bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–12–17
33 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain.
  2. Involvement of Mitochondria in Parkinson's Disease.
  3. Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?
  4. Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort.
  5. The critical roles of STING in mitochondrial homeostasis.
  6. Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis.
  7. The Protective Mechanism of TFAM on Mitochondrial DNA and its Role in Neurodegenerative Diseases.
  8. The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
  9. The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
  10. Methylmalonic aciduria as a biochemical marker for mitochondrial DNA depletion syndrome in patients with developmental delay and movement disorders: a case series.
  11. Mitochondrial temperature homeostasis resists external metabolic stresses.
  12. GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
  13. Targeted genetic therapies for inherited disorders that affect both cardiac and skeletal muscle.
  14. First in vivo base editing lowers cholesterol.
  15. Novel COX11 Mutations Associated with Mitochondrial Disorder: Functional Characterization in Patient Fibroblasts and Saccharomyces cerevisiae.
  16. Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
  17. Ndufs4 KO mice: A model to study comorbid mood disorders associated with mitochondrial dysfunction.
  18. Genetic, metabolic and clinical delineation of an MRPS23-associated mitochondrial disorder.
  19. LKB1/AMPK treats myocardial disease by boosting mitochondrial function.
  20. CRISPR 2.0: a new wave of gene editors heads for clinical trials.
  21. Single-cell DNA methylome and 3D multi-omic atlas of the adult mouse brain.
  22. AMPKα2 is a skeletal muscle stem cell intrinsic regulator of myonuclear accretion.
  23. Intraneuronal β-amyloid impaired mitochondrial proteostasis through the impact on LONP1.
  24. Mitochondrially Targeted Gene Therapy Rescues Visual Loss in a Mouse Model of Leber's Hereditary Optic Neuropathy.
  25. Are your organs ageing well? The blood holds clues.
  26. Copper homeostasis and cuproptosis in mitochondria.
  27. Second-generation antipsychotics and metabolic syndrome: a role for mitochondria.
  28. Database screening as a strategy to identify endogenous candidate metabolites to probe and assess mitochondrial drug toxicity.
  29. Conserved and divergent gene regulatory programs of the mammalian neocortex.
  30. Editorial: Mitochondrial Gene Variations Increase Autism Risk: Uncovering the Complex Polygenetic Landscape of Autism.
  31. Atlas of fetal metabolism during mid-to-late gestation and diabetic pregnancy.
  32. Modeling post-implantation human development to yolk sac blood emergence.
  33. Decreased fetal movements: Report from the International Stillbirth Alliance conference workshop.
  1. Cell Death Dis. 2023 Dec 08. 14(12): 805
    Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain.
    Doni Davide, Cavion Federica, Bortolus Marco, Baschiera Elisa, Muccioli Silvia, Tombesi Giulia, d'Ettorre Federica, Daniele Ottaviani, Marchesan Elena, Leanza Luigi, Greggio Elisa, Ziviani Elena, Russo Antonella, Bellin Milena, Sartori Geppo, Carbonera Donatella, Salviati Leonardo, Costantini Paola.
      Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease caused by an expanded GAA repeat in the first intron of the FXN gene, leading to transcriptional silencing and reduced expression of frataxin. Frataxin participates in the mitochondrial assembly of FeS clusters, redox cofactors of the respiratory complexes I, II and III. To date it is still unclear how frataxin deficiency culminates in the decrease of bioenergetics efficiency in FRDA patients' cells. We previously demonstrated that in healthy cells frataxin is closely attached to the mitochondrial cristae, which contain both the FeS cluster assembly machinery and the respiratory chain complexes, whereas in FRDA patients' cells with impaired respiration the residual frataxin is largely displaced in the matrix. To gain novel insights into the function of frataxin in the mitochondrial pathophysiology, and in the upstream metabolic defects leading to FRDA disease onset and progression, here we explored the potential interaction of frataxin with the FeS cluster-containing respiratory complexes I, II and III. Using healthy cells and different FRDA cellular models we found that frataxin interacts with these three respiratory complexes. Furthermore, by EPR spectroscopy, we observed that in mitochondria from FRDA patients' cells the decreased level of frataxin specifically affects the FeS cluster content of complex I. Remarkably, we also found that the frataxin-like protein Nqo15 from T. thermophilus complex I ameliorates the mitochondrial respiratory phenotype when expressed in FRDA patient's cells. Our data point to a structural and functional interaction of frataxin with complex I and open a perspective to explore therapeutic rationales for FRDA targeted to this respiratory complex.
    DOI:  https://doi.org/10.1038/s41419-023-06320-y
  2. Int J Mol Sci. 2023 Dec 01. pii: 17027. [Epub ahead of print]24(23):
    Involvement of Mitochondria in Parkinson's Disease.
    Chi-Jing Choong, Hideki Mochizuki.
      Mitochondrial dysregulation, such as mitochondrial complex I deficiency, increased oxidative stress, perturbation of mitochondrial dynamics and mitophagy, has long been implicated in the pathogenesis of PD. Initiating from the observation that mitochondrial toxins cause PD-like symptoms and mitochondrial DNA mutations are associated with increased risk of PD, many mutated genes linked to familial forms of PD, including PRKN, PINK1, DJ-1 and SNCA, have also been found to affect the mitochondrial features. Recent research has uncovered a much more complex involvement of mitochondria in PD. Disruption of mitochondrial quality control coupled with abnormal secretion of mitochondrial contents to dispose damaged organelles may play a role in the pathogenesis of PD. Furthermore, due to its bacterial ancestry, circulating mitochondrial DNAs can function as damage-associated molecular patterns eliciting inflammatory response. In this review, we summarize and discuss the connection between mitochondrial dysfunction and PD, highlighting the molecular triggers of the disease process, the intra- and extracellular roles of mitochondria in PD as well as the therapeutic potential of mitochondrial transplantation.
