bims-medebr 2024-11-17 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024‒11‒17
thirty papers selected by
Regina F. Fernández, Johns Hopkins University

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
High-Resolution Respirometry Methodology for Bioenergetic and Metabolic Studies in Intact Brain Slices.
Expanding the genetic and clinical spectrum of SLC25A42-associated disorders and testing of pantothenic acid to improve CoA level in vitro.
"Brain propane'': Propionate Fuels the Brain in Mice With Brain Energy Deficits.
A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.
CRISPR-Cas9 mediated knockout of NDUFS4 in human iPSCs: A model for mitochondrial complex I deficiency.
Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice.
Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.
Balancing brain metabolic states during sickness and recovery sleep.
Mitochondrial dysfunction as a therapeutic strategy for neurodegenerative diseases: Current insights and future directions.
Metabolic Phenotyping of Synaptic Mitochondria Using MitoPlates™ and Synaptoneurosomes.
Mitochondrial E3 ligase TRIM71 affects mitochondrial complex assembly and sensitizes dopaminergic neuronal cells to apoptosis in Parkinson's Disease (PD).
Palmitoyl-L-carnitine induces tau phosphorylation and mitochondrial dysfunction in neuronal cells.
Multiple activities of sphingomyelin synthase 2 generate saturated fatty acid- and/or monounsaturated fatty acid-containing diacylglycerol.
In vivo glycerol metabolism in patients with glycerol kinase deficiency.
A rotenone organotypic whole hemisphere slice model of mitochondrial abnormalities in the neonatal brain.
Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome.
Metabolic-driven analytics of traumatic brain injury and neuroprotection by ethyl pyruvate.
Nonvesicular lipid transfer drives myelin growth in the central nervous system.
Tau processing and tau-mediated inflammation differ in human APOEε2 and APOEε4 astrocytes.
New perspective on central nervous system disorders: focus on mass spectrometry imaging.
Insulin potential in preventing brain damage after traumatic brain injury: What we know.
Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits.
Mass Spectrometry Imaging of Two Neocortical Areas Reveals the Histological Selectivity of Schizophrenia-Associated Lipid Alterations.
Cerebellar Structural and N-Acetylaspartate, Choline, and Creatine Metabolic Profiles in Parkinson's Disease and Essential Tremor.
Up-regulated succinylation modifications induce a senescence phenotype in microglia by altering mitochondrial energy metabolism.
Understanding Mitochondrial and Lysosomal Dynamics by Fluorescent Microscopy.
Impairment of neuromotor development and cognition associated with histopathological and neurochemical abnormalities in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase deficient mice.
Mitochondrial Dysfunction in Parkinson's Disease: A Contribution to Cognitive Impairment?
Molecular and cellular mechanisms of mitochondria transfer in models of central nervous system disease.

Sci Adv. 2024 Nov 15. 10(46): eadp7423

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.

Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Marion I Stunault, Hao Zhang, Xiangfeng Niu, Marissa A Laramie, Jasmin Sponagel, Leah P Shriver, Gary J Patti, Vitaly A Klyachko, Ghazaleh Ashrafi.

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval-functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.

DOI: https://doi.org/10.1126/sciadv.adp7423
Methods Mol Biol. 2025 ;2878 35-48

High-Resolution Respirometry Methodology for Bioenergetic and Metabolic Studies in Intact Brain Slices.

Cândida Dias, Cátia F Lourenço, João Laranjinha, Ana Ledo.

  The brain is critically dependent on energetic substrates as it consumes circa 20% of glucose and oxygen under normal physiological conditions. Although different cell types and at different locations might experience particular specificities in the utilization of these substrates, overall, mitochondrial oxidative phosphorylation supports the most efficient energy transduction process, enabling the complete oxidation of glucose to CO2 coupled to ATP synthesis in the presence of O2. Impairment of mitochondrial bioenergetics has been identified as an early event in many brain diseases and aging. Thus, novel methodologies to readily assess mitochondrial respiration in brain tissue, while preserving cellular and mitochondrial architecture and overcoming the serious drawbacks of studies using isolated mitochondrial preparations, are needed. Here we describe a methodology for studying functional parameters defining tissue metabolic respiration in brain hippocampal slices. The methodology can be used for physiological, pharmacological, and toxicological studies.

Keywords:  Brain tissue bioenergetics; High-resolution respirometry; Oxidative phosphorylation; Oxygen consumption rate; Whole brain slices

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_2
JIMD Rep. 2024 Nov;65(6): 417-425

Expanding the genetic and clinical spectrum of SLC25A42-associated disorders and testing of pantothenic acid to improve CoA level in vitro.

Katharina Heckmann, Arcangela Iuso, Janine Reunert, Marianne Grüneberg, Anja Seelhöfer, Stephan Rust, Giuseppe Fiermonte, Eleonora Paradies, Carmela Piazzolla, Manoj Mannil, Thorsten Marquardt.

  SLC25A42 encodes the mitochondrial coenzyme A (CoA) transporter localized at the inner mitochondrial membrane. SLC25A42 deficiency leads to a congenital disease with a heterogeneous clinical presentation, including myopathy, developmental delay, lactic acidosis, and encephalopathy. Twenty-one patients have been described so far. In the current study, we report on the identification of new biallelic variants in SLC25A42 in three siblings. Patients presented with symmetrical T2 hyperintensity of the putamen with minor volume depression at the brain MRI, elevated lactate, reduced oxygen consumption rates in muscle and fibroblasts, and reduced CoA levels in fibroblasts. Administration of pantothenic acid led to clinical stabilization and increased CoA levels in fibroblasts, thus confirming a role for SLC25A42 in energy metabolism and CoA homeostasis.

Keywords:  SLC25A42; cellular CoA; mitochondrial coenzyme transporter; mitochondrial respiration; pantothenic acid

DOI:  https://doi.org/10.1002/jmd2.12441
Epilepsy Curr. 2024 Nov 13. 15357597241293843

"Brain propane'': Propionate Fuels the Brain in Mice With Brain Energy Deficits.

