bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2024–03–24
seventeen papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
  2. Poly(ADP-ribose) mediates bioenergetic defects and redox imbalance in neurons following oxygen and glucose deprivation.
  3. Prostaglandin D2 synthase controls Schwann cells metabolism.
  4. A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
  5. The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
  6. The role of glia in the dysregulation of neuronal spinogenesis in Ube3a-dependent ASD.
  7. Structural determinants of mitochondrial STAT3 targeting and function.
  8. The effects of cholesterol and statins on Parkinson's neuropathology: a narrative review.
  9. Mitochondrial metabolism and neuroinflammation in the cerebral cortex and cortical synapses of rats: effect of milk intake through DNA methylation.
  10. TIGAR reduces neuronal ferroptosis by inhibiting succinate dehydrogenase activity in cerebral ischemia.
  11. Manifestations of X-linked pyruvate dehydrogenase complex deficiency in female PDHA1 carriers.
  12. Metabolic etiologies in children with infantile epileptic spasm syndrome: Experience at a tertiary pediatric neurology center.
  13. The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions.
  14. The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency.
  15. Armcx1 reduces neurological damage via a mitochondrial transport pathway involving Miro1 after traumatic brain injury.
  16. A partial Drp1 knockout improves autophagy flux independent of mitochondrial function.
  17. Neurodevelopmental disorders associated variants in ADAT3 disrupt the activity of the ADAT2/ADAT3 tRNA deaminase complex and impair neuronal migration.
  1. bioRxiv. 2024 Mar 07. pii: 2024.03.06.583589. [Epub ahead of print]
    Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
    Francesco Agostini, Leonardo Pereyra, Justin Dale, King Faisal Yambire, Silvia Maglioni, Alfonso Schiavi, Natascia Ventura, Ira Milosevic, Nuno Raimundo.
      Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in the cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Nevertheless, the signaling consequences of primary mitochondrial malfunction and of primary lysosomal defects are not similar, despite in both cases there are impairments of mitochondria and of lysosomes. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects, to identify what are the global cellular consequences that are associated with malfunction of mitochondria or lysosomes. We used these data to determine what are the pathways that are affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. This pathway is transcriptionally up-regulated in cellular and mouse models of lysosomal defects and is transcriptionally down-regulated in cellular and mouse models of mitochondrial defects. We identified a role for post-transcriptional regulation of the transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, the retention of Ca 2+ in the lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo , using models of mitochondria-associated diseases in C. elegans , that normalization of lysosomal Ca 2+ levels results in partial rescue of the developmental arrest induced by the respiratory chain deficiency.
    DOI:  https://doi.org/10.1101/2024.03.06.583589
  2. FASEB J. 2024 Mar 31. 38(6): e23556
    Poly(ADP-ribose) mediates bioenergetic defects and redox imbalance in neurons following oxygen and glucose deprivation.
    M Iqbal Hossain, Jun Hee Lee, Jean-Philippe Gagné, Junaid Khan, Guy G Poirier, Peter H King, Valina L Dawson, Ted M Dawson, Shaida A Andrabi.
      PARP-1 over-activation results in cell death via excessive PAR generation in different cell types, including neurons following brain ischemia. Glycolysis, mitochondrial function, and redox balance are key cellular processes altered in brain ischemia. Studies show that PAR generated after PARP-1 over-activation can bind hexokinase-1 (HK-1) and result in glycolytic defects and subsequent mitochondrial dysfunction. HK-1 is the neuronal hexokinase and catalyzes the first reaction of glycolysis, converting glucose to glucose-6-phosphate (G6P), a common substrate for glycolysis, and the pentose phosphate pathway (PPP). PPP is critical in maintaining NADPH and GSH levels via G6P dehydrogenase activity. Therefore, defects in HK-1 will not only decrease cellular bioenergetics but will also cause redox imbalance due to the depletion of GSH. In brain ischemia, whether PAR-mediated inhibition of HK-1 results in bioenergetics defects and redox imbalance is not known. We used oxygen-glucose deprivation (OGD) in mouse cortical neurons to mimic brain ischemia in neuronal cultures and observed that PARP-1 activation via PAR formation alters glycolysis, mitochondrial function, and redox homeostasis in neurons. We used pharmacological inhibition of PARP-1 and adenoviral-mediated overexpression of wild-type HK-1 (wtHK-1) and PAR-binding mutant HK-1 (pbmHK-1). Our data show that PAR inhibition or overexpression of HK-1 significantly improves glycolysis, mitochondrial function, redox homeostasis, and cell survival in mouse cortical neurons exposed to OGD. These results suggest that PAR binding and inhibition of HK-1 during OGD drive bioenergetic defects in neurons due to inhibition of glycolysis and impairment of mitochondrial function.
    Keywords:  DPQ; PAR-binding motif; glycolysis; hexokinase; ischemic stroke; mitochondria; pentose-phosphate pathway; poly(ADP-ribose)
    DOI:  https://doi.org/10.1096/fj.202302559R
  3. bioRxiv. 2024 Mar 04. pii: 2024.02.29.582775. [Epub ahead of print]
    Prostaglandin D2 synthase controls Schwann cells metabolism.
    Amelia Trimarco, Matteo Audano, Rosa La Marca, Mariaconcetta Cariello, Marta Falco, Silvia Pedretti, Gabriele Imperato, Alessandro Cestaro, Paola Podini, Giorgia Dina, Angelo Quattrini, Luca Massimino, Donatella Caruso, Nico Mitro, Carla Taveggia.
      We previously reported that in the absence of Prostaglandin D2 synthase (L-PGDS) peripheral nerves are hypomyelinated in development and that with aging they present aberrant myelin sheaths. We now demonstrate that L-PGDS expressed in Schwann cells is part of a coordinated program aiming at preserving myelin integrity. In vivo and in vitro lipidomic, metabolomic and transcriptomic analyses confirmed that myelin lipids composition, Schwann cells energetic metabolism and key enzymes controlling these processes are altered in the absence of L-PGDS. Moreover, Schwann cells undergo a metabolic rewiring and turn to acetate as the main energetic source. Further, they produce ketone bodies to ensure glial cell and neuronal survival. Importantly, we demonstrate that all these changes correlate with morphological myelin alterations and describe the first physiological pathway implicated in preserving PNS myelin. Collectively, we posit that myelin lipids serve as a reservoir to provide ketone bodies, which together with acetate represent the adaptive substrates Schwann cells can rely on to sustain the axo-glial unit and preserve the integrity of the PNS.
    DOI:  https://doi.org/10.1101/2024.02.29.582775
  4. bioRxiv. 2024 Mar 07. pii: 2024.03.05.583623. [Epub ahead of print]
    A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
    Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.
      Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity 1,2 , and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders 3,4 , underscoring the need to define the brain's molecular energetic landscape 5-10 . To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3×3×3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities 11 , thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.
    DOI:  https://doi.org/10.1101/2024.03.05.583623
  5. J Cell Biol. 2024 May 06. pii: e202302069. [Epub ahead of print]223(5):
    The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
    Tianyao Xiao, Alyssa M English, Zachary N Wilson, J Alan Maschek, James E Cox, Adam L Hughes.
      Cells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.
    DOI:  https://doi.org/10.1083/jcb.202302069
  6. Exp Neurol. 2024 Mar 18. pii: S0014-4886(24)00082-7. [Epub ahead of print]376 114756
    The role of glia in the dysregulation of neuronal spinogenesis in Ube3a-dependent ASD.
    Zachary Gardner, Otto Holbrook, Yuan Tian, KathrynAnn Odamah, Heng-Ye Man.
      Overexpression of the Ube3a gene and the resulting increase in Ube3a protein are linked to autism spectrum disorder (ASD). However, the cellular and molecular processes underlying Ube3a-dependent ASD remain unclear. Using both male and female mice, we find that neurons in the somatosensory cortex of the Ube3a 2× Tg ASD mouse model display reduced dendritic spine density and increased immature filopodia density. Importantly, the increased gene dosage of Ube3a in astrocytes alone is sufficient to confer alterations in neurons as immature dendritic protrusions, as observed in primary hippocampal neuron cultures. We show that Ube3a overexpression in astrocytes leads to a loss of astrocyte-derived spinogenic protein, thrombospondin-2 (TSP2), due to a suppression of TSP2 gene transcription. By neonatal intraventricular injection of astrocyte-specific virus, we demonstrate that Ube3a overexpression in astrocytes in vivo results in a reduction in dendritic spine maturation in prelimbic cortical neurons, accompanied with autistic-like behaviors in mice. These findings reveal an astrocytic dominance in initiating ASD pathobiology at the neuronal and behavior levels. SIGNIFICANCE STATEMENT: Increased gene dosage of Ube3a is tied to autism spectrum disorders (ASDs), yet cellular and molecular alterations underlying autistic phenotypes remain unclear. We show that Ube3a overexpression leads to impaired dendritic spine maturation, resulting in reduced spine density and increased filopodia density. We find that dysregulation of spine development is not neuron autonomous, rather, it is mediated by an astrocytic mechanism. Increased gene dosage of Ube3a in astrocytes leads to reduced production of the spinogenic glycoprotein thrombospondin-2 (TSP2), leading to abnormalities in spines. Astrocyte-specific Ube3a overexpression in the brain in vivo confers dysregulated spine maturation concomitant with autistic-like behaviors in mice. These findings indicate the importance of astrocytes in aberrant neurodevelopment and brain function in Ube3a-depdendent ASD.
    Keywords:  Astrocyte; Autism spectrum disorders; Glia; Spinogenesis; TSP2; Ube3a
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114756
  7. Mitochondrial Commun. 2024 ;2 1-13
    Structural determinants of mitochondrial STAT3 targeting and function.
    Isabelle J Marié, Tanaya Lahiri, Özlem Önder, Kojo S J Elenitoba-Johnson, David E Levy.
      Signal transducer and activator of transcription (STAT) 3 has been found within mitochondria in addition to its canonical role of shuttling between cytoplasm and nucleus during cytokine signaling. Mitochondrial STAT3 has been implicated in modulation of cellular metabolism, largely through effects on the respiratory electron transport chain. However, the structural requirements underlying mitochondrial targeting and function have remained unclear. Here, we show that mitochondrial STAT3 partitions between mitochondrial compartments defined by differential detergent solubility, suggesting that mitochondrial STAT3 is membrane associated. The majority of STAT3 was found in an SDS soluble fraction copurifying with respiratory chain proteins, including numerous components of the complex I NADH dehydrogenase, while a minor component was found with proteins of the mitochondrial translation machinery. Mitochondrial targeting of STAT3 required the amino-terminal domain, and an internal linker domain motif also directed mitochondrial translocation. However, neither the phosphorylation of serine 727 nor the presence of mitochondrial DNA was required for the mitochondrial localization of STAT3. Two cysteine residues in the STAT3 SH2 domain, which have been previously suggested to be targets for protein palmitoylation, were also not required for mitochondrial translocation, but were required for its function as an enhancer of complex I activity. These structural determinants of STAT3 mitochondrial targeting and function provide potential therapeutic targets for disrupting the activity of mitochondrial STAT3 in diseases such as cancer.
    Keywords:  Electron transport chain; Mitochondrial import; Stat3
    DOI:  https://doi.org/10.1016/j.mitoco.2024.01.001
  8. Inflammopharmacology. 2024 Mar 18.
    The effects of cholesterol and statins on Parkinson's neuropathology: a narrative review.
    Hayder M Al-Kuraishy, Esraa H Fahad, Salah Al-Windy, Suzy A El-Sherbeni, Walaa A Negm, Gaber El-Saber Batiha.
      Parkinson disease (PD) is chronic and progressive neurodegenerative disease of the brain characterized by motor symptoms including tremors, rigidity, postural instability, and bradykinesia. PD neuropathology is due to the progressive degeneration of dopaminergic neurons in the substantia nigra and accumulation of Lewy bodies in the survival neurons. The brain contains a largest amount of cholesterol which is mainly synthesized from astrocytes and glial cells. Cholesterol is intricate in the pathogenesis of PD and may be beneficial or deleterious. Therefore, there are controversial points concerning the role of cholesterol in PD neuropathology. In addition, cholesterol-lowering agents' statins can affect brain cholesterol. Different studies highlighted that statins, via inhibition of brain HMG-CoA, can affect neuronal integrity through suppression of neuronal cholesterol, which regulates synaptic plasticity and neurotransmitter release. Furthermore, statins affect the development and progression of different neurodegenerative diseases in bidirectional ways that could be beneficial or detrimental. Therefore, the objective of the present review was to clarify the double-sward effects of cholesterol and statins on PD neuropathology.
    Keywords:  Brain; Cholesterol; Neurodegenerative; Parkinson’s disease; Statins
    DOI:  https://doi.org/10.1007/s10787-023-01400-z
  9. J Nutr Biochem. 2024 Mar 20. pii: S0955-2863(24)00057-3. [Epub ahead of print] 109624
    Mitochondrial metabolism and neuroinflammation in the cerebral cortex and cortical synapses of rats: effect of milk intake through DNA methylation.
    Giovanna Trinchese, Antonia Feola, Gina Cavaliere, Fabiano Cimmino, Angela Catapano, Eduardo Penna, Giovanni Scala, Luigi Greco, Luca Bernardo, Antonio Porcellini, Marianna Crispino, Antonio Pezone, Maria Pina Mollica.
      Brain plasticity and cognitive functions are tightly influenced by foods or nutrients, which determine a metabolic modulation having a long-term effect on health, involving also epigenetic mechanisms. Breast milk or formula based on cow milk is the first food for human beings, who, throughout their lives, are then exposed to different types of milk. We previously demonstrated that rats fed with milk derived from distinct species, with different compositions and nutritional properties, display selective modulation of systemic metabolic and inflammatory profiles through changes of mitochondrial functions and redox state in liver, skeletal and cardiac muscle. Here, in a rat model, we demonstrated that isoenergetic supplementation of milk from cow (CM), donkey (DM) or human (HM) impacts mitochondrial functions and redox state in the brain cortex and cortical synapses, affecting neuroinflammation and synaptic plasticity. Interestingly, we found that the administration of different milk modulates DNA methylation in rat brain cortex and consequently affects gene expression. Our results emphasize the importance of nutrition in brain and synapse physiology, and highlight the key role played in this context by mitochondria, nutrient-sensitive organelles able to orchestrate metabolic and inflammatory responses.
    Keywords:  DNA methylation; gene expression; milk; mitochondria dysfunction; neuroinflammation; synapse
    DOI:  https://doi.org/10.1016/j.jnutbio.2024.109624
  10. Free Radic Biol Med. 2024 Mar 15. pii: S0891-5849(24)00136-9. [Epub ahead of print]
    TIGAR reduces neuronal ferroptosis by inhibiting succinate dehydrogenase activity in cerebral ischemia.
    Xinxin Wang, Mei Li, Fan Wang, Guanghui Mao, Junchao Wu, Rong Han, Rui Sheng, Zhenghong Qin, Hong Ni.
      Ischemia Stroke (IS) is an acute neurological condition with high morbidity, disability, and mortality due to a severe reduction in local cerebral blood flow to the brain and blockage of oxygen and glucose supply. Oxidative stress induced by IS predisposes neurons to ferroptosis. TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits the intracellular glycolytic pathway to increase pentose phosphate pathway (PPP) flux, promotes NADPH production and thus generates reduced glutathione (GSH) to scavenge reactive oxygen species (ROS), and thus shows strong antioxidant effects to ameliorate cerebral ischemia/reperfusion injury. However, in the current study, prolonged ischemia impaired the PPP, and TIGAR was unable to produce NADPH but was still able to reduce neuronal ferroptosis and attenuate ischemic brain injury. Ferroptosis is a form of cell death caused by free radical-driven lipid peroxidation, and the vast majority of ROS leading to oxidative stress are generated by mitochondrial succinate dehydrogenase (SDH) driving reverse electron transfer (RET) via the mitochondrial electron transport chain. Overexpression of TIGAR significantly inhibited hypoxia-induced enhancement of SDH activity, and TIGAR deficiency further enhanced SDH activity. We also found that the inhibitory effect of TIGAR on SDH activity was related to its mitochondrial translocation under hypoxic conditions. TIGAR may inhibit SDH activity by mediating post-translational modifications (acetylation and succinylation) of SDH A through interaction with SDH A. SDH activity inhibition reduces neuronal ferroptosis by decreasing ROS production, eliminating MitoROS levels and attenuating lipid peroxide accumulation. Notably, TIGAR-mediated inhibition of SDH activity and ferroptosis was not dependent on the PPP-NADPH-GPX4 pathways. In conclusion, mitochondrial translocation of TIGAR in prolonged ischemia is an important pathway to reduce neuronal ferroptosis and provide sustainable antioxidant defense for the brain under prolonged ischemia, further complementing the mechanism of TIGAR resistance to oxidative stress induced by IS.
    Keywords:  Ferroptosis; Lipid peroxidation; Oxidative stress; Succinate dehydrogenase (SDH); TIGAR
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.03.011
  11. Eur J Neurol. 2024 Mar 18. e16283
    Manifestations of X-linked pyruvate dehydrogenase complex deficiency in female PDHA1 carriers.
    Antri Savvidou, Kalliopi Sofou, Erik A Eklund, Johan Aronsson, Niklas Darin.
       BACKGROUND AND PURPOSE: Pyruvate dehydrogenase complex deficiency is in up to 90% caused by pathogenic variants in the X-linked PDHA1 gene. We aimed to investigate female relatives of index patients with PDHA1-related disease to (i) describe the prevalence of female PDHA1 carriers, (ii) determine whether they had symptoms and signs, and (iii) delineate the associated phenotype.
    METHODS: In a national population-based study, we identified 37 patients with pathogenic variants in PDHA1. Sanger sequencing for the presence of the pathogenic variant was performed in their mothers and female relatives. The identified female carriers were clinically assessed, and their medical records were reviewed.
    RESULTS: The proportion carrying a de novo variant was 86%. We identified seven female PDHA1 carriers from five families. Five of them exhibited clinical features of the disease and were previously undiagnosed; all had signs of peripheral axonal neuropathy, four presented with strokelike episodes including two with Leigh-like lesions, and three had facial stigmata.
    CONCLUSIONS: PDHA1-related disease is underrecognized in heterozygous female carriers. Peripheral axonal neuropathy, strokelike and Leigh-like changes, and facial dysmorphism should raise suspicion of the disorder. Genetic analysis and clinical examination of potential female carriers are important for genetic counseling and have implications for treatment.
    Keywords:   PDHA1 ; PDHc deficiency; mitochondrial; peripheral axonal neuropathy; stroke
    DOI:  https://doi.org/10.1111/ene.16283
  12. Brain Dev. 2024 Mar 16. pii: S0387-7604(24)00042-1. [Epub ahead of print]
    Metabolic etiologies in children with infantile epileptic spasm syndrome: Experience at a tertiary pediatric neurology center.
    Merve Feyza Yüksel, Neslihan Doğulu, Miraç Yıldırım, Engin Köse, Ömer Bektaş, Fatma Tuba Eminoğlu, Serap Teber.
       OBJECTIVE: Infantile epileptic spasm syndrome (IESS), including West syndrome (WS) and infantile spasm (IS), causes a challenging prognosis, particularly when associated with metabolic etiologies.
    METHODS: This study, conducted at a tertiary pediatric neurology center, explored the prevalence and clinical features of inborn errors of metabolism in 112 children with IESS over 10 years.
    RESULTS: Most patients presented with seizures, primarily flexor spasms, and the median age at onset was 5 months. Comprehensive clinical evaluation and neuroimaging revealed structural-acquired causes as the most common etiology. Notably, inborn errors of metabolism were identified in 5.4 % of cases, with six distinct diagnoses including nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, primary coenzyme Q10 deficiency 7, congenital disorder of glycosylation type IIM, 6-pyruvoyl tetrahydrobiopterin synthase deficiency, and argininosuccinate lyase deficiency. The prevalence of inborn errors of metabolism in this cohort was consistent with global variations reported in the literature. Genetic testing, including karyotype analysis and whole exome sequencing, was performed in a subset of cases with no clear diagnosis, revealing abnormalities in approximately 50 % of cases. Adrenocorticotropic hormone emerged as the most frequently prescribed antiseizure medication.
    CONCLUSION: This study provides insight into the diagnostic challenges associated with IESS and highlights the importance of metabolic investigations, especially in cases without a clear etiology. The findings emphasize the need for further genetic and metabolic studies to enhance prognostic accuracy and guide potential treatment options for children with IESS, particularly in populations with high rates of consanguinity.
    Keywords:  Children; Epilepsy; Inborn errors of metabolism; Infantile epileptic spasm syndrome; Metabolic etiology
    DOI:  https://doi.org/10.1016/j.braindev.2024.03.003
  13. Nat Commun. 2024 Mar 21. 15(1): 2487
    The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions.
    Marine Lanfranchi, Sozerko Yandiev, Géraldine Meyer-Dilhet, Salma Ellouze, Martijn Kerkhofs, Raphael Dos Reis, Audrey Garcia, Camille Blondet, Alizée Amar, Anita Kneppers, Hélène Polvèche, Damien Plassard, Marc Foretz, Benoit Viollet, Kei Sakamoto, Rémi Mounier, Cyril F Bourgeois, Olivier Raineteau, Evelyne Goillot, Julien Courchet.
      The cellular mechanisms underlying axonal morphogenesis are essential to the formation of functional neuronal networks. We previously identified the autism-linked kinase NUAK1 as a central regulator of axon branching through the control of mitochondria trafficking. However, (1) the relationship between mitochondrial position, function and axon branching and (2) the downstream effectors whereby NUAK1 regulates axon branching remain unknown. Here, we report that mitochondria recruitment to synaptic boutons supports collateral branches stabilization rather than formation in mouse cortical neurons. NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration, and upregulation of mitochondrial function is sufficient to rescue axonal branching in NUAK1 null neurons in vitro and in vivo. Finally, we found that NUAK1 regulates axon branching through the mitochondria-targeted microprotein BRAWNIN. Our results demonstrate that NUAK1 exerts a dual function during axon branching through its ability to control mitochondrial distribution and metabolic activity.
    DOI:  https://doi.org/10.1038/s41467-024-46146-6
  14. J Inherit Metab Dis. 2024 Mar 18.
    The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency.
    Natalia Alexandra Julia-Palacios, Oya Kuseyri Hübschmann, Mireia Olivella, Roser Pons, Gabriella Horvath, Thomas Lücke, Cheuk-Wing Fung, Suet-Na Wong, Elisenda Cortès-Saladelafont, M Mar Rovira-Remisa, Yılmaz Yıldız, Saadet Mercimek-Andrews, Birgit Assmann, Galina Stevanović, Filippo Manti, Heiko Brennenstuhl, Sabine Jung-Klawitter, Kathrin Jeltsch, H Serap Sivri, Sven F Garbade, Àngels García-Cazorla, Thomas Opladen.
      The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8-33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.
    Keywords:  SSADH deficiency; evolving phenotype; genetic spectrum; in silico analyses; long-term follow-up
    DOI:  https://doi.org/10.1002/jimd.12723
  15. Neuroscience. 2024 Mar 14. pii: S0306-4522(24)00120-9. [Epub ahead of print]
    Armcx1 reduces neurological damage via a mitochondrial transport pathway involving Miro1 after traumatic brain injury.
    Qiuying Li, Haibo Ni, Qin Rui, Jiasheng Ding, Xianghu Kong, Xugang Kan, Rong Gao, Hongbo Shen.
      Armcx1 is a member of the ARMadillo repeat-Containing protein on the X chromosome (ARMCX) family, which is recognized to have evolutionary conserved roles in regulating mitochondrial transport and dynamics. Previous research has shown that Armcx1 is expressed at higher levels in mice after axotomy and in adult retinal ganglion cells after crush injury, and this protein increases neuronal survival and axonal regeneration. However, its role in traumatic brain injury (TBI) is unclear. Therefore, the aim of this study was to assess the expression of Armcx1 after TBI and to explore possible related mechanisms by which Armcx1 is involved in TBI.We used C57BL/6 male mice to model TBI and evaluated the role of Armcx1 in TBI by transfecting mice with Armcx1 small interfering RNA (siRNA) to inhibit Armcx1 expression 24 h before TBI modeling. Western blotting, immunofluorescence, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, Nissl staining, transmission electron microscopy, adenosine triphosphate (ATP) level measurement, neuronal apoptosis analysis, neurological function scoring and the Morris water maze were performed. The results demonstrated that Armcx1 protein expression was elevated after TBI and that the Armcx1 protein was localized in neurons and astroglial cells in cortical tissue surrounding the injury site. In addition, inhibition of Armcx1 expression further led to impaired mitochondrial transport, abnormal morphology, reduced ATP levels, aggravation of neuronal apoptosis and neurological dysfunction, and decrease Miro1 expression. In conclusion, our findings indicate that Armcx1 may exert neuroprotective effects by ameliorating neurological injury after TBI through a mitochondrial transport pathway involving Miro1.
    Keywords:  Armcx1; Miro1; apoptosis; mitochondria; traumatic brain injury
    DOI:  https://doi.org/10.1016/j.neuroscience.2024.03.009
  16. Mol Neurodegener. 2024 Mar 19. 19(1): 26
    A partial Drp1 knockout improves autophagy flux independent of mitochondrial function.
    Rebecca Z Fan, Carolina Sportelli, Yanhao Lai, Said S Salehe, Jennifer R Pinnell, Harry J Brown, Jason R Richardson, Shouqing Luo, Kim Tieu.
       BACKGROUND: Dynamin-related protein 1 (Drp1) plays a critical role in mitochondrial dynamics. Partial inhibition of this protein is protective in experimental models of neurological disorders such as Parkinson's disease and Alzheimer's disease. The protective mechanism has been attributed primarily to improved mitochondrial function. However, the observations that Drp1 inhibition reduces protein aggregation in such neurological disorders suggest the involvement of autophagy. To investigate this potential novel protective mechanism of Drp1 inhibition, a model with impaired autophagy without mitochondrial involvement is needed.
    METHODS: We characterized the effects of manganese (Mn), which causes parkinsonian-like symptoms in humans, on autophagy and mitochondria by performing dose-response studies in two cell culture models (stable autophagy HeLa reporter cells and N27 rat immortalized dopamine neuronal cells). Mitochondrial function was assessed using the Seahorse Flux Analyzer. Autophagy flux was monitored by quantifying the number of autophagosomes and autolysosomes, as well as the levels of other autophagy proteins. To strengthen the in vitro data, multiple mouse models (autophagy reporter mice and mutant Drp1+/- mice and their wild-type littermates) were orally treated with a low chronic Mn regimen that was previously reported to increase α-synuclein aggregation and transmission via exosomes. RNAseq, laser captured microdissection, immunofluorescence, immunoblotting, stereological cell counting, and behavioural studies were used. RESULTS IN VITRO: data demonstrate that at low non-toxic concentrations, Mn impaired autophagy flux but not mitochondrial function and morphology. In the mouse midbrain, RNAseq data further confirmed autophagy pathways were dysregulated but not mitochondrial related genes. Additionally, Mn selectively impaired autophagy in the nigral dopamine neurons but not the nearby nigral GABA neurons. In cells with a partial Drp1-knockdown and Drp1+/- mice, Mn induced autophagic impairment was significantly prevented. Consistent with these observations, Mn increased the levels of proteinase-K resistant α-synuclein and Drp1-knockdown protected against this pathology.
    CONCLUSIONS: This study demonstrates that improved autophagy flux is a separate mechanism conferred by Drp1 inhibition independent of its role in mitochondrial fission. Given that impaired autophagy and mitochondrial dysfunction are two prominent features of neurodegenerative diseases, the combined protective mechanisms targeting these two pathways conferred by Drp1 inhibition make this protein an attractive therapeutic target.
    Keywords:  Autophagy; Dynamin related protein 1; Manganese; Mitochondrial dynamics; Mitochondrial dysfunction; Parkinson’s disease; Protein aggregation; α-synuclein
    DOI:  https://doi.org/10.1186/s13024-024-00708-w
  17. medRxiv. 2024 Mar 05. pii: 2024.03.01.24303485. [Epub ahead of print]
    Neurodevelopmental disorders associated variants in ADAT3 disrupt the activity of the ADAT2/ADAT3 tRNA deaminase complex and impair neuronal migration.
    Jordi Del-Pozo-Rodriguez, Peggy Tilly, Romain Lecat, Hugo Rolando Vaca, Laureline Mosser, Till Balla, Marina Vitoria Gomes, Elizabeth Ramos-Morales, Elena Brivio, Thalia Salinas-Giégé, Grace VanNoy, Eleina M England, Alysia Kern Lovgren, Melanie O'Leary, Maya Chopra, Dustin Gable, Aisha Alnuzha, Mona Kamel, Nihal Almenabawy, Anne O'Donnell-Luria, Jennifer E Neil, Joseph G Gleeson, Christopher A Walsh, Nour Elkhateeb, Laila Selim, Siddharth Srivastava, Danny D Nedialkova, Laurence Drouard, Christophe Romier, Efil Bayam, Juliette D Godin.
      The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3 , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here we showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for correct radial migration of projection neurons in the developing mouse cortex. In addition, we not only reported 7 new NDD patients carrying biallelic variants in ADAT3 but also deeply characterize the impact of those variants on ADAT2/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. We demonstrated that all the identified variants alter both the expression and the activity of the complex leading to a significant decrease of I 34 with direct consequence on their steady-state. Using in vivo complementation assays, we correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results indicate a critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenicity of ADAT3-related neurodevelopmental disorder.
    DOI:  https://doi.org/10.1101/2024.03.01.24303485
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