    Keywords:  PINK1; Parkin; Parkinson’s disease; extracellular mitochondria; mitochondria; mitochondria transplantation
    DOI:  https://doi.org/10.3390/ijms242317027
  3. Int J Mol Sci. 2023 Nov 25. pii: 16746. [Epub ahead of print]24(23):
    Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?
    Federica Conti, Serena Di Martino, Filippo Drago, Claudio Bucolo, Vincenzo Micale, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso, Piervito Lopriore.
      Primary mitochondrial diseases (PMDs) are complex group of metabolic disorders caused by genetically determined impairment of the mitochondrial oxidative phosphorylation (OXPHOS). The unique features of mitochondrial genetics and the pivotal role of mitochondria in cell biology explain the phenotypical heterogeneity of primary mitochondrial diseases and the resulting diagnostic challenges that follow. Some peculiar features ("red flags") may indicate a primary mitochondrial disease, helping the physician to orient in this diagnostic maze. In this narrative review, we aimed to outline the features of the most common mitochondrial red flags offering a general overview on the topic that could help physicians to untangle mitochondrial medicine complexity.
    Keywords:  mitochondria; primary mitochondrial diseases; rare diseases; red flags
    DOI:  https://doi.org/10.3390/ijms242316746
  4. J Neurol. 2023 Dec 08.
    Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort.
    David R Lynch, Teerapat Rojsajjakul, S H Subramony, Susan L Perlman, Medina Keita, Clementina Mesaros, Ian A Blair.
       BACKGROUND: Friedreich ataxia is a progressive multisystem disorder caused by deficiency of the protein frataxin; a small mitochondrial protein involved in iron sulfur cluster synthesis. Two types of frataxin exist: FXN-M, found in most cells, and FXN-E, found almost exclusively in red blood cells. Treatments in clinical trials include frataxin restoration by gene therapy, protein replacement, and epigenetic therapies, all of which necessitate sensitive assays for assessing frataxin levels.
    METHODS: In the present study, we have used a triple quadrupole mass spectrometry-based assay to examine the features of both types of frataxin levels in blood in a large heterogenous cohort of 106 patients with FRDA.
    RESULTS: Frataxin levels (FXN-E and FXN M) were predicted by GAA repeat length in regression models (R2 values = 0.51 and 0.27, respectively), and conversely frataxin levels predicted clinical status as determined by modified Friedreich Ataxia Rating scale scores and by disability status (R2 values = 0.13-0.16). There was no significant change in frataxin levels in individual subjects over time, and apart from start codon mutations, FXN-E and FXN-M levels were roughly equal. Accounting for hemoglobin levels in a smaller sub-cohort improved prediction of both FXN-E and FXN-M levels from R2 values of (0.3-0.38 to 0.20-0.51).
    CONCLUSION: The present data show that assay of FXN-M and FXN-E levels in blood provides an appropriate biofluid for assessing their repletion in particular clinical contexts.
    Keywords:  Disability status; Frataxin blood levels; Friedreich Ataxia Rating scale; GAA repeat length; Mitochondrial protein
    DOI:  https://doi.org/10.1007/s00415-023-12118-x
  5. Biochem Pharmacol. 2023 Dec 10. pii: S0006-2952(23)00531-2. [Epub ahead of print] 115938
    The critical roles of STING in mitochondrial homeostasis.
    Shishi Zou, Bo Wang, Ke Yi, Dandan Su, Yukai Chen, Ning Li, Qing Geng.
      The stimulator of interferon genes (STING) is a crucial signaling hub in the immune system's antiviral and antimicrobial defense by detecting exogenous and endogenous DNA. The multifaceted functions of STING have been uncovered gradually during past decades, including homeostasis maintenance and overfull immunity or inflammation induction. However, the subcellular regulation of STING and mitochondria is poorly understood. The main functions of STING are outlined in this review. Moreover, we discuss how mitochondria and STING interact through multiple mechanisms, including the release of mitochondrial DNA (mtDNA), modulation of mitochondria-associated membrane (MAM) and mitochondrial dynamics, alterations in mitochondrial metabolism, regulation of reactive oxygen species (ROS) production, and mitochondria-related cell death. Finally, we discuss how STING is crucial to disease development, providing a novel perspective on its role in cellular physiology and pathology.
    Keywords:  Cell death; Innate immunity; Mitochondrial dynamics; Mitochondrial metabolism; MtDNA; STING
    DOI:  https://doi.org/10.1016/j.bcp.2023.115938
  6. Int J Mol Sci. 2023 Nov 27. pii: 16833. [Epub ahead of print]24(23):
    Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis.
    Natalia V Belosludtseva, Lyudmila A Matveeva, Konstantin N Belosludtsev.
      Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing "quality control" and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.
    Keywords:  SOD1; amyotrophic lateral sclerosis; bioenergetic stress; mitochondria; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dyshomeostasis; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/ijms242316833
  7. Mol Neurobiol. 2023 Dec 12.
    The Protective Mechanism of TFAM on Mitochondrial DNA and its Role in Neurodegenerative Diseases.
    Ying Song, Wenjun Wang, Beibei Wang, Qiwen Shi.
      Mitochondrial transcription factor A (TFAM) is a mitochondrial protein encoded by nuclear genes and transported from the cytoplasm to the mitochondria. TFAM is essential for the maintenance, expression, and delivery of mitochondrial DNA (mtDNA) and can regulate the replication and transcription of mtDNA. TFAM is associated with the formation of mtDNA nucleomimetic structures, mtDNA repair, and mtDNA stability. However, the mechanism by which TFAM protects mtDNA is still being studied. This review provides a summary of the protective mechanism of TFAM on mtDNA including the discrete regulatory effects of TFAM acetylation and phosphorylation on mtDNA, the regulation of Ca2+ levels by TFAM to activate transcription in mitochondria, and the increased binding of TFAM to mtDNA damage hot spots. This review also discusses the association between TFAM and some neurodegenerative diseases.
    Keywords:  Mitochondria; Mitochondrial DNA; Mitochondrial transcription factor A; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-023-03841-7
  8. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2303713120
    The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
    Ryan Pekson, Felix G Liang, Joshua L Axelrod, Jaehoon Lee, Dongze Qin, Andre J H Wittig, Victor M Paulino, Min Zheng, Pablo M Peixoto, Richard N Kitsis.
      The mitochondrial permeability transition pore (mPTP) is a channel in the inner mitochondrial membrane whose sustained opening in response to elevated mitochondrial matrix Ca2+ concentrations triggers necrotic cell death. The molecular identity of mPTP is unknown. One proposed candidate is the mitochondrial ATP synthase, whose canonical function is to generate most ATP in multicellular organisms. Here, we present mitochondrial, cellular, and in vivo evidence that, rather than serving as mPTP, the mitochondrial ATP synthase inhibits this pore. Our studies confirm previous work showing persistence of mPTP in HAP1 cell lines lacking an assembled mitochondrial ATP synthase. Unexpectedly, however, we observe that Ca2+-induced pore opening is markedly sensitized by loss of the mitochondrial ATP synthase. Further, mPTP opening in cells lacking the mitochondrial ATP synthase is desensitized by pharmacological inhibition and genetic depletion of the mitochondrial cis-trans prolyl isomerase cyclophilin D as in wild-type cells, indicating that cyclophilin D can modulate mPTP through substrates other than subunits in the assembled mitochondrial ATP synthase. Mitoplast patch clamping studies showed that mPTP channel conductance was unaffected by loss of the mitochondrial ATP synthase but still blocked by cyclophilin D inhibition. Cardiac mitochondria from mice whose heart muscle cells we engineered deficient in the mitochondrial ATP synthase also demonstrate sensitization of Ca2+-induced mPTP opening and desensitization by cyclophilin D inhibition. Further, these mice exhibit strikingly larger myocardial infarctions when challenged with ischemia/reperfusion in vivo. We conclude that the mitochondrial ATP synthase does not function as mPTP and instead negatively regulates this pore.
    Keywords:  mitochondrial ATP synthase; mitochondrial permeability transition pore; necrosis
    DOI:  https://doi.org/10.1073/pnas.2303713120
  9. Nat Commun. 2023 Dec 12. 14(1): 8248
    The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
    Lindsay McGregor, Samira Acajjaoui, Ambroise Desfosses, Melissa Saïdi, Maria Bacia-Verloop, Jennifer J Schwarz, Pauline Juyoux, Jill von Velsen, Matthew W Bowler, Andrew A McCarthy, Eaazhisai Kandiah, Irina Gutsche, Montserrat Soler-Lopez.
      The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer's disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD.
    DOI:  https://doi.org/10.1038/s41467-023-43865-0
  10. Front Neurol. 2023 ;14 1265115
    Methylmalonic aciduria as a biochemical marker for mitochondrial DNA depletion syndrome in patients with developmental delay and movement disorders: a case series.
    Montaha Almudhry, Arushi Gahlot Saini, Mohammed A Al-Omari, Yashu Sharma, Maryam Nabavi Nouri, C Anthony Rupar, Chitra Prasad, Andrea C Yu, Savita Verma Attri, Asuri Narayan Prasad.
       Background: Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are genetically and clinically variable disorders resulting from a reduction in mtDNA content in the cells, tissues, and organ systems, leading to symptoms related to energy deficits. Deficiency of the mitochondrial succinyl-CoA ligase/synthetase enzyme secondary to pathogenic variations in the SUCLG1 and SUCLA2 genes is a subtype of MDDS that presents with neurological manifestations and a specific biochemical profile.
    Methods: This cross-sectional series describes five patients with MDDS secondary to pathogenic variations in the SUCLG1 and SUCLA2 genes from two tertiary care centers in Canada and India. Clinical data concerning the course, investigations, and outcome were gathered through chart reviews.
    Results: All subjects presented in early infancy with neurological manifestations, including movement disorder, psychomotor regression, developmental delay, hearing loss, behavioral issues, or a combination thereof. Elevated methylmalonic acid metabolites, an abnormal acylcarnitine profile, and lactic acidemia were noted in the biochemical profile of each patient (n = 5/5, 100%). Molecular genetic testing disclosed the presence of pathogenic homozygous mutations in four subjects and compound heterozygosity in one subject.
    Conclusion: MDDS associated with SUCLG1 and SUCLA2 genes can be detected biochemically by the presence of methylmalonic aciduria besides the elevation of lactate, C3, C4DC, and C5-OH acylcarnitine. Conducting metabolic workups including MMA and acylcarnitine profiles in patients with heterogeneity of clinical symptoms associated with the presence of this biochemical marker may potentially reduce the time to diagnosis and management.
    Keywords:  SUCLA2; SUCLG1; dystonia; methylmalonic acid; mitochondrial DNA depletion syndrome; mitochondrial disorder; movement disorder
    DOI:  https://doi.org/10.3389/fneur.2023.1265115
  11. Elife. 2023 Dec 11. pii: RP89232. [Epub ahead of print]12
    Mitochondrial temperature homeostasis resists external metabolic stresses.
    Mügen Terzioglu, Kristo Veeroja, Toni Montonen, Teemu O Ihalainen, Tiina S Salminen, Paule Bénit, Pierre Rustin, Young-Tae Chang, Takeharu Nagai, Howard T Jacobs.
      Based on studies with a fluorescent reporter dye, Mito Thermo Yellow (MTY), and the genetically encoded gTEMP ratiometric fluorescent temperature indicator targeted to mitochondria, the temperature of active mitochondria in four mammalian and one insect cell line was estimated to be up to 15°C above that of the external environment to which the cells were exposed. High mitochondrial temperature was maintained in the face of a variety of metabolic stresses, including substrate starvation or modification, decreased ATP demand due to inhibition of cytosolic protein synthesis, inhibition of the mitochondrial adenine nucleotide transporter and, if an auxiliary pathway for electron transfer was available via the alternative oxidase, even respiratory poisons acting downstream of oxidative phosphorylation (OXPHOS) complex I. We propose that the high temperature of active mitochondria is an inescapable consequence of the biochemistry of OXPHOS and is homeostatically maintained as a primary feature of mitochondrial metabolism.
    Keywords:  D. melanogaster; OXPHOS; biochemistry; bioenergetics; cell biology; chemical biology; human; mitochondria; mouse; organelle; temperature; thermogenesis
    DOI:  https://doi.org/10.7554/eLife.89232
  12. Nat Commun. 2023 Dec 11. 14(1): 8187
    GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
    Qiang Zhu, Matthew E Combs, Juan Liu, Xue Bai, Wenbo B Wang, Laura E Herring, Jiandong Liu, Jason W Locasale, Dawn E Bowles, Ryan T Gross, Michelle Mendiola Pla, Christopher P Mack, Joan M Taylor.
      The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, Parkin, are known to facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this process contribute to a variety of cardiometabolic and neurological diseases. Although recent evidence indicates that dynamic actin remodeling plays an important role in PINK1/Parkin-mediated mitochondrial autophagy (mitophagy), the underlying signaling mechanisms remain unknown. Here, we identify the RhoGAP GRAF1 (Arhgap26) as a PINK1 substrate that regulates mitophagy. GRAF1 promotes the release of damaged mitochondria from F-actin anchors, regulates mitochondrial-associated Arp2/3-mediated actin remodeling and facilitates Parkin-LC3 interactions to enhance mitochondria capture by autophagosomes. Graf1 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure, and cardiomyocyte-restricted Graf1 depletion in mice blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress. Overall, we identify GRAF1 as an enzyme that coordinates cytoskeletal and metabolic remodeling to promote cardioprotection.
    DOI:  https://doi.org/10.1038/s41467-023-43889-6
  13. Exp Physiol. 2023 Dec 14.
    Targeted genetic therapies for inherited disorders that affect both cardiac and skeletal muscle.
    Yiangos Psaras, Christopher N Toepfer.
      Skeletal myopathies and ataxias with secondary cardiac involvement are complex, progressive and debilitating conditions. As life expectancy increases across these conditions, cardiac involvement often becomes more prominent. This highlights the need for targeted therapies that address these evolving cardiac pathologies. Musculopathies by and large lack cures that directly target the genetic basis of the diseases; however, as our understanding of the genetic causes of these conditions has evolved, it has become tractable to develop targeted therapies using biologics, to design precision approaches to target the primary genetic causes of these varied diseases. Using the examples of Duchenne muscular dystrophy, Friedreich ataxia and Pompe disease, we discuss how the genetic causes of such diseases derail diverse homeostatic, energetic and signalling pathways, which span multiple cellular systems in varied tissues across the body. We outline existing therapeutics and treatments in the context of emerging novel genetic approaches. We discuss the hurdles that the field must overcome to deliver targeted therapies across the many tissue types affected in primary myopathies. NEW FINDINGS: What is the topic of this review? Overlapping disease pathomechanisms and therapeutic opportunities in neuromuscular, skeletal and cardiac muscle diseases in the context of novel genetic therapies. What advances does it highlight? This review outlines the diverse genetic changes that drive pathomechanism across a set of neuromuscular conditions and highlight the emerging targeted biological therapies that are being developed to treat these conditions, with additional discussion of the hurdles to actualising genetically targeted precision medicine.
    Keywords:  Duchenne muscular dystrophy; Friedreich's ataxia; Pompe disease; gene therapy; skeletal and cardiac muscle disease; therapeutics
    DOI:  https://doi.org/10.1113/EP090436
  14. Nat Biotechnol. 2023 Dec;41(12): 1665
    First in vivo base editing lowers cholesterol.
      
    DOI:  https://doi.org/10.1038/s41587-023-02070-6
  15. Int J Mol Sci. 2023 Nov 23. pii: 16636. [Epub ahead of print]24(23):
    Novel COX11 Mutations Associated with Mitochondrial Disorder: Functional Characterization in Patient Fibroblasts and Saccharomyces cerevisiae.
    Chenelle A Caron-Godon, Stefania Della Vecchia, Alessandro Romano, Stefano Doccini, Flavio Dal Canto, Rosa Pasquariello, Anna Rubegni, Roberta Battini, Filippo Maria Santorelli, D Moira Glerum, Claudia Nesti.
      Genetic defects in the nuclear encoded subunits and assembly factors of cytochrome c oxidase (mitochondrial complex IV) are very rare and are associated with a wide variety of phenotypes. Biallelic pathogenic variants in the COX11 protein were previously identified in two unrelated children with infantile-onset mitochondrial encephalopathies. Through comprehensive clinical, genetic and functional analyses, here we report on a new patient harboring novel heterozygous variants in COX11, presenting with Leigh-like features, and provide additional experimental evidence for a direct correlation between COX11 protein expression and sensitivity to oxidative stress. To sort out the contribution of the single mutations to the phenotype, we employed a multi-faceted approach using Saccharomyces cerevisiae as a genetically manipulable system, and in silico structure-based analysis of human COX11. Our results reveal differential effects of the two novel COX11 mutations on yeast growth, respiration, and cellular redox status, as well as their potential impact on human protein stability and function. Strikingly, the functional deficits observed in patient fibroblasts are recapitulated in yeast models, validating the conservation of COX11's role in mitochondrial integrity across evolutionarily distant organisms. This study not only expands the mutational landscape of COX11-associated mitochondrial disorders but also underscores the continued translational relevance of yeast models in dissecting complex molecular pathways.
    Keywords:  COX11 mutation; COX11 protein structure; mitochondrial diseases; yeast model
    DOI:  https://doi.org/10.3390/ijms242316636
  16. Commun Biol. 2023 Dec 08. 6(1): 1240
    Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
    Raquel Fernando, Anastasia V Shindyapina, Mario Ost, Didac Santesmasses, Yan Hu, Alexander Tyshkovskiy, Sun Hee Yim, Jürgen Weiss, Vadim N Gladyshev, Tilman Grune, José Pedro Castro.
      Skeletal muscle aging is characterized by the loss of muscle mass, strength and function, mainly attributed to the atrophy of glycolytic fibers. Underlying mechanisms driving the skeletal muscle functional impairment are yet to be elucidated. To unbiasedly uncover its molecular mechanisms, we recurred to gene expression and metabolite profiling in a glycolytic muscle, Extensor digitorum longus (EDL), from young and aged C57BL/6JRj mice. Employing multi-omics approaches we found that the main age-related changes are connected to mitochondria, exhibiting a downregulation in mitochondrial processes. Consistent is the altered mitochondrial morphology. We further compared our mouse EDL aging signature with human data from the GTEx database, reinforcing the idea that our model may recapitulate muscle loss in humans. We are able to show that age-related mitochondrial downregulation is likely to be detrimental, as gene expression signatures from commonly used lifespan extending interventions displayed the opposite direction compared to our EDL aging signature.
    DOI:  https://doi.org/10.1038/s42003-023-05595-3
  17. Pharmacol Biochem Behav. 2023 Dec 07. pii: S0091-3057(23)00176-4. [Epub ahead of print]234 173689
    Ndufs4 KO mice: A model to study comorbid mood disorders associated with mitochondrial dysfunction.
    Daniël J van Rensburg, Zander Lindeque, Brian H Harvey, Stephan F Steyn.
      The Ndufs4 knockout (KO) mouse is a validated and robust preclinical model of mitochondrial diseases (specifically Leigh syndrome), that displays a narrow window of relative phenotypical normality, despite its inherent mitochondrial complex I dysfunction and severe phenotype. Preclinical observations related to psychiatric comorbidities that arise in patients with mitochondrial diseases and indeed in Leigh syndrome are, however, yet to be investigated in this model. Strengthening this narrative is the fact that major depression and bipolar disorder are known to present with deficits in mitochondrial function. We therefore screened the behavioural profile of male and female Ndufs4 KO mice (relative to heterozygous; HET and wildtype; WT mice) between postnatal days 28 and 35 for locomotor, depressive- and anxiety-like alterations and linked it with selected brain biomarkers, viz. serotonin, kynurenine, and redox status in brain areas relevant to psychiatric pathologies (i.e., prefrontal cortex, hippocampus, and striatum). The Ndufs4 KO mice initially displayed depressive-like behaviour in the tail suspension test on PND31 but not on PND35 in the forced swim test. In the mirror box test, increased risk resilience was observed. Serotonin levels of KO mice, compared to HET controls, were increased on PND36, together with increased tryptophan to serotonin and kynurenine turnover. Kynurenine to kynurenic acid turnover was however decreased, while reduced versus oxidized glutathione ratio (GSH/GSSG) was increased. When considering the comorbid psychiatric traits of patients with mitochondrial disorders, this work elaborates on the neuropsychiatric profile of the Ndufs KO mouse. Secondly, despite locomotor differences, Ndufs4 KO mice present with a behavioural profile not unlike rodent models of bipolar disorder, namely variable mood states and risk-taking behaviour. The model may elucidate the bio-energetic mechanisms underlying mood disorders, especially in the presence of mitochondrial disease. Studies are however required to further validate the model's translational relevance.
    Keywords:  Monoamines; Mood; Oxidative stress; Tryptophan metabolism
    DOI:  https://doi.org/10.1016/j.pbb.2023.173689
  18. Sci Rep. 2023 Dec 12. 13(1): 22005
    Genetic, metabolic and clinical delineation of an MRPS23-associated mitochondrial disorder.
    Chupong Ittiwut, Rungnapa Ittiwut, Chulaluck Kuptanon, Tetsuro Matsuhashi, Masaru Shimura, Yohei Sugiyama, Takanori Onuki, Akira Ohtake, Kei Murayama, Nithiwat Vatanavicharn, Waralee Dejputtawat, Nitchanund Tantisirivit, Phawin Kor-Anantakul, Wuttichart Kamolvisit, Kanya Suphapeetiporn, Vorasuk Shotelersuk.
      MRPS23 is a nuclear gene encoding a mitochondrial ribosomal protein. A patient with a mitochondrial disorder was found to carry a variant in MRPS23. More cases are necessary to establish MRPS23 as a mitochondrial disease gene. Of 5134 exomes performed in our center, we identified five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23. Detailed clinical findings, mitochondrial enzyme activity assays from cultured skin fibroblasts, PCR-Sanger-sequencing, and variant age estimation were performed. Their available family members were also studied. Eight members homozygous for the MRPS23 p.P40L were identified. All were from Hmong hilltribe. Seven presented with alteration of consciousness and recurrent vomiting, while the eighth who was a younger brother of a proband was found pre-symptomatically. Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV. PCR-Sanger-sequencing confirmed the variant, which was estimated to have occurred 1550 years ago. These results establish the MRPS23-associated mitochondrial disorder inherited in an autosomal recessive pattern and provide insight into its clinical and metabolic features.
    DOI:  https://doi.org/10.1038/s41598-023-49161-7
  19. Int J Cardiol. 2023 Dec 06. pii: S0167-5273(23)01780-1. [Epub ahead of print] 131645
    LKB1/AMPK treats myocardial disease by boosting mitochondrial function.
    Zhihuan Luo, Luyuan Yao.
      
    Keywords:  AMPK; Cardiomyopathy; LKB1; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.ijcard.2023.131645
  20. Nature. 2023 Dec;624(7991): 234-235
    CRISPR 2.0: a new wave of gene editors heads for clinical trials.
    Heidi Ledford.
      
    Keywords:  CRISPR-Cas9 genome editing; Gene therapy; Medical research
    DOI:  https://doi.org/10.1038/d41586-023-03797-7
  21. Nature. 2023 Dec;624(7991): 366-377
    Single-cell DNA methylome and 3D multi-omic atlas of the adult mouse brain.
    Hanqing Liu, Qiurui Zeng, Jingtian Zhou, Anna Bartlett, Bang-An Wang, Peter Berube, Wei Tian, Mia Kenworthy, Jordan Altshul, Joseph R Nery, Huaming Chen, Rosa G Castanon, Songpeng Zu, Yang Eric Li, Jacinta Lucero, Julia K Osteen, Antonio Pinto-Duarte, Jasper Lee, Jon Rink, Silvia Cho, Nora Emerson, Michael Nunn, Carolyn O'Connor, Zhanghao Wu, Ion Stoica, Zizhen Yao, Kimberly A Smith, Bosiljka Tasic, Chongyuan Luo, Jesse R Dixon, Hongkui Zeng, Bing Ren, M Margarita Behrens, Joseph R Ecker.
      Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq)1 technologies to generate 301,626 methylomes and 176,003 chromatin conformation-methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq2 dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular-spatial and regulatory genome diversity of the mouse brain.
    DOI:  https://doi.org/10.1038/s41586-023-06805-y
  22. iScience. 2023 Dec 15. 26(12): 108343
    AMPKα2 is a skeletal muscle stem cell intrinsic regulator of myonuclear accretion.
    Anita Kneppers, Sabrina Ben Larbi, Marine Theret, Audrey Saugues, Carole Dabadie, Linda Gsaier, Arnaud Ferry, Philipp Rhein, Julien Gondin, Kei Sakamoto, Rémi Mounier.
      Due to the post-mitotic nature of skeletal muscle fibers, adult muscle maintenance relies on dedicated muscle stem cells (MuSCs). In most physiological contexts, MuSCs support myofiber homeostasis by contributing to myonuclear accretion, which requires a coordination of cell-type specific events between the myofiber and MuSCs. Here, we addressed the role of the kinase AMPKα2 in the coordination of these events supporting myonuclear accretion. We demonstrate that AMPKα2 deletion impairs skeletal muscle regeneration. Through in vitro assessments of MuSC myogenic fate and EdU-based cell tracing, we reveal a MuSC-specific role of AMPKα2 in the regulation of myonuclear accretion, which is mediated by phosphorylation of the non-metabolic substrate BAIAP2. Similar cell tracing in vivo shows that AMPKα2 knockout mice have a lower rate of myonuclear accretion during regeneration, and that MuSC-specific AMPKα2 deletion decreases myonuclear accretion in response to myofiber contraction. Together, this demonstrates that AMPKα2 is a MuSC-intrinsic regulator of myonuclear accretion.
    Keywords:  Molecular biology experimental approach; Molecular mechanism of behavior; Specialized functions of cells; Stem cells research; cell Biology
    DOI:  https://doi.org/10.1016/j.isci.2023.108343
  23. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2316823120
    Intraneuronal β-amyloid impaired mitochondrial proteostasis through the impact on LONP1.
    Wenzhang Wang, Xiaopin Ma, Sabina Bhatta, Changjuan Shao, Fanpeng Zhao, Hisashi Fujioka, Sandy Torres, Fengqin Wu, Xiongwei Zhu.
      Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD. In this study, we identified LONP1, an ATP-dependent protease in the matrix, as a top Aβ42 interacting mitochondrial protein through an unbiased screening and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m6A signaling contributed at least in part to Aβ42-induced LONP1 reduction. Moreover, Aβ42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aβ and in the brain of CRND8 APP transgenic mice rescued Aβ-induced mitochondrial deficits and cognitive deficits. These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a mechanism underlying intracellular Aβ42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.
    Keywords:  Alzheimer’s disease; Aβ42; LONP1; mitochondrial dysfunction; protein aggregate
    DOI:  https://doi.org/10.1073/pnas.2316823120
  24. Int J Mol Sci. 2023 Dec 02. pii: 17068. [Epub ahead of print]24(23):
    Mitochondrially Targeted Gene Therapy Rescues Visual Loss in a Mouse Model of Leber's Hereditary Optic Neuropathy.
    Tsung-Han Chou, Zixuan Hao, Diego Alba, Angelina Lazo, Gabriele Gallo Afflitto, Jeremy D Eastwood, Vittorio Porciatti, John Guy, Hong Yu.
      Leber's hereditary optic neuropathy (LHON) is a common mitochondrial genetic disease, causing irreversible blindness in young individuals. Current treatments are inadequate, and there is no definitive cure. This study evaluates the effectiveness of delivering wildtype human NADH ubiquinone oxidoreductase subunit 4 (hND4) gene using mito-targeted AAV(MTSAAV) to rescue LHOH mice. We observed a declining pattern in electroretinograms amplitudes as mice aged across all groups (p < 0.001), with significant differences among groups (p = 0.023; Control vs. LHON, p = 0.008; Control vs. Rescue, p = 0.228). Inner retinal thickness and intraocular pressure did not change significantly with age or groups. Compared to LHON mice, those rescued with wildtype hND4 exhibited improved retinal visual acuity (0.29 ± 0.1 cy/deg vs. 0.15 ± 0.1 cy/deg) and increased functional hyperemia response (effect of flicker, p < 0.001, effect of Group, p = 0.004; Interaction Flicker × Group, p < 0.001). Postmortem analysis shows a marked reduction in retinal ganglion cell density in the LHON group compared to the other groups (Effect of Group, p < 0.001, Control vs. LHON, p < 0.001, Control vs. Rescue, p = 0.106). These results suggest that MTSAAV-delivered wildtype hND4 gene rescues, at least in part, visual impairment in an LHON mouse model and has the therapeutic potential to treat this disease.
    Keywords:  LHON; MTSAAV; gene therapy; human ND4
    DOI:  https://doi.org/10.3390/ijms242317068
  25. Nature. 2023 Dec;624(7991): 237-238
    Are your organs ageing well? The blood holds clues.
    Max Kozlov.
      
    Keywords:  Ageing; Diseases; Medical research; Proteomics
    DOI:  https://doi.org/10.1038/d41586-023-03821-w
  26. Life Sci. 2023 Dec 01. pii: S0024-3205(23)00858-5. [Epub ahead of print]334 122223
    Copper homeostasis and cuproptosis in mitochondria.
    Ziying Tian, Su Jiang, Jieyu Zhou, Wenling Zhang.
      Mitochondria serve as sites for energy production and are essential for regulating various forms of cell death induced by metal metabolism, targeted anticancer drugs, radiotherapy and immunotherapy. Cuproptosis is an autonomous form of cell death that depends on copper (Cu) and mitochondrial metabolism. Although the recent discovery of cuproptosis highlights the significance of Cu and mitochondria, there is still a lack of biological evidence and experimental verification for the underlying mechanism. We provide an overview of how Cu and cuproptosis affect mitochondrial morphology and function. Through comparison with ferroptosis, similarities and differences in mitochondrial metabolism between cuproptosis and ferroptosis have been identified. These findings provide implications for further exploration of cuproptotic mechanisms. Furthermore, we explore the correlation between cuproptosis and immunotherapy or radiosensitivity. Ultimately, we emphasize the therapeutic potential of targeting cuproptosis as a novel approach for disease treatment.
    Keywords:  Copper homeostasis; Cuproptosis; Immunotherapy; Mitochondria; Radiosensitivity
    DOI:  https://doi.org/10.1016/j.lfs.2023.122223
  27. Front Psychiatry. 2023 ;14 1257460
    Second-generation antipsychotics and metabolic syndrome: a role for mitochondria.
    Katherine R H Mortimer, Mohammed Zia Ul Haq Katshu, Lisa Chakrabarti.
      Psychosis is a known risk factor for developing metabolic syndrome (MetS). The risk is even greater in patients who are taking second-generation antipsychotics (SGAs). SGAs exacerbate metabolic abnormalities and lead to a 3-fold increased risk of severe weight gain, type 2 diabetes, and cardiovascular disease in patients. Mitochondrial dysfunction is a hallmark of MetS. Mitochondria process glucose and fatty acids into ATP. If these processes are impaired, it can result in dyslipidaemia, hyperglycaemia and an imbalance between nutrient input and energy output. This leads to increased adiposity, insulin resistance and atherosclerosis. It is unclear how SGAs induce MetS and how mitochondria might be involved in this process. It has been found that SGAs impair cellular glucose uptake in liver, dysregulating glucose and fatty acid metabolism which leads to an accumulation of glucose and/or lipids and an increase reactive oxygen species (ROS) which target mitochondrial proteins. This affects complexes of the electron transport chain (ETC) to reduce mitochondrial respiration. While there is a suggestion that SGAs may interact with a variety of processes that disrupt mitochondrial function, some of the results are conflicting, and a clear picture of how SGAs interact with mitochondria in different cell types has not yet emerged. Here, we outline the current evidence showing how SGAs may trigger mitochondrial dysfunction and lead to the development of MetS.
    Keywords:  antipsychotics; energy metabolism; metabolic syndrome; mitochondria; psychosis
    DOI:  https://doi.org/10.3389/fpsyt.2023.1257460
  28. Sci Rep. 2023 Dec 12. 13(1): 22013
    Database screening as a strategy to identify endogenous candidate metabolites to probe and assess mitochondrial drug toxicity.
    Mery Vet George De la Rosa, Dipali Patel, Marc R McCann, Kathleen A Stringer, Gus R Rosania.
      Adverse drug reactions (ADRs) are considered an inherent risk of medication use, and some ADRs have been associated with off-target drug interactions with mitochondria. Metabolites that reflect mitochondrial function may help identify patients at risk of mitochondrial toxicity. We employed a database strategy to identify candidate mitochondrial metabolites that could be clinically useful to identify individuals at increased risk of mitochondrial-related ADRs. This led to L-carnitine being identified as the candidate mitochondrial metabolite. L-carnitine, its acetylated metabolite, acetylcarnitine and other acylcarnitines are mitochondrial biomarkers used to detect inborn errors of metabolism. We hypothesized that changes in L-carnitine disposition, induced by a "challenge test" of intravenous L-carnitine, could identify mitochondrial-related ADRs by provoking variation in L-carnitine and/or acetylcarnitine blood levels. To test this hypothesis, we induced mitochondrial drug toxicity with clofazimine (CFZ) in a mouse model. Following CFZ treatment, mice received an L-carnitine "challenge test". CFZ-induced changes in weight were consistent with previous work and reflect CFZ-induced catabolism. L-carnitine induced differences in whole blood acetylcarnitine concentrations in a manner that was dependent on CFZ treatment. This supports the usefulness of a database strategy for the discovery of candidate metabolite biomarkers of drug toxicity and substantiates the potential of the L-carnitine "challenge test" as a "probe" to identify drug-related toxicological manifestations.
    DOI:  https://doi.org/10.1038/s41598-023-49443-0
  29. Nature. 2023 Dec;624(7991): 390-402
    Conserved and divergent gene regulatory programs of the mammalian neocortex.
    Nathan R Zemke, Ethan J Armand, Wenliang Wang, Seoyeon Lee, Jingtian Zhou, Yang Eric Li, Hanqing Liu, Wei Tian, Joseph R Nery, Rosa G Castanon, Anna Bartlett, Julia K Osteen, Daofeng Li, Xiaoyu Zhuo, Vincent Xu, Lei Chang, Keyi Dong, Hannah S Indralingam, Jonathan A Rink, Yang Xie, Michael Miller, Fenna M Krienen, Qiangge Zhang, Naz Taskin, Jonathan Ting, Guoping Feng, Steven A McCarroll, Edward M Callaway, Ting Wang, Ed S Lein, M Margarita Behrens, Joseph R Ecker, Bing Ren.
      Divergence of cis-regulatory elements drives species-specific traits1, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains unclear. Here we investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset and mouse using single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome and chromosomal conformation profiles from a total of over 200,000 cells. From these data, we show evidence that divergence of transcription factor expression corresponds to species-specific epigenome landscapes. We find that conserved and divergent gene regulatory features are reflected in the evolution of the three-dimensional genome. Transposable elements contribute to nearly 80% of the human-specific candidate cis-regulatory elements in cortical cells. Through machine learning, we develop sequence-based predictors of candidate cis-regulatory elements in different species and demonstrate that the genomic regulatory syntax is highly preserved from rodents to primates. Finally, we show that epigenetic conservation combined with sequence similarity helps to uncover functional cis-regulatory elements and enhances our ability to interpret genetic variants contributing to neurological disease and traits.
    DOI:  https://doi.org/10.1038/s41586-023-06819-6
  30. J Am Acad Child Adolesc Psychiatry. 2023 Dec 04. pii: S0890-8567(23)02243-8. [Epub ahead of print]
    Editorial: Mitochondrial Gene Variations Increase Autism Risk: Uncovering the Complex Polygenetic Landscape of Autism.
    Richard E Frye.
      
    DOI:  https://doi.org/10.1016/j.jaac.2023.12.002
  31. Cell. 2023 Nov 28. pii: S0092-8674(23)01228-X. [Epub ahead of print]
    Atlas of fetal metabolism during mid-to-late gestation and diabetic pregnancy.
    Cesar A Perez-Ramirez, Haruko Nakano, Richard C Law, Nedas Matulionis, Jennifer Thompson, Andrew Pfeiffer, Junyoung O Park, Atsushi Nakano, Heather R Christofk.
      Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using 13C-glucose and liquid chromatography-mass spectrometry (LC-MS), we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Our analysis revealed metabolic features specific to a hyperglycemic environment and signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from hyperglycemic dams. Tracing 13C-glucose revealed disparate fetal nutrient sourcing depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated in late-stage fetal tissues. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations due to maternal hyperglycemia.
    Keywords:  development; diabetes; fetal metabolism; isotope tracing; metabolism; metabolomics; pregnancy
    DOI:  https://doi.org/10.1016/j.cell.2023.11.011
  32. Nature. 2023 Dec 13.
    Modeling post-implantation human development to yolk sac blood emergence.
    Joshua Hislop, Qi Song, Kamyar Keshavarz F, Amir Alavi, Rayna Schoenberger, Ryan LeGraw, Jeremy Velazquez, Tahere Mokhtari, Mohammad Naser Taheri, Matthew Rytel, Susana M Chuva de Sousa Lopes, Simon Watkins, Donna Stolz, Samira Kiani, Berna Sozen, Ziv Bar-Joseph, Mo R Ebrahimkhani.
      Implantation of the human embryo commences a critical developmental stage that comprises profound events including axis formation, gastrulation, and the emergence of hematopoietic system1,2. Our mechanistic knowledge of this window of human life remains limited due to restricted access to in vivo samples for both technical and ethical reasons3-5. Stem cell models of human embryo have emerged to help unlock the mysteries of this stage6-16. Here, we present a genetically inducible stem cell-derived embryoid model of early post-implantation human embryogenesis that captures the reciprocal co-development of embryonic tissue and extra-embryonic endoderm and mesoderm niche with early hematopoiesis. This model is produced from induced pluripotent stem cells and shows unanticipated self-organizing cellular programs similar to those that occur in embryogenesis, including the formation of amniotic cavity and bilaminar disc morphologies as well as the generation of an anterior hypoblast pole and posterior domain. The extra-embryonic layer in these embryoids lacks trophoblast and exhibits advanced multilineage yolk sac tissue-like morphogenesis that harbors a process similar to distinct waves of hematopoiesis, including the emergence of erythroid-, megakaryocyte-, myeloid-, and lymphoid-like cells. This model presents an easy-to-use, high-throughput, reproducible, and scalable platform to probe multifaceted aspects of human development and blood formation at the early post-implantation stage. It will provide a tractable human-based model for drug testing, and disease modeling.
    DOI:  https://doi.org/10.1038/s41586-023-06914-8
  33. Int J Gynaecol Obstet. 2023 Dec 08.
    Decreased fetal movements: Report from the International Stillbirth Alliance conference workshop.
    Billie F Bradford, Dexter J L Hayes, Stefanie Damhuis, Alexis Shub, Anna Akselsson, Ingela Radestad, Alexander E P Heazell, Vicki Flenady, Sanne J Gordijn.
      Maternal reports of decreased fetal movement (DFM) are a common reason to present to maternity care and are associated with stillbirth and other adverse outcomes. Promoting awareness of fetal movements and prompt assessment of DFM has been recommended to reduce stillbirths. However, evidence to guide clinical management of such presentations is limited. Educational approaches to increasing awareness of fetal movements in pregnant women and maternity care providers with the aim of reducing stillbirths have recently been evaluated in a several large clinical trials internationally. The International Stillbirth Alliance Virtual Conference in Sydney 2021 provided an opportunity for international experts in fetal movements to share reports on the findings of fetal movement awareness trials, consider evidence for biological mechanisms linking DFM and fetal death, appraise approaches to clinical assessment of DFM, and highlight research priorities in this area. Following this workshop summaries of the sessions prepared by the authors provide an overview of understandings of fetal movements in maternity care at the current time and highlights future directions in fetal movement research.
    Keywords:  fetal growth restriction; fetal movements; pregnancy; stillbirth
    DOI:  https://doi.org/10.1002/ijgo.15242
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