Elliott S Neal, Karin Borges.

DOI: https://doi.org/10.1177/15357597241293843
Cell. 2024 Nov 07. pii: S0092-8674(24)01214-5. [Epub ahead of print]

A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.

Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long.

  β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.

Keywords:  BHB; enzyme; ketone; metabolite; metabolomics; obesity

DOI:  https://doi.org/10.1016/j.cell.2024.10.032
Biochim Biophys Acta Mol Basis Dis. 2024 Nov 13. pii: S0925-4439(24)00563-5. [Epub ahead of print] 167569

CRISPR-Cas9 mediated knockout of NDUFS4 in human iPSCs: A model for mitochondrial complex I deficiency.

Shivani Goolab, Karin Terburgh, Charl du Plessis, Janine Scholefield, Roan Louw.

  Mitochondrial diseases, often caused by defects in complex I (CI) of the oxidative phosphorylation system, currently lack curative treatments. Human-relevant, high-throughput drug screening platforms are crucial for the discovery of effective therapeutics, with induced pluripotent stem cells (iPSCs) emerging as a valuable technology for this purpose. Here, we present a novel iPSC model of NDUFS4-related CI deficiency that displays a strong metabolic phenotype in the pluripotent state. Human iPSCs were edited using CRISPR-Cas9 to target the NDUFS4 gene, generating isogenic NDUFS4 knockout (KO) cell lines. Sanger sequencing detected heterozygous biallelic deletions, whereas no indel mutations were found in isogenic control cells. Western blotting confirmed the absence of NDUFS4 protein in KO iPSCs and CI enzyme kinetics showed a ~56 % reduction in activity compared to isogenic controls. Comprehensive metabolomic profiling revealed a distinct metabolic phenotype in NDUFS4 KO iPSCs, predominantly associated with an elevated NADH/NAD+ ratio, consistent with alterations observed in other models of mitochondrial dysfunction. Additionally, β-lapachone, a recognized NAD+ modulator, alleviated reductive stress in KO iPSCs by modifying the redox state in both the cytosol and mitochondria. Although undifferentiated iPSCs cannot fully replicate the complex cellular dynamics of the disease seen in vivo, these findings highlight the utility of iPSCs in providing a relevant metabolic milieu that can facilitate early-stage, high-throughput exploration of therapeutic strategies for mitochondrial dysfunction.

Keywords:  CI deficiency; CRISPR-Cas9; Mitochondrial disease; iPSC

DOI:  https://doi.org/10.1016/j.bbadis.2024.167569
Eur J Neurosci. 2024 Nov 11.

Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice.

Vikrant R Mahajan, Jacob A Nadel, M Todd King, Robert J Pawlosky, Margaret I Davis, Richard L Veech, David M Lovinger, Armando G Salinas.

  Parkinson's disease (PD) is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark (MP) mouse model of PD recapitulates several facets of Parkinson's disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress. Thus, we hypothesized that administration of a ketone ester-enriched diet (KEED) would improve motor and dopamine release deficits in MP mice. Motor function (rotarod and open field tests), dopamine release (fast-scan cyclic voltammetry), tissue dopamine levels (gas chromatography-mass spectrometry) and dopamine neurons and axons (immunofluorescence) were assessed in MP, and control mice fed either the standard or a KEED. When started on the ketone diet before motor dysfunction onset, MP mice had improved motor function relative to standard diet (SD) MP mice. While the KEED did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MP mice was greater than SD MP mice but less than control mice. In a follow-up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MP mice relative to SD MP mice. The improvement in motor dysfunction indicates that a KEED or ketone supplement may have a beneficial effect on delaying motor deficit progression in Parkinson's disease.

Keywords:  Parkinson's disease; dopamine neurons; ketosis; neuroprotection; striatum

DOI:  https://doi.org/10.1111/ejn.16601
Sci Rep. 2024 11 08. 14(1): 27182

Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.

Lena Wischhof, Amal John Mathew, Lorenzo Bonaguro, Marc Beyer, Dan Ehninger, Pierluigi Nicotera, Daniele Bano.

  Inhibition of the mitochondrial oxidative phosphorylation (OXPHOS) system can lead to metabolic disorders and neurodegenerative diseases. In primary mitochondrial disorders, reactive astrocytes often accompany neuronal degeneration and may contribute to neurotoxic inflammatory cascades that elicit brain lesions. The influence of mitochondria to astrocyte reactivity as well as the underlying molecular mechanisms remain elusive. Here we report that mitochondrial Complex I dysfunction promotes neural progenitor cell differentiation into astrocytes that are more responsive to neuroinflammatory stimuli. We show that the SWItch/Sucrose Non-Fermentable (SWI/SNF/BAF) chromatin remodeling complex takes part in the epigenetic regulation of astrocyte responsiveness, since its pharmacological inhibition abrogates the expression of inflammatory genes. Furthermore, we demonstrate that Complex I deficient human iPSC-derived astrocytes negatively influence neuronal physiology upon cytokine stimulation. Together, our data describe the SWI/SNF/BAF complex as a sensor of altered mitochondrial OXPHOS and a downstream epigenetic regulator of astrocyte-mediated neuroinflammation.

Keywords:  ATP-dependent chromatin remodeling SWI/SNF/BAF complex; Mitochondria; Reactive astrocytes

DOI:  https://doi.org/10.1038/s41598-024-78434-y
Eur J Neurosci. 2024 Nov 14.

Balancing brain metabolic states during sickness and recovery sleep.

Sara B Noya, Arjun Sengupta, Zhifeng Yue, Aalim Weljie, Amita Sehgal.

  Sickness sleep and rebound following sleep deprivation share humoral signals including the rise of cytokines, in particular interleukins. Nevertheless, they represent unique physiological states with unique brain firing patterns and involvement of specific circuitry. Here, we performed untargeted metabolomics of mouse cortex and hippocampus to uncover changes with sickness and rebound sleep as compared with normal daily sleep. We found that the three settings are biochemically unique with larger differences in the cortex than in the hippocampus. Both sickness and rebound sleep shared an increase in tryptophan. Surprisingly, these two sleep conditions showed opposite modulation of the methionine-homocysteine cycle and differences in terms of the energetic signature, with sickness impinging on glycolysis intermediates whilst rebound increased the triphosphorylated form of nucleotides. These findings indicate that rebound following sleep deprivation stimulates an energy rich setting in the brain that is devoid during sickness sleep.

Keywords:  LPS; brain; metabolomics; sleep deprivation

DOI:  https://doi.org/10.1111/ejn.16588
Ageing Res Rev. 2024 Nov 10. pii: S1568-1637(24)00395-7. [Epub ahead of print]102 102577

Mitochondrial dysfunction as a therapeutic strategy for neurodegenerative diseases: Current insights and future directions.

Ying-Ying Gu, Xin-Ru Zhao, Nan Zhang, Yuan Yang, Ying Yi, Qian-Hang Shao, Ming-Xuan Liu, Xiao-Ling Zhang.

  Neurodegenerative diseases, as common diseases in the elderly, tend to become younger due to environmental changes, social development and other factors. They are mainly characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system, and common diseases include Parkinson's disease, Alzheimer's disease, Huntington's disease and so on. Mitochondria are important organelles for adenosine triphosphate (ATP) production in the brain. In recent years, a large amount of evidence has shown that mitochondrial dysfunction plays a direct role in neurodegenerative diseases, which is expected to provide new ideas for the treatment of related diseases. This review will summarize the main mechanisms of mitochondrial dysfunction in neurodegenerative diseases, as well as collating recent advances in the study of mitochondrial disorders and new therapies.

Keywords:  Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Neurodegenerative diseases; Oxidative stress

DOI:  https://doi.org/10.1016/j.arr.2024.102577
Methods Mol Biol. 2025 ;2878 67-74

Metabolic Phenotyping of Synaptic Mitochondria Using MitoPlates™ and Synaptoneurosomes.

Aleksandra Stawikowska, Magdalena Dziembowska, Bozena Kuzniewska.

  Mitochondrial functional assays using MitoPlates™ S-1 allow us to characterize mitochondria in terms of substrate metabolism. MitoPlates™ are 96-well microplates pre-coated with a diverse set of substrates. The electron flow from NADH and FADH2 producing mitochondrial substrates is measured based on the reduction of redox dye, that acts as a terminal electron acceptor. Here, we describe the application of MitoPlates™ to characterize the metabolism of synaptic mitochondria enclosed in isolated pre- and postsynaptic terminals (synaptoneurosomes).

Keywords:  MitoPlates™; Mitochondrial substrate metabolism; Synaptic mitochondria; Synaptoneurosomes

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_4
Int J Biochem Cell Biol. 2024 Nov 08. pii: S1357-2725(24)00182-1. [Epub ahead of print] 106689

Mitochondrial E3 ligase TRIM71 affects mitochondrial complex assembly and sensitizes dopaminergic neuronal cells to apoptosis in Parkinson's Disease (PD).

Shanikumar Goyani, Shatakshi Shukla, Minal Mane, M V Saranga, Nisha Chandak, Anjali Shinde, Fatema Currim, Jyoti Singh, Rajesh Singh.

  Parkinson's Disease (PD) is a chronic neurodegenerative disorder that impacts the substantia niagra region of the midbrain leading to impaired motor as well as non-motor symptoms of the central nervous system (CNS). Mitochondrial dysfunction has been characterized as the primary cause of dopaminergic neuronal loss, however, the molecular mechanisms leading to mitochondrial dysfunction are not completely understood. PARKIN, E3 ubiquitin ligase, plays a crucial role in maintaining mitochondrial quality control, albeit the role of other E3 ligases in regulating mitochondrial functions is not understood. In the current study, we explored the implication of TRIM71, E3 ubiquitin ligase, in the modulation of mitochondrial functions and neuronal death in PD stress conditions induced by rotenone and 6-OHDA. Ectopic expression of TRIM71 in SH-SY5Y dopaminergic neuronal cells sensitizes to PD stress-induced cell death, while its knock-down rescues neuronal cell death. TRIM71 turnover is enhanced in neurons under PD stress conditions. TRIM71 predominantly localizes on the outer mitochondrial membrane and translocation increases during PD stress conditions. TRIM71 regulates mitochondrial complex I and IV assembly and activity. TRIM71 knock-down decreases mitochondrial ROS and enhances ATP level as well as mitochondrial membrane potential in PD stress conditions. TRIM71-mediated mitochondrial ROS and cell death were rescued by mitoTEMPO, a mitochondrial-targeted antioxidant. Altogether, the evidence strongly suggests TRIM71-mediated modulation of mitochondrial functions and neuronal apoptosis in PD stress conditions.

Keywords:  Parkinson’s disease; ROS; TRIM71; cell death; mitochondria

DOI:  https://doi.org/10.1016/j.biocel.2024.106689
PLoS One. 2024 ;19(11): e0313507

Palmitoyl-L-carnitine induces tau phosphorylation and mitochondrial dysfunction in neuronal cells.

Gwangho Yoon, Min Kyoung Kam, Young Ho Koh, Chulman Jo.

Alzheimer's disease (AD) is characterized by cognitive decline and memory loss, involving mechanisms such as tau hyperphosphorylation and mitochondrial dysfunction. Increasing evidence suggests that age-related alterations in metabolite levels are crucial for the pathogenesis of AD. Here, we analyzed serum metabolites from mice of various ages (2, 4, 14, and 21 months old) using mass spectrometry. We identified palmitoyl-L-carnitine as a key metabolite with significantly increased levels in aged mice. In vitro experiments with SH-SY5Y neuronal cells demonstrated that palmitoyl-L-carnitine treatment enhanced tau phosphorylation, increased mitochondrial fission, and elevated intracellular calcium levels. Furthermore, the increased levels of tau phosphorylation were significantly reduced by the inhibition of GSK-3β, CDK5, and calpain, indicating that tau kinases activated by calcium overload are directly involved in the increase of tau phosphorylation. Considering that mitochondrial fission is related to mitochondrial dysfunction, we propose that the elevated level of serum palmitoyl-L-carnitine during aging contributes to AD pathology through these pathways. These findings highlight the significant role of lipid metabolism in neurodegeneration and offer potential therapeutic targets for age-related diseases, including AD.

DOI: https://doi.org/10.1371/journal.pone.0313507
J Biol Chem. 2024 Nov 05. pii: S0021-9258(24)02462-1. [Epub ahead of print] 107960

Multiple activities of sphingomyelin synthase 2 generate saturated fatty acid- and/or monounsaturated fatty acid-containing diacylglycerol.

Chiaki Murakami, Kamila Dilimulati, Kyoko Atsuta-Tsunoda, Takuma Kawai, Sho Inomata, Yasuhisa Hijikata, Hiromichi Sakai, Fumio Sakane.

  Phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) (EC 3.1.4.3) and phosphatidylethanolamine (PE)-specific PLC (PE-PLC) (EC 3.1.4.62), which generate diacylglycerol (DG) and are tricyclodecan-9-yl-xanthogenate (D609)-sensitive, were detected in detergent-insoluble fractions of mammalian tissues approximately 70 and 35 years ago, respectively. However, the genes and proteins involved in PC-PLC and PE-PLC activities remain unknown. In a recent study, we observed that mammalian sphingomyelin synthase (SMS) 1 and SMS-related protein (SMSr) display PC-PLC and PE-PLC activities in vitro. In the present study, we showed that human SMS2, which is located in detergent-insoluble fractions of the plasma membrane, also possesses PC-PLC activity (approximately 41% of SMS activity), PE-PLC activity (approximately 4%), ceramide phosphoethanolamine synthase (CPES) activity (approximately 46%), and SMS activity in the presence of phospholipid-detergent mixed micelles. Moreover, purified SMS2 reconstituted in detergent-free proteoliposomes (near-native environments) showed PC-PLC, PE-PLC, and CPES activities. Notably, in the presence of approximately 2 mol% ceramide and 4 mol% PC (1:2 ratio), PC-PLC activity was almost equal to SMS activity. SMS2 as PC/PE-PLC showed substrate selectivity for saturated fatty acid- and/or monounsaturated fatty acid-containing PC and PE species. The PC-PLC/SMS inhibitor D609 inhibited all enzyme activities (SMS, PC-PLC, PE-PLC, and CPES) of SMS2. Moreover, Zn2+ strongly inhibited all the enzymatic activities of SMS2. Interestingly, DG inhibited the SMS activity of SMS2 (feedback control). These results indicate that mammalian SMS2 has unique enzymatic properties and is a candidate for a long-sought mammalian PC/PE-PLC.

Keywords:  Ceramide; Ceramide phosphoethanolamine synthase; D609; Diacylglycerol; Phosphatidylcholine-phospholipase C; Phosphatidylethanolamine-phospholipase C; Phospholipase C; Sphingomyelin synthase

DOI:  https://doi.org/10.1016/j.jbc.2024.107960
JIMD Rep. 2024 Nov;65(6): 392-400

In vivo glycerol metabolism in patients with glycerol kinase deficiency.

Ankit Shah, Huiting Xu, Hyok Joon Kwon, Fredric E Wondisford.

  Glycerol kinase deficiency (GKD) is an X-linked recessive disorder due to glycerol kinase (GK) gene mutations resulting in hyperglycerolermia, hyperglyceroluria, and "pseudohypertriglyceridemia." In vivo glycerol metabolism has not been assessed in GKD. A 62-year-old man with suspected GKD and his extended family underwent whole exome sequencing and fasting blood work with two modes of lipid measurements: (1) standard lipase-based methodology and (2) nuclear magnetic resonance (NMR). Two overnight fasted men with GKD and a heterozygote female carrier then underwent 13C3-glycerol infusion. Affected family members had a novel two-nucleotide deletion in exon 5 of the GK gene (c.373_374del). Compared to their family members (n = 14), men with GKD (n = 5) had significantly lower total cholesterol levels (3.72 ± 0.70 vs. 4.77 ± 0.85 mmol/L, p = 0.024). Compared to NMR, lipase-based assays overreported triglycerides (5.28 ± 1.38 vs. 0.81 ± 0.32, mmol/L, p < 0.001) and underreported low-density lipoprotein cholesterol values (0.93 ± 0.23 vs. 2.18 ± 0.42 mmol/L, p = 0.001) in GKD. Men with GKD could not convert glycerol into glucose or triglycerides, which was preserved in the heterozygote carrier. Glycolytic metabolism of glycerol to lactate persisted in GKD, but it was reduced by a magnitude and, possibly, due to homologous glycerol kinases encoded by other genes. In summary, we report a novel GK pathogenic variant; affected men cannot convert circulating glycerol to glucose or triglycerides and have lower cholesterol levels. These results offer a human model for potentially targeting glycerol kinase to treat conditions associated with hyperglycemia and hyperlipidemia and warrant further investigation.

Keywords:  gluconeogenesis; glycerol; glycerol kinase; glycolysis; inborn error of metabolism; mass spectrometry; triglyceride synthesis

DOI:  https://doi.org/10.1002/jmd2.12452
J Biol Eng. 2024 Nov 14. 18(1): 67

A rotenone organotypic whole hemisphere slice model of mitochondrial abnormalities in the neonatal brain.

Brendan Butler, Malcolm Renney, Kristin Bennett, Gisele Charpentier, Elizabeth Nance.

  Mitochondrial abnormalities underscore a variety of neurologic injuries and diseases and are well-studied in adult populations. Clinical studies identify critical roles of mitochondria in a wide range of developmental brain injuries, but models that capture mitochondrial abnormalities in systems representative of the neonatal brain environment are lacking. Here, we develop an organotypic whole-hemisphere (OWH) brain slice model of mitochondrial dysfunction in the neonatal brain. We extended the utility of complex I inhibitor rotenone (ROT), canonically used in models of adult neurodegenerative diseases, to inflict mitochondrial damage in OWH slices from term-equivalent rats. We quantified whole-slice health over 6 days of exposure for a range of doses represented in ROT literature. We identified 50 nM ROT as a suitable exposure level for OWH slices to inflict injury without compromising viability. At the selected exposure level, we confirmed exposure- and time-dependent mitochondrial responses showing differences in mitochondrial fluorescence and nuclear localization using MitoTracker imaging in live OWH slices and dysregulated mitochondrial markers via RT-qPCR screening. We leveraged the regional structures present in OWH slices to quantify cell density and cell death in the cortex and the midbrain regions, observing higher susceptibilities to damage in the midbrain as a function of exposure and culture time. We supplemented these findings with analysis of microglia and mature neurons showing time-, region-, and exposure-dependent differences in microglial responses. We demonstrated changes in tissue microstructure as a function of region, culture time, and exposure level using live-video epifluorescence microscopy of extracellularly diffusing nanoparticle probes in live OWH slices. Our results highlight severity-, time-, and region-dependent responses and establish a complimentary model system of mitochondrial abnormalities for high-throughput or live-tissue experimental needs.

Keywords:  Cellular metabolism; Confocal microscopy; Ex vivo model; Nanoparticle tracking; Neurodevelopment

DOI:  https://doi.org/10.1186/s13036-024-00465-w
Hum Mol Genet. 2024 Nov 13. pii: ddae152. [Epub ahead of print]

Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome.

Olivia Sniezek Carney, Kodi W Harris, Yvonne Wohlfarter, Kyuna Lee, Grant Butschek, Arianna F Anzmann, Anne Hamacher-Brady, Markus A Keller, Hilary J Vernon.

  Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although TAFAZZIN is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ-KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype.

Keywords:  Barth syndrome; TAFAZZIN; cardiomyopathy; mitophagy

DOI:  https://doi.org/10.1093/hmg/ddae152
J Neuroinflammation. 2024 Nov 14. 21(1): 294

Metabolic-driven analytics of traumatic brain injury and neuroprotection by ethyl pyruvate.

Nikita Golovachev, Lorraine Siebold, Richard L Sutton, Sima Ghavim, Neil G Harris, Brenda Bartnik-Olson.

  BACKGROUND: Research on traumatic brain injury (TBI) highlights the significance of counteracting its metabolic impact via exogenous fuels to support metabolism and diminish cellular damage. While ethyl pyruvate (EP) treatment shows promise in normalizing cellular metabolism and providing neuroprotection, there is a gap in understanding the precise metabolic pathways involved. Metabolomic analysis of the acute post-injury metabolic effects, with and without EP treatment, aims to deepen our knowledge by identifying and comparing the metabolite profiles, thereby illuminating the injury's effects and EP's therapeutic potential.METHODS: In the current study, an untargeted metabolomics approach was used to reveal brain metabolism changes in rats 24 h after a controlled cortical impact (CCI) injury, with or without EP treatment. Using principal component analysis (PCA), volcano plots, Random Forest and pathway analysis we differentiated the brain metabolomes of CCI and sham injured animals treated with saline (Veh) or EP, identifying key metabolites and pathways affected by injury. Additionally, the effect of EP on the non-injured brain was also explored.
RESULTS: PCA showed a clear separation of the four study groups (sham-Veh, CCI-Veh, sham-EP, CCI-EP) based on injury. Following CCI injury (CCI-Veh), 109 metabolites belonging to the amino acid, carbohydrate, lipid, nucleotide, and xenobiotic families exhibited a twofold change at 24 h compared to the sham-Veh group, with 93 of these significantly increasing and 16 significantly decreasing (p < 0.05). CCI animals were treated with EP (CCI-EP) showed only 5 metabolites in the carbohydrate, amino acids, peptides, nucleotides, lipids, and xenobiotics super families that exhibited a twofold change, compared to the CCI-Veh group (p < 0.05). In the non-injured brain, EP treatment (sham-EP) resulted in a twofold change in 6 metabolites within the amino acid, peptide, nucleotide, and lipid super families compared to saline treated sham animals (sham-Veh, p < 0.05).
CONCLUSIONS: This study delineates the unique metabolic signatures resulting from a CCI injury and those related to EP treatment in both the injured and non-injured brain, underscoring the metabolic adaptations to brain injury and the effects of EP. Our analysis uncovers significant shifts in metabolites associated with inflammation, energy metabolism, and neuroprotection after injury, and demonstrates how EP intervention after injury alters metabolites associated with mitigating inflammation and oxidative damage.

Keywords:  Controlled cortical impact; Gas chromatography–mass spectrometry; Inflammation; Liquid chromatography–mass spectrometry; Metabolomics; Oxidative stress; Traumatic brain injury

DOI:  https://doi.org/10.1186/s12974-024-03280-8
Nat Commun. 2024 Nov 11. 15(1): 9756

Nonvesicular lipid transfer drives myelin growth in the central nervous system.

Jianping Wu, Georg Kislinger, Jerome Duschek, Ayşe Damla Durmaz, Benedikt Wefers, Ruoqing Feng, Karsten Nalbach, Wolfgang Wurst, Christian Behrends, Martina Schifferer, Mikael Simons.

Oligodendrocytes extend numerous cellular processes that wrap multiple times around axons to generate lipid-rich myelin sheaths. Myelin biogenesis requires an enormously productive biosynthetic machinery for generating and delivering these large amounts of newly synthesized lipids. Yet, a complete understanding of this process remains elusive. Utilizing volume electron microscopy, we demonstrate that the oligodendroglial endoplasmic reticulum (ER) is enriched in developing myelin, extending into and making contact with the innermost myelin layer where growth occurs. We explore the possibility of transfer of lipids from the ER to myelin, and find that the glycolipid transfer protein (GLTP), implicated in nonvesicular lipid transport, is highly enriched in the growing myelin sheath. Mice with a specific knockout of Gltp in oligodendrocytes exhibit ER pathology, hypomyelination and a decrease in myelin glycolipid content. In summary, our results demonstrate a role for nonvesicular lipid transport in CNS myelin growth, revealing a cellular pathway in developmental myelination.

DOI: https://doi.org/10.1038/s41467-024-53511-y
iScience. 2024 Nov 15. 27(11): 111163

Tau processing and tau-mediated inflammation differ in human APOEε2 and APOEε4 astrocytes.

Tobias Mothes, Evangelos Konstantinidis, Khalid Eltom, Abdulkhalek Dakhel, Jinar Rostami, Anna Erlandsson.

  Alzheimer's disease (AD) and progressive supra-nuclear palsy (PSP) are both proteinopathies, characterized by the accumulation of tau aggregates. APOEε4 is the greatest genetic risk factor for developing AD, while APOEε2 is a significant risk factor for developing PSP. In the brain, astrocytes are the predominant producer of ApoE, but they are also important for inflammation and overall brain homeostasis. Although, tau inclusions appear frequently in astrocytes in both AD and PSP brains, their connection to ApoE remains unclear. Here, we show that hiPSC-derived APOE 2/2 astrocytes accumulate, process, and spread pathogenic tau aggregates more efficiently than isogenic APOE 4/4 astrocytes. Moreover, the APOE 2/2 astrocytes display a more robust inflammatory response, which could be of relevance for the disease course. Taken together, our data highlight a central role of ApoE in astrocyte-mediated tau pathology.

Keywords:  disease; genes; neuroscience

DOI:  https://doi.org/10.1016/j.isci.2024.111163
Anal Methods. 2024 Nov 07.

New perspective on central nervous system disorders: focus on mass spectrometry imaging.

Huaqing Lai, Pinglong Fan, Huiqin Wang, Zhenzhen Wang, Naihong Chen.

An abnormally organized brain spatial network is linked to the development of various central nervous system (CNS) disorders, including neurodegenerative diseases and neuropsychiatric disorders. However, the complicated molecular mechanisms of these diseases remain unresolved, making the development of treatment strategies difficult. A novel molecular imaging technique, called mass spectrometry imaging (MSI), captures molecular information on the surface of samples in situ. With MSI, multiple compounds can be simultaneously visualized in a single experiment. The high spatial resolution enables the simultaneous visualization of the spatial distribution and relative content of various compounds. The wide application of MSI in biomedicine has facilitated extensive studies on CNS disorders in recent years. This review provides a concise overview of the processes, applications, advantages, and disadvantages, as well as mechanisms of the main types of MSI. Meanwhile, this review summarizes the main applications of MSI in studying CNS diseases, including Alzheimer's disease (AD), CNS tumors, stroke, depression, Huntington's disease (HD), and Parkinson's disease (PD). Finally, this review comprehensively discusses the synergistic application of MSI with other advanced imaging modalities, its utilization in organoid models, its integration with spatial omics techniques, and provides an outlook on its future potential in single-cell analysis.

DOI: https://doi.org/10.1039/d4ay01205d
J Neuroendocrinol. 2024 Nov 11. e13458

Insulin potential in preventing brain damage after traumatic brain injury: What we know.

Bardia Hajikarimloo, Sama Jabbaripour, Amir Mohammad Tohidinia, Aysan Valinejad Qanati, Farzan Fahim, Pegah Javadpour, Rasoul Ghasemi.

  Traumatic brain injury (TBI) is a major global cause of disability and mortality. TBI results in a spectrum of primary and secondary injuries that impact neural function and overall survival. Insulin, beyond its well-known role in regulating blood glucose levels, plays critical roles in the central nervous system (CNS). These roles include the modulation of synaptic plasticity, neurotransmitter levels, neurogenesis, and neuroprotection. Central insulin resistance, a reduced sensitivity to insulin in the brain, has been observed in TBI patients. This insulin resistance impairs insulin function in the brain and increases the risk of neurodegenerative processes. This review will delve into the central role of insulin resistance in the pathological changes observed after TBI and explore the potential benefits of insulin therapy as a treatment approach for TBI.

Keywords:  central nervous system; cognition; insulin resistance; insulin ; traumatic brain injury

DOI:  https://doi.org/10.1111/jne.13458
Nat Genet. 2024 Nov 11.

Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits.

Dominantly Inherited Alzheimer Network (DIAN)

Brain metabolism perturbation can contribute to traits and diseases. We conducted a genome-wide association study for cerebrospinal fluid (CSF) and brain metabolite levels, identifying 205 independent associations (47.3% new signals, containing 11 new loci) for 139 CSF metabolites, and 32 independent associations (43.8% new signals, containing 4 new loci) for 31 brain metabolites. Of these, 96.9% (CSF) and 71.4% (brain) of the new signals belonged to previously analyzed metabolites in blood or urine. We integrated the metabolite quantitative trait loci (MQTLs) with 23 neurological, psychiatric and common human traits and diseases through colocalization to identify metabolites and biological processes implicated in these phenotypes. Combining CSF and brain, we identified 71 metabolite-trait associations, such as glycerophosphocholines with Alzheimer's disease, O-sulfo-L-tyrosine with Parkinson's disease, glycine, xanthine with waist-to-hip ratio and ergothioneine with inflammatory bowel disease. Our study expanded the knowledge of MQTLs in the central nervous system, providing insights into human traits.

DOI: https://doi.org/10.1038/s41588-024-01973-7
Consort Psychiatr. 2024 ;5(3): 4-16

Mass Spectrometry Imaging of Two Neocortical Areas Reveals the Histological Selectivity of Schizophrenia-Associated Lipid Alterations.

Maria Osetrova, Marina Zavolskova, Pavel Mazin, Elena Stekolschikova, Gleb Vladimirov, Olga Efimova, Anna Morozova, Yana Zorkina, Denis Andreyuk, George Kostyuk, Evgeniy Nikolaev, Philipp Khaitovich.

  BACKGROUND: Schizophrenia is a psychiatric disorder known to affect brain structure and functionality. Structural changes in the brain at the level of gross anatomical structures have been fairly well studied, while microstructural changes, especially those associated with changes in the molecular composition of the brain, are still being investigated. Of special interest are lipids and metabolites, for which some previous studies have shown association with schizophrenia.AIM: To utilize a spatially resolved analysis of the brain lipidome composition to investigate the degree and nature of schizophrenia-associated lipidome alterations in the gray and white matter structures of two neocortical regions - the dorsolateral prefrontal cortex (Brodmann area 9, BA9) and the posterior part of the superior temporal gyrus (Brodmann area 22, posterior part, BA22p), as well compare the distribution of the changes between the two regions and tissue types.
METHODS: We employed Matrix-Assisted Laser Desorption/Ionization Mass Spectrometric Imaging (MALDI-MSI), supplemented by a statistical analysis, to examine the lipid composition of brain sections. A total of 24 neocortical sections from schizophrenia patients (n=2) and a healthy control group (n=2), representing the two aforementioned neocortical areas, were studied, yielding data for 131 lipid compounds measured across more than a million MALDI-MSI pixels.
RESULTS: Our findings revealed an uneven distribution of schizophrenia-related lipid alterations across the two neocortical regions. The BA22p showed double the differences in its subcortical white matter structures compared to BA9, while less bias was detected in the gray matter layers. While the schizophrenia-associated lipid differences generally showed good agreement between brain regions at the lipid class level for both gray and white matter, there were consistently more discrepancies for white matter structures.
CONCLUSION: Our study found a consistent yet differential association of schizophrenia with the brain lipidome composition of distinct neocortical areas, particularly subcortical white matter. These findings highlight the need for broader brain coverage in future schizophrenia research and underscore the potential of spatially resolved molecular analysis methods in identifying structure-specific effects.

Keywords:  MALDI-MSI; lipidomics; mass-spectrometry; neocortex; schizophrenia

DOI:  https://doi.org/10.17816/CP15488
Diagnostics (Basel). 2024 Oct 30. pii: 2430. [Epub ahead of print]14(21):

Cerebellar Structural and N-Acetylaspartate, Choline, and Creatine Metabolic Profiles in Parkinson's Disease and Essential Tremor.

Chien-Tai Hong, Cheng-Chang Yang, David Yen-Ting Chen, Shu-Ping Chao, Lung Chan.

  BACKGROUND: The role of the cerebellum in Parkinson's disease (PD), particularly in tremor-dominant subtypes, is increasingly recognized. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) provide anatomical and metabolic insights, suggesting compensatory hyperactivity or degenerative changes in the cerebellum in PD. Volumetric analysis of cerebellar structures in MRI images, combined with metabolic profiles from MRS, offers possibilities for differentiating PD from essential tremor (ET). The cerebellum may be a potential therapeutic target due to its role in neurocircuitry of PD and ET.METHODS: Brain structural data were obtained using MRI, and cerebellar metabolic profiles, focusing on the quantification of N-acetylaspartate (NAA), choline, and creatine peaks were obtained using MRS. This study enrolled patients with ET and PD, both with and without tremor, as well as disease controls with cerebellar atrophy (including spinocerebellar ataxia and multiple system atrophy). Volumetric analysis of cerebellar structures was performed. Differences in MRI and MRS parameters were analyzed using one-way analysis of covariance with a significance threshold of p < 0.05.
RESULTS: From November 2018 to March 2023, 111 patients were enrolled, including 29 ET, 29 cerebellar atrophy, 12 PD without tremor, and 41 PD with tremor. No significant differences in cerebellar volume and N-acetylaspartate/creatine and choline/creatine ratios were found between ET and PD with tremor.
CONCLUSIONS: This preliminary retrospective study suggests similarities in cerebellar structures and metabolic profiles between ET and PD, highlighting the need for advanced imaging techniques to better differentiate between these conditions. Future research should integrate clinical data, such as tremor severity and cognitive assessments, to explore the relationships with cerebellar MRI parameters.

Keywords:  Parkinson’s disease; essential tremor; magnetic resonance imaging; magnetic resonance spectroscopy

DOI:  https://doi.org/10.3390/diagnostics14212430
J Neuroinflammation. 2024 Nov 14. 21(1): 296

Up-regulated succinylation modifications induce a senescence phenotype in microglia by altering mitochondrial energy metabolism.

Xinnan Zhao, Xiaohan Yang, Cong Du, Huimin Hao, Shuang Liu, Gang Liu, Guangyin Zhang, Kai Fan, Jianmei Ma.

  The aging of the central nervous system(CNS) is a primary contributor to neurodegenerative diseases in older individuals and significantly impacts their quality of life. Neuroinflammation, characterized by activation of microglia(MG) and release of cytokines, is closely associated with the onset of these neurodegenerative diseases. The activated status of MG is modulated by specifically programmed metabolic changes under various conditions. Succinylation, a novel post-translational modification(PTM) mainly involved in regulating mitochondrial energy metabolism pathways, remains unknown in its role in MG activation and aging. In the present study, we found that succinylation levels were significantly increased both during aging and upon lipopolysaccharide-induced(LPS-induced) MG activation undergoing metabolic reprogramming. Up-regulated succinylation induced by sirtuin 5 knockdown(Sirt5 KD) in microglial cell line BV2 resulted in significant up-regulation of aging-related genes, accompanied by impaired mitochondrial adaptability and a shift towards glycolysis as a major metabolic pathway. Furthermore, after LPS treatment, Sirt5 KD BV2 cells exhibited increased generation of reactive oxygen species(ROS), accumulation of lipid droplets, and elevated levels of lipid peroxidation. By employing immunoprecipitation, introducing point mutation to critical succinylation sites, and conducting enzyme activity assays for succinate dehydrogenase(SDH) and trifunctional enzyme subunit alpha(ECHA), we demonstrated that succinylation plays a regulatory role in modulating the activities of these mitochondrial enzymes. Finally, down-regulation the succinylation levels achieved through administration of succinyl phosphonate(SP) led to amelioration of MG senescence in vitro and neuroinflammation in vivo. To our knowledge, our data provide preliminary evidence indicating that up-regulated succinylation modifications elicit a senescence phenotype in MG through alterations in energy metabolism. Moreover, these findings suggest that manipulation of succinylation levels may offer valuable insights into the treatment of aging-related neuroinflammation.

Keywords:  Aging; Metabolic reprogramming; Microglia; Neuroinflammation; Succinylation

DOI:  https://doi.org/10.1186/s12974-024-03284-4
Methods Mol Biol. 2025 ;2878 211-221

Understanding Mitochondrial and Lysosomal Dynamics by Fluorescent Microscopy.

Pedro A Dionísio, Vilma A Sardão, Nuno Raimundo.

  Live cell imaging is a robust method to visualize dynamic cellular structures, especially organelles with network-like structures such as mitochondria. In this regard, mitochondrial dynamics, namely mitochondrial fission and fusion, are highly dynamic processes that regulate mitochondrial size and morphology depending on a plethora of cellular cues. Likewise, lysosome size and distribution may hint at their function and state.Here, we describe how to perform live cell confocal imaging using commercially available organelle dyes (MitoTracker, LysoTracker), followed by either 2D or 3D analyses of mitochondrial morphology/network connectivity and lysosomal morphology using the freely available Mitochondria Analyzer plugin for ImageJ/Fiji.

Keywords:  Cell imaging; Fluorescent probes; LysoTracker; Lysosomes; Microscopy; MitoTracker; Mitochondria; Mitochondrial dynamics

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_11
Neurochem Int. 2024 Nov 08. pii: S0197-0186(24)00225-0. [Epub ahead of print]181 105898

Impairment of neuromotor development and cognition associated with histopathological and neurochemical abnormalities in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase deficient mice.

Ediandra Tissot Castro, Rafael Teixeira Ribeiro, Andrey Vinicios Soares Carvalho, Diorlon Nunes Machado, Ângela Beatris Zemniaçak, Rafael Palavro, Sâmela de Azevedo Cunha, Tailine Quevedo Tavares, Diogo Onofre Gomes de Souza, Carlos Alexandre Netto, Guilhian Leipnitz, Alexandre Umpierrez Amaral, Moacir Wajner.

  Patients with glutaric acidemia type I (GA I) manifest motor and intellectual disabilities whose pathogenesis has been so far poorly explored. Therefore, we evaluated neuromotor and cognitive abilities, as well as histopathological and immunohistochemical features in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase (GCDH) deficient knockout mice (Gcdh-/-), a well-recognized model of GA I. The effects of a single intracerebroventricular glutaric acid (GA) injection in one-day-old pups on the same neurobehavioral and histopathological/immunohistochemical endpoints were also investigated. Seven-day-old Gcdh-/- mice presented altered gait, whereas those receiving a GA neonatal administration manifested other sensorimotor deficits, including an abnormal response to negative geotaxis, cliff aversion and righting reflex, and muscle tone impairment. Compared to the WT mice, adult Gcdh-/- mice exhibited motor impairment, evidenced by poor performance in the Rota-rod test. Furthermore, neonatal GA administration provoked long-standing short- and long-term memory impairment in adult Gcdh-/- mice. Regarding the histopathological features, a significant increase in vacuoles and neurodegenerative cells was observed in both the cerebral cortex and striatum of 15- and 60-day-old Gcdh-/- mice and was more pronounced in mice injected with GA. Neuronal loss (decrease of NeuN staining) was also significantly increased in the cerebral cortex and striatum of Gcdh-/- mice, particularly in those neonatally injected with GA. In contrast, immunohistochemistry of MBP, astrocytic proteins GFAP and S100B, and the microglial marker Iba1 was not changed in 60-day-old Gcdh-/- mice, suggesting no myelination disturbance, reactive astrogliosis, and microglia activation, respectively. These data highlight the neurotoxicity of GA and the importance of early treatment aiming to decrease GA accumulation at early stages of development to prevent brain damage and learning/memory disabilities in GA I patients.

Keywords:  Gcdh(−/−) mice; Glutaric acid; Glutaric aciduria; Histopathology; Neurodegeneration; Neurodevelopment and cognition

DOI:  https://doi.org/10.1016/j.neuint.2024.105898
Int J Mol Sci. 2024 Oct 25. pii: 11490. [Epub ahead of print]25(21):

Mitochondrial Dysfunction in Parkinson's Disease: A Contribution to Cognitive Impairment?

Antonella Scorziello, Rossana Sirabella, Maria Josè Sisalli, Michele Tufano, Lucia Giaccio, Elena D'Apolito, Lorenzo Castellano, Lucio Annunziato.

  Among the non-motor symptoms associated with Parkinson's disease (PD), cognitive impairment is one of the most common and disabling. It can occur either early or late during the disease, and it is heterogeneous in terms of its clinical manifestations, such as Subjective Cognitive Dysfunction (SCD), Mild Cognitive Impairment (MCI), and Parkinson's Disease Dementia (PDD). The aim of the present review is to delve deeper into the molecular mechanisms underlying cognitive decline in PD. This is extremely important to delineate the guidelines for the differential diagnosis and prognosis of the dysfunction, to identify the molecular and neuronal mechanisms involved, and to plan therapeutic strategies that can halt cognitive impairment progression. Specifically, the present review will discuss the pathogenetic mechanisms involved in the progression of cognitive impairment in PD, with attention to mitochondria and their contribution to synaptic dysfunction and neuronal deterioration in the brain regions responsible for non-motor manifestations of the disease.

Keywords:  Parkinson’s disease; cognitