Akt/FoxO1 pathway.
    Qian Wang, Chang You, Xiaoning Qu, YiQing Zhang, Yuxiao Bai, Xianlong Lin, Zhaoxia Wang, Hezhi Fang, Jianxin Lyu, Minghua Jiang, Ya Wang.
      Mitochondrial disease caused by mitochondrial DNA (mtDNA) 3243A>G mutation is characterized by high levels of clinical heterogeneity. Varied m.3243A>G mutation loads among patients are used to, but cannot fully explain, disease heterogeneity. Here, we found that mtDNA genotypes (haplogroups) modify m.3243A>G-associated natural selection and cell fate determination. mtDNA haplogroup M7 was less prevalent in a multi-center m.3243A>G disease cohort. Further functional studies using cybrids showed that M7 accelerated cell proliferation and shortened G0/G1 cell cycle when compared with cybrid carrying a non-M7 haplogroup (D5). However, mitochondrial function and cell viability were even worse in M7 cybrid than D5 cybrid when treated with mitochondrial oxidative phosphorylation (OXPHOS) inhibitors, indicating that M7 drives negative selection in patients with m.3243A>G during evolution. By adopting multi-omics strategies, we showed a lesser increase of 15-hydroxyeicosatetraenoic acid (15-HETE) levels in M7 cybrid owing to OXPHOS inhibition, leading to insufficient Akt/FoxO1 activation and increased apoptosis. Notably, 15-HETE administration activated Akt/FoxO1 phosphorylation and abolished apoptosis difference between M7 and D5 cybrids, suggesting that augmented 15-HETE was vital to protect cells from death. Collectively, our work identified a genetic modifier of m.3243A>G-associated mitochondrial disease and demonstrated that the mitochondrial retrograde 15-HETE/Akt/FOXO1 signaling cascade plays an important role in protecting cells from OXPHOS dysfunction-induced cell death.
    Keywords:  15-HETE; Akt-FoxO1 signaling; Mitochondrial disease; m.3243A>G; mtDNA haplogroup
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120012
  5. Elife. 2025 Jun 30. pii: RP104461. [Epub ahead of print]14
    Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice.
    Laura Sophie Kremer, Guanbin Gao, Giovanni Rigoni, Roberta Filograna, Mara Mennuni, Rolf Wibom, Ákos Végvári, Camilla Koolmeister, Nils-Göran Larsson.
      Somatic mitochondrial DNA (mtDNA) mutations are implicated as important drivers of ageing and age-related diseases. Their pathological effect can be counteracted by increasing the absolute amount of wild-type mtDNA via moderately upregulating TFAM, a protein important for mtDNA packaging and expression. However, strong TFAM overexpression can also have detrimental effects as it results in mtDNA hypercompaction and subsequent impairment of mtDNA gene expression. Here, we have experimentally addressed the propensity of moderate TFAM modulation to improve the premature ageing phenotypes of mtDNA mutator mice, carrying random mtDNA mutations. Surprisingly, we detect tissue-specific endogenous compensatory mechanisms acting in mtDNA mutator mice, which largely affect the outcome of TFAM modulation. Accordingly, moderate overexpression of TFAM can have negative and beneficial effects in different tissues of mtDNA mutator mice. We see a similar behavior for TFAM reduction, which improves brown adipocyte tissue homeostasis, while other tissues are unaffected. Our findings highlight that the regulation of mtDNA copy number and gene expression is complex and causes tissue-specific effects that should be considered when modulating TFAM levels. Additionally, we suggest that TFAM is not the sole determinant of mtDNA copy number in situations where oxidative phosphorylation (OXPHOS) is compromised, but other important players must be involved.
    Keywords:  biochemistry; chemical biology; genetics; genomics; mitochondrial DNA; mouse; mtDNA copy number; mtDNA mutations; tissue specificity
    DOI:  https://doi.org/10.7554/eLife.104461
  6. Nat Commun. 2025 Jul 02. 16(1): 6083
    Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
    Iman Man Hu, Marte Molenaars, Yorrick R J Jaspers, Bauke V Schomakers, Michel van Weeghel, Amber Bakker, Melanie Modder, Joseph P Dewulf, Guido T Bommer, Arwen W Gao, Georges E Janssens, Riekelt H Houtkooper.
      Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Here, we explore whether other mechanisms may contribute to lifespan extension upon mitochondrial translation inhibition. Using multi-omics and functional in vivo screening, we identify the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as an essential factor for longevity induced by mitochondrial translation inhibition. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition, while mitochondrial unfolded protein response activation remains unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Mechanistically, sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the "immuno-metabolic stress responses" in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses.
    DOI:  https://doi.org/10.1038/s41467-025-61433-6
  7. Nat Commun. 2025 Jul 01. 16(1): 5996
    The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
    Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige K Boneski, Hiromi Sesaki, Ruteja A Barve, John A Collins, Makarand V Risbud.
      Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of autophagy. Metabolic profiling and 13C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy, Opa1AcanCreERT2 mice showed age-dependent disc degeneration, osteoarthritis, and vertebral osteopenia. RNA-Sequencing of Opa1cKO NP tissue revealed dysregulation of metabolism, autophagy, cytoskeletal reorganization, and extracellular matrix and shared strong thematic similarities with a subset of human degenerative NP samples. Our findings underscore that maintenance of mitochondrial dynamics and multi-organelle cross-talk is critical in preserving metabolic homeostasis of disc and cartilage.
    DOI:  https://doi.org/10.1038/s41467-025-60933-9
  8. Sci Rep. 2025 Jul 01. 15(1): 21751
    Role of mitochondrial dynamics in mouse preimplantation embryonic development and its molecular mechanisms.
    Xiaoyan Sun, Qingyang Li, Bo Chen.
      This study investigated the impact of mitochondrial dynamics on mouse preimplantation embryonic development and its underlying molecular mechanisms. Using pharmacological and genetic approaches, we demonstrated that balanced mitochondrial fusion and fission are essential for optimal embryonic development. Disruption of mitochondrial dynamics significantly impaired blastocyst formation, altered cell lineage allocation, and compromised energy metabolism. Our findings revealed that mitochondrial dynamics regulate gene expression through epigenetic modifications and influence cell survival through the modulation of apoptotic pathways. We also identified key metabolic intermediates and signaling pathways that mediate the effects of mitochondrial dynamics on embryonic development. These results provide new insights into the molecular mechanisms linking mitochondrial function to early embryonic development and suggest potential strategies for improving assisted reproductive technologies.
    Keywords:  Apoptosis; Cell fate; Energy metabolism; Epigenetic modification; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mouse embryo; Preimplantation embryonic development; Reproductive biology
    DOI:  https://doi.org/10.1038/s41598-025-05622-9
  9. Biophys Rep. 2025 Jun 30. 11(3): 143-155
    Modulating mitochondrial dynamics in CMT2A: a multifaceted platform for drug discovery and evaluation.
    Yang Liu, Chen Yan, Borui Cao, Dejun Kong, Jiaqi Li, Wenlei Li, Yingjie Guo, Zhongyang Yuan, Yumiao Gao, Yubo Zhang, Ran Sui, Guo Chen, Xiaojiang Hao, Quan Chen.
      Mitochondrial dynamics, encompassing fusion and fission processes, plays a crucial role in regulating mitochondrial distribution, motility, and material exchange within cells, particularly in the nervous system. Mitofusin-2 (MFN2), a GTPase localized to the outer mitochondrial membrane, mediates mitochondrial fusion through dimerization and conformational changes. Mutations in MFN2 are causal for Charcot-Marie-Tooth disease type 2A (CMT2A), an inherited peripheral neuropathy for which no curative treatment currently exists. Herein, we have developed a comprehensive mitochondrial drug-screening and evaluation platform to facilitate the identification of potential therapeutic candidates. This work builds upon our previous research with S89, a small molecule agonist derived from spiramine alkaloids that promotes mitochondrial fusion by interacting with endogenous MFN1 and effectively mitigates axonal degeneration in CMT2A patient-derived motor neurons. This platform integrates three sequential stages of assessment: (1) initial screening in Mfn knockout mouse embryonic fibroblasts (MEFs) to identify compounds capable of reversibly rescuing mitochondrial fragmentation; (2) evaluation in primary neuronal cultures derived from CMT2A mouse dorsal root ganglia and cortex to assess the compounds' efficacy in restoring mitochondrial morphology, axonal transport, and neurite outgrowth; and (3) final assessment in CMT2A patient-derived induced pluripotent stem cell (iPSC)-differentiated motor neurons to determine the candidates' therapeutic potential in human peripheral nervous system cells. This multi-tiered approach facilitates rapid compound screening with increasing physiological relevance, enhancing the efficiency and translational potential of identifying therapeutic candidates for CMT2A.
    Keywords:  CMT2A neuronal system; Charcot-Marie-Tooth disease type 2A (CMT2A); Mitochondrial fusion; Mitofusin-2 (MFN2); Screening and evaluation platform; Small molecule compounds
    DOI:  https://doi.org/10.52601/bpr.2024.240037
  10. Nat Aging. 2025 Jun 30.
    A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.
    Tim J Nonninger, Jennifer Mak, Birgit Gerisch, Valentina Ramponi, Kazuto Kawamura, Roberto Ripa, Klara Schilling, Christian Latza, Jonathan Kölschbach, Manuel Serrano, Adam Antebi.
      Diapause is a long-lived state of resilience that allows organisms to outlast adversity. Caenorhabditis elegans can endure months in a fasting-induced adult reproductive diapause (ARD) and, upon refeeding, regenerate and reproduce. Here we find that mutants of ARD master regulator hlh-30/TFEB arrest in a senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest and mitochondrial dysfunction, alongside dysregulated immune and growth metabolic signatures, elevated senescence-associated β-galactosidase and premature aging at the organismal level. Forward genetic screens reveal a TFEB-TGFβ signaling axis that systemically controls diapause, stem cell longevity and senescence, aligning nutrient supply to proper metabolism and growth signaling. Notably, TFEB's vital role is conserved in mouse embryonic and human cancer diapause. Thus, ARD offers a powerful model to study stem cell longevity and senescence in vivo, directly relevant to mammals.
    DOI:  https://doi.org/10.1038/s43587-025-00911-4
  11. J Obstet Gynaecol Res. 2025 Jul;51(7): e16358
    Endometriosis-related infertility focusing on mitochondrial DNA damage and its repair mechanism: Considering treatment strategies.
    Hiroshi Kobayashi, Shogo Imanaka.
       AIM: Endometriosis is a chronic gynecological condition characterized by persistent inflammation and frequently associated with dysmenorrhea and infertility. The success rate of assisted reproductive technology (ART) in individuals with endometriosis is often reported to be suboptimal. This review consolidates recent insights into mitochondrial DNA (mtDNA) damage and repair mechanisms in endometriosis patients and examines prospective therapeutic strategies.
    METHODS: For this narrative review, an extensive search of electronic databases was undertaken to identify relevant studies published up to August 31, 2024.
    RESULTS: In oocytes and granulosa cells from endometriosis patients, elevated levels of reactive oxygen species (ROS), driven by hypoxia and oxidative stress, contribute to the accumulation of mtDNA mutations. mtDNA repair is primarily dependent on the base excision repair (BER) pathway, mediated by poly(ADP-ribose) polymerase (PARP-1), due to a deficiency in double-strand break repair mechanisms. Upon mtDNA damage, PARP-1 activates single-strand break repair, utilizing nicotinamide adenine dinucleotide (NAD+) as a substrate. This process depletes ATP and leads to mitochondrial dysfunction in oocytes and granulosa cells. Such mitochondrial impairment may underlie the reduced efficacy of ART in endometriosis patients. Therapeutic interventions aimed at enhancing mitochondrial function, particularly by increasing mitochondrial NAD+ levels, represent a promising approach to addressing endometriosis-associated infertility.
    CONCLUSIONS: mtDNA mutations and defective repair pathways in endometriosis are key contributors to mitochondrial dysfunction, which compromises ART success. This review highlights the potential of mitochondrial function-enhancing therapies as innovative strategies for improving reproductive outcomes in patients with endometriosis.
    Keywords:  endometriosis; mitochondrial DNA damage; mitochondrial DNA repair; nicotinamide adenine dinucleotide; oxidative stress
    DOI:  https://doi.org/10.1111/jog.16358
  12. Nat Rev Mol Cell Biol. 2025 Jul 03.
    Molecular machineries and pathways of mitochondrial protein transport.
    Toshiya Endo, Nils Wiedemann.
      Mitochondria contain about 1,000-1,500 different proteins, most of which are encoded by the nuclear genome and synthesized in the cytosol, although a handful are specified by the mitochondrial DNA and translated within mitochondria. The coordinated transport of nucleus-encoded proteins into mitochondria, followed by their proper folding, assembly and/or integration into mitochondrial membranes, is central to mitochondrial biogenesis. In this Review, we describe the pathways and machineries for protein transport across and insertion into the inner and outer mitochondrial membranes, as well as the targeting and sorting signals, and energy requirements for these processes. These machineries include the TOM and SAM complexes in the outer membrane and the TIM complexes in the inner membrane, and some components in the intermembrane space. We emphasize recent developments in our understanding of the protein structures of the transport machineries and discuss mechanisms for the shift of protein localization and correction of mislocalization.
    DOI:  https://doi.org/10.1038/s41580-025-00865-w
  13. Mol Cell. 2025 Jul 03. pii: S1097-2765(25)00505-2. [Epub ahead of print]85(13): 2610-2625.e5
    MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction.
    Zhangcheng Ding, Rui Wang, Yuhua Li, Xiaodong Wang.
      Necroptosis is a pro-inflammatory, lytic cell death executed by a pseudokinase mixed lineage kinase-like protein MLKL. Upon necroptosis induction by various inflammatory signals, MLKL is phosphorylated by receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and translocates from the cytosol to the plasma membrane, causing membrane disruption and the release of damage-associated molecular patterns (DAMPs). We report here that phosphor-MLKL also translocates to mitochondria and induces a microtubule-dependent release of mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway, resulting in the upregulation of interferon-beta (Ifnb) expression. In a necroptosis-mediated inflammatory bowel disease (IBD) mouse model, interfering with the cGAS-STING pathway reduced inflammation and promoted intestinal recovery. Thus, MLKL induces inflammation not only in a cell non-autonomous fashion by releasing DAMP signals, but also in a cell-autonomous manner by causing mtDNA leakage into the cytosol, thereby activating the cGAS-STING pathway.
    Keywords:  IBD; MLKL; cGAS; mitochondrail DNA; mitochondria; mtDNA; necroptosis
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.005
  14. Trends Biochem Sci. 2025 Jun 27. pii: S0968-0004(25)00140-9. [Epub ahead of print]
    Cell-specific mitoproteomics reveals mitochondrial plasticity and applications.
    Domingos F M Neto, Rita de Cassia Monteiro-Batista, Adriano Nunes-Nesi, Wagner L Araújo.
      Understanding the tissue-specific mitochondrial proteome is essential for advancing understanding of plant biology. In a recent study, Boussardon et al. applied Isolation of Mitochondria Tagged in Specific Cell Types (IMTACT) to investigate mitoproteome dynamics during pollen development. Here, we explore the broader potential of high-purity mitochondrial isolation in elucidating specific roles across tissues and developmental stages.
    Keywords:  mitochondrial proteomics; plant stress; single cell mitochondria
    DOI:  https://doi.org/10.1016/j.tibs.2025.06.010
  15. J Clin Invest. 2025 Jul 01. pii: e185000. [Epub ahead of print]135(13):
    Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.
    Milan Stoiljkovic, Jae Eun Song, Hee-Kyung Hong, Heiko Endle, Luis Varela, Jonatas Catarino, Xiao-Bing Gao, Zong-Wu Liu, Peter Sotonyi, Sabrina Diano, Jonathan Cedernaes, Joseph T Bass, Tamas L Horvath.
      Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark (LD) cycle. Here, we demonstrate that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide-expressing (VIP-expressing) neurons showed circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons caused disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons, leading to desynchronization of entrainment to the LD cycle in Mfn2-deficient mice that resulted in an advanced phase angle of their locomotor activity onset, alterations in core body temperature, and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance, Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.
    Keywords:  Behavior; Cell biology; Metabolism; Mitochondria; Neuroscience; Synapses
    DOI:  https://doi.org/10.1172/JCI185000
  16. J Physiol. 2025 Jun 30.
    Muscle-specific AXIN1 and AXIN2 double knockout does not alter AMPK/mTORC1 signalling or glucose metabolism.
    Kaspar W Persson, Roberto Meneses-Valdés, Nicoline R Andersen, Frederik S Pedersen, Samantha Gallero, Sofie A Hesselager, Carlos Henriquez-Olguin, Thomas E Jensen.
      AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are crucial kinase signalling hubs that regulate the balance between catabolism and anabolism in skeletal muscle. The scaffold protein AXIN1 has been proposed to regulate the switch between these pathways and be required for GLUT4 translocation in skeletal muscle and adipocyte cell lines. Muscle-specific AXIN1 knockout (KO) mice exhibit no discernable phenotype, possibly due to compensation by AXIN2 upon AXIN1 loss. Thus we generated and characterized muscle-specific inducible AXIN1 and AXIN2 double knockout (dKO) mice. Surprisingly AXIN1/2 dKO mice displayed normal AMPK and mTORC1 signalling and glucose uptake in response to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), insulin and in situ muscle contraction. These findings suggest that AXIN proteins are not essential for the regulation of AMPK and mTORC1 signalling or glucose uptake in skeletal muscle. This study challenges the previously indicated critical roles of AXIN1 in exercise-stimulated AMPK activation and GLUT4-mediated glucose uptake in skeletal muscle. KEY POINTS: Phenotyping of tamoxifen-inducible muscle-specific AXIN1/2 double knockout (dKO) mice. We find no evidence for AXIN-dependent AMPK or mTORC1 regulation in skeletal muscle by insulin, AMPK activation or contraction. Glucose uptake regulation by insulin and AMPK activation is normal in AXIN1/2 dKO mice.
    Keywords:  AMPK; exercise; glucose transport; mTOR; skeletal muscle
    DOI:  https://doi.org/10.1113/JP288854
  17. Trends Endocrinol Metab. 2025 Jul 02. pii: S1043-2760(25)00120-1. [Epub ahead of print]
    Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
    Daniel Jimenez-Blasco, Rebeca Lapresa, Jesus Agulla, Angeles Almeida, Juan P Bolaños.
      Neurons are exceptionally energy-demanding cells but have limited energy storage, relying on a constant supply of fuel and oxygen. Although glucose is the brain's main energy source, neurons reduce glycolysis under normal conditions. This surprising strategy helps to protect mitochondria by preserving nicotinamide-adenine dinucleotide (NAD+), a vital cofactor consumed by glycolysis. NAD+ is needed for sirtuin-driven mitophagy, a process that removes damaged mitochondria. By saving NAD+, neurons can maintain healthy, energy-efficient mitochondria. These mitochondria then use alternative fuels such as lactate and ketone bodies from astrocytes. Here, we discuss the way in which this balance between reduced glycolysis and active mitophagy supports brain function and overall metabolic health, highlighting a sophisticated system that prioritizes mitochondrial quality for long-term cognitive performance and systemic homeostasis.
    Keywords:  NAD; glycolysis; mitophay; neuron; organismal wellbeing
    DOI:  https://doi.org/10.1016/j.tem.2025.05.005
  18. Cell Metab. 2025 Jul 01. pii: S1550-4131(25)00296-7. [Epub ahead of print]37(7): 1455-1456
    Muscle needs NAD, but how much?
    David W Frederick, Joseph P McGaunn, Joseph A Baur.
      Supplements that increase nicotinamide adenine dinucleotide (NAD) have become increasingly popular, and much of the attention has focused on potential benefits to skeletal muscle. In this issue of Cell Metabolism, Chubanava et al.1 use an inducible model to lower NAD concentration in the muscles of adult mice, revealing a surprising lack of functional consequences.
    DOI:  https://doi.org/10.1016/j.cmet.2025.06.001
  19. Nat Commun. 2025 Jul 01. 16(1): 5465
    Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
    Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.
      The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.
    DOI:  https://doi.org/10.1038/s41467-025-60670-z
  20. Nat Metab. 2025 Jul 01.
    Triglycerides are an important fuel reserve for synapse function in the brain.
    Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L Pontius, Daehun Park, Rose E Witte, Rachel McAllister, Kallol Gupta, Kartik N Rajagopalan, Pietro De Camilli, Timothy A Ryan.
      Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.
    DOI:  https://doi.org/10.1038/s42255-025-01321-x
  21. J Rare Dis (Berlin). 2025 ;4(1): 31
    Disruption of Lrpprc affects B cell development and proliferation in a mouse model of Leigh Syndrome French Canadian type.
    LSFC Consortium
       Purpose: Leigh Syndrome French Canadian (LSFC) is a rare autosomal recessive metabolic disorder characterized by severe lactic acidosis crises and early mortality. LSFC patients carry variants in the Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) nuclear gene, which lead to defects in the respiratory chain complexes and mitochondrial dysfunction. Mitochondrial respiration modulates cellular metabolic activity, which impacts many cell processes, including the differentiation and function of immune cells. The purpose of this study is to define the role of Lrpprc on immune cell function.
    Methods: As genetic deletion of Lrpprc is not viable, we generated two conditional mouse models: a model for systemic deletion of Lrpprc and a knock-in (KI) model carrying the most common LSFC pathogenic variant in Quebec, NM_133259.4(LRPPRC):c.1061C > T (p.Ala354Val).
    Results: We demonstrate that Lrpprc is an essential gene even in adult mice, as systemic deletion of Lrpprc leads to prominent weight loss and mortality. We also find an increase in lactate levels, a symptom of metabolic crises in LSFC. Lrpprc deletion and pathogenic variant affect various immune cell subsets, with a strong impact on B cell development and proliferation.
    Conclusions: We generated a viable disease-relevant mouse model to study the role of Lrpprc in vivo and find that disruption of Lrpprc strongly impairs B cell development and proliferation.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s44162-025-00094-x.
    Keywords:  B cells; Immune cells; LRPPRC; LSFC; Mitochondria; Proliferation
    DOI:  https://doi.org/10.1007/s44162-025-00094-x
  22. Cell Death Dis. 2025 Jul 01. 16(1): 473
    Mitochondrial transplantation: adaptive bio-enhancement.
    Xiaomeng Lu.
      Mitochondria, often referred to the powerhouse of the cell, are essential for cellular energy production, and their dysfunction can profoundly affect various organs. Transplantation of healthy mitochondria can restore the bioenergetics in diseased cells and address multiple conditions, but more potentials of this approach remain unclear. In this study, I demonstrated that the source of transplanted mitochondria is not limited by species, as exhibit no significant responses to mitochondria derived from different germlines. Moreover, I identified that metabolic compatibility between the recipient and exogenous mitochondria as a crucial factor in mitochondrial transplantation, which confers unique metabolic properties to recipient cells, enabling them to combat different diseases. Additionally, my findings indicated competitive interactions among mitochondria with varying functions, with more bioenergetic-active mitochondria yielded superior therapeutic benefits. Notably, no upper limit for the bioenhancement provided by exogenous mitochondria has been identified. Based on these insights, I proposes a novel therapeutic approach-adaptive bioenhancement through mitochondrial transplantation.
    DOI:  https://doi.org/10.1038/s41419-025-07643-8
  23. JCI Insight. 2025 Jul 01. pii: e182578. [Epub ahead of print]
    Impaired AMPK control of alveolar epithelial cell metabolism promotes pulmonary fibrosis.
    Luis R Rodríguez, Konstantinos-Dionysios Alysandratos, Jeremy Katzen, Aditi Murthy, Willy Roque Barboza, Yaniv Tomer, Sarah Bui, Rebeca Acín-Pérez, Anton Petcherski, Kasey Minakin, Paige Carson, Swati Iyer, Katrina Chavez, Charlotte H Cooper, Apoorva Babu, Aaron I Weiner, Andrew E Vaughan, Zoltan Arany, Orian S Shirihai, Darrell N Kotton, Michael F Beers.
      Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously demonstrated that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here, using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a critical component of AT2 cell dysfunction and demonstrate that targeting this druggable signaling hub can rescue the aberrant AT2 cell metabolic phenotype and mitigate lung fibrosis in vivo.
    Keywords:  Adult stem cells; Fibrosis; Metabolism; Mitochondria; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.182578
  24. Sci Adv. 2025 Jul 04. 11(27): eadx4562
    Small molecule OPA1 inhibitors amplify cytochrome c release and reverse cancer cells resistance to Bcl-2 inhibitors.
    Anna Pellattiero, Charlotte Quirin, Federico Magrin, Mattia Sturlese, Alberto Fracasso, Nikolaos Biris, Stéphanie Herkenne, Laura Cendron, Evripidis Gavathiotis, Stefano Moro, Andrea Mattarei, Luca Scorrano.
      The guanosine triphosphatase (GTPase) activity of the mitochondrial dynamin-related protein Optic Atrophy 1 (OPA1) regulates cristae remodeling, cytochrome c release, and apoptosis. Elevated OPA1 levels in multiple cancers correlate with reduced therapy sensitivity and poor survival, calling for specific OPA1 GTPase inhibitors. A high-throughput screening of ~10,000 compounds identified MYLS22, a heterocyclic N-pyrazole derivative as a reversible, noncompetitive OPA1 GTPase inhibitor. MYLS22 engaged with OPA1 in vitro and in cells where it induced cristae remodeling and mitochondrial fragmentation contingent on intactness of its predicted OPA1 binding site. MYLS22 enhanced proapoptotic cytochrome c release and sensitized breast adenocarcinoma cells to anti-Bcl-2 therapy, without toxicity on noncancer cells. By MYLS22 structure-activity relationship studies, we obtained Opa1 inhibitor 0 (Opitor-0) that inhibited OPA1, promoted cytochrome c release, and restored anti-Bcl-2 therapy sensitivity more efficiently than MYLS22. These chemical probes validate OPA1 as a therapeutic target to increase cancer cell apoptosis at the mitochondrial level.
    DOI:  https://doi.org/10.1126/sciadv.adx4562
  25. Nat Commun. 2025 Jul 04. 16(1): 6173
    Structural-functional characterization of the MIRO1-TRAK1 complex.
    Erika E Ravitch, Elana E Baltrusaitis, Tania A Perez, Kyle R Barrie, Adam R Fenton, Erika L F Holzbaur, Roberto Dominguez.
      Mitochondrial Rho GTPase (MIRO) features N- and C-terminal GTPase domains (nGTPase and cGTPase) flanking two pairs of EF-hands, and functions as a master scaffold on the outer mitochondrial membrane. It regulates mitochondrial motility by recruiting trafficking kinesin-binding protein (TRAK), which in turn recruits kinesin-1 and dynein-dynactin. The MIRO-TRAK interaction remains incompletely understood. Here, we describe the cryo-electron microscopy structure of TRAK1569-623 bound to MIRO1. The complex forms a dimer, mediated by interactions through the second EF-hand pair, cGTPase, and TRAK1. TRAK1569-623 binds in a cleft between the nGTPase and first EF-hand pair, inserting side chains into hydrophobic pockets of both domains. Another MIRO1-binding site involves TRAK1425-428, which binds in a pocket between the second EF-hand pair and cGTPase. Both binding sites are validated by mutagenesis and binding assays, showing no clear dependence on cofactor conditions (calcium or nucleotide). In cells, both sites contribute to TRAK1's mitochondrial localization.
    DOI:  https://doi.org/10.1038/s41467-025-61174-6
  26. Nat Commun. 2025 Jul 01. 16(1): 5840
    Reduction of neuronal activity mediated by blood-vessel regression in the adult brain.
    Xiaofei Gao, Xing-Jun Chen, Meng Ye, Jun-Liszt Li, Nannan Lu, Di Yao, Bo Ci, Fei Chen, Lijun Zheng, Yating Yi, Shiwen Zhang, Zhanying Bi, Xinwei Gao, Yuanlei Yue, Tingbo Li, Jiafu Lin, Ying-Chao Shi, Kaibin Shi, Nicholas E Propson, Yubin Huang, Katherine Poinsatte, Zhaohuan Zhang, Dale B Bosco, Shi-Bing Yang, Ralf H Adams, Volkhard Lindner, Fen Huang, Long-Jun Wu, Hui Zheng, Simon Hippenmeyer, Ann M Stowe, Bo Peng, Marta Margeta, Qingchun Guo, Xiaoqun Wang, Qiang Liu, Jakob Körbelin, Martin Trepel, Hui Lu, Guoen Cai, Bo O Zhou, Bo Shen, Ying-Mei Lu, Wenzhi Sun, Jie-Min Jia, Feng Han, Hu Zhao, Robert M Bachoo, Woo-Ping Ge.
      The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we report that a substantial proportion of blood vessels in the adult mouse brain sporadically occlude and regress. Their regression proceeds through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels are found to be widespread in mouse, monkey and human brains. We further reveal that blood vessel regression cause a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and glutamate production. Our results elucidate the mechanism of vessel regression and its role in neuronal function in the adult brain.
    DOI:  https://doi.org/10.1038/s41467-025-60308-0
  27. Clin Epigenetics. 2025 Jul 02. 17(1): 112
    Newborn mitochondrial DNA copy number is associated with changes to DNA methylation that persist into childhood and are associated with cognitive development.
    Allison Kupsco, Jonathan A Heiss, Marco Sanchez-Guerra, Guadalupe Estrada-Gutierrez, Corina Lesseur, Carmen Hernández, Tessa R Bloomquist, Gaylord Abigail, Jia Guo, Shuang Wang, Julie B Herbstman, Allan C Just, Martha M Téllez-Rojo, Robert O Wright, Andrea A Baccarelli.
       BACKGROUND/OBJECTIVES: Mitochondrial-nuclear crosstalk is critical for cell function, and nuclear DNA methylation (DNAm) may regulate this process. Mitochondria maintain an extranuclear genome, and mitochondrial DNA copy number (mtDNA-CN) has been previously associated with DNAm. However, there is little information on this relationship in children, whose brains are particularly vulnerable to energetic perturbations during development. Our objectives were to (1) characterize associations of mtDNA-CN with nuclear DNAm at birth; (2) determine their persistence into childhood; and (3) investigate associations in relation to neurodevelopment.
    METHODS: We quantified mtDNA-CN with qRT-PCR and DNAm with the MethylationEPIC BeadChip array in umbilical cord leukocytes (N = 422) in newborns from the PROGRESS birth cohort in Mexico City (2007-2011). At the 48-month visit, we measured DNAm in peripheral blood leukocytes (N = 177) and assessed the McCarthy Scales of Children's Abilities (N = 290). We performed an epigenome-wide association study (EWAS) with cord mtDNA-CN in mitochondrially relevant genes (23,261 CpG sites) and across the genome (745,691 sites). We determined if our results persisted until childhood and were associated with cognitive scales. The findings were replicated in a US-based cohort (N = 130).
    RESULTS: We observed 11 and 165 differentially methylated positions (DMPs) in mitochondria-related nuclear genes and across the genome, respectively, after correction for multiple comparisons. In mitochondrial genes, two significant DMPs mapped to PRELID3A and a DMP in the promoter region of SLC25A24 replicated in our external cohort. At 48 months of age, 17 of 165 DMPs remained associated with cord mtDNA-CN, 12 were associated with child memory scales, and associations with 17 replicated in our external cohort. Several positions mapped to genes in immune activation and development.
    CONCLUSIONS: In newborns, mtDNA-CN was associated with DNAm in mitochondria-related genes and throughout the genome, several of which remained associated in childhood, were associated with child memory scales, and were replicated in a US-based cohort. These findings open new avenues for future targets for children's health and disease.
    Keywords:  DNA methylation; Developmental origins of health and disease; Mitochondria; Neurodevelopment; mtDNA
    DOI:  https://doi.org/10.1186/s13148-025-01896-y
  28. J Biol Chem. 2025 Jun 26. pii: S0021-9258(25)02280-X. [Epub ahead of print] 110430
    The ability of SAMHD1-deficient monocytes to trigger the type I IFN response depends on cGAS and mitochondrial DNA.
    Jesse Rabinowitz, Isabelle K Vila, Charlotte Luchsinger, Cinzia Bertelli, Moritz Schüssler, Clara Taffoni, Bin Cui, Annie Zhi Dai, Mohammad M Rashid, William J Cisneros, Daphne Cornish, Juan Redondo, Kathryn A Jackson-Jones, Lacy M Simons, Ramon Lorenzo-Redondo, Nadine Laguette, Judd F Hultquist, Felipe Diaz-Griffero.
      In humans, mutations in sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) lead to the development of a type I interferonopathy known as Aicardi-Goutières syndrome (AGS). AGS can present with a variety of severe phenotypes in patients, and a hallmark of this disease is chronic activation of type I interferon (IFN) signaling. However, the mechanism through which type I IFN signaling is activated in the absence of functional SAMHD1 is not known. Here, we investigated the molecular pathways that lead to type I IFN signaling activation in the absence of SAMHD1. Our investigations revealed that chronic activation of type I IFN signaling in SAMHD1-knockout(KO) monocytes is cyclic GMP-AMP synthase (cGAS)-dependent. Analysis of other nucleic acid sensors showed that type I IFN signaling in SAMHD1-KO cells is not dependent on melanoma differentiation-associated protein 5 (MDA5) or retinoic acid-inducible gene I (RIG-I). In agreement with our observation that type I IFN signaling is dependent on cGAS, two inhibitors of the cGAS-stimulator of IFN genes pathway, G140 and H151, effectively prevented type I IFN activation in SAMHD1-KO monocytes. We also found that type I IFN signaling in SAMHD1-KO monocytes is dependent on type I IFN receptor expression. Further exploration revealed mitochondrial malfunction in SAMHD1-KO monocytes that is likely to leak mitochondrial components into the cytoplasm. Overall, our work suggests that genetic knock out of SAMHD1 leads to mitochondrial disfunction, resulting in the presence of mitochondrial DNA in the cytoplasm, which triggers cGAS and the type I IFN response.
    Keywords:  Aicardi–Goutières syndrome; THP-1; cGAS; mitochondria; type I IFN response
    DOI:  https://doi.org/10.1016/j.jbc.2025.110430
  29. Nat Rev Drug Discov. 2025 Jul;24(7): 502
    In utero ASO therapy for spinal muscular atrophy.
    M Teresa Villanueva.
      
    Keywords:  Biotechnology; Drug discovery; Gene therapy; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41573-025-00097-9
  30. Oxf Med Case Reports. 2025 Jun;2025(6): omaf061
    Rare presentation of dandy-walker variant syndrome associated with leigh syndrome: a promising therapeutic approach for prognosis in children related in a case report.
    Bianca Frigo Pires, Graziele Ines Silva Lopo, Anaí Ramoa Siqueira, Luiza Resende Felisberto, Rafaella Simão Martini, Ana Beatriz Valim Alves, Amanda Carolina Rodrigues Silva, Flávia Xavier Lima Carvalho, Aline Pirola Aliseda, Mariane Martinhon Martins, Carla Kreuzberg Salgado, Salum Bueno da Silveira Junior, Camila Garcia Ferrari Jacob.
       INTRODUCTION: Dandy-Walker syndrome (D-WS) is a rare congenital brain anomaly that primarily impacts the fourth ventricle and cerebellum. Its variant is even rarer and includes cerebellar dysgenesis, with possible posterior fossa enlargement and variable cerebellar vermis hypoplasia.
    CASE REPORT: We present the case of a patient diagnosed late with the Dandy-Walker Syndrome variant, associated with Leigh Syndrome, at a tertiary hospital. The patient received an optimized, multidisciplinary treatment approach to improve prognosis.
    DISCUSSION: Early intervention in pediatric neurodegenerative diseases through a multidisciplinary team that includes medical, speech therapy, and physiotherapy support is crucial for a better prognosis in these cases.
    Keywords:  dandy-walker variant; leigh syndrome; pediatric syndrome
    DOI:  https://doi.org/10.1093/omcr/omaf061
  31. Nat Commun. 2025 Jul 01. 16(1): 5755
    An ex vivo uterine system captures implantation, embryogenesis, and trophoblast invasion via maternal-embryonic signaling.
    Takehiro Hiraoka, Shizu Aikawa, Daisuke Mashiko, Tatsuya Nakagawa, Hiroki Shirai, Yasushi Hirota, Hiroshi Kimura, Masahito Ikawa.
      Embryo implantation remains challenging to study because of its inaccessibility in situ despite its essentiality and clinical significance. Although recent studies on long-term culture of authentic and model embryos have provided significant advances in elucidating embryogenesis in vitro, they, without the uterus, cannot genuinely replicate implantation. Here, we have recapitulated bona fide implantation ex vivo at more than 90% efficiency followed by embryogenesis and trophoblast invasion using authentic mouse embryos and uterine tissue. We utilized air-liquid interface culture method with originally developed devices manufactured with polydimethylsiloxane. Notably, the system replicated the robust induction of a maternal implantation regulator COX-2 at the attachment interface, which was accompanied by trophoblastic AKT activation, suggesting a possible signaling that mediates maternal COX-2 and embryonic AKT1 that accelerates implantation. By expanding the ex vivo findings, embryonic AKT1 transduction ameliorated defective implantation of uterine origin by a COX-2 inhibitor in vivo. The system, proposing a potentially standard platform of embryogenesis, offers a concise, reproducible, and scalable screening system, suggesting significant implications for developmental biology and therapeutic strategies for recurrent implantation failure in assisted reproductive technology.
    DOI:  https://doi.org/10.1038/s41467-025-60610-x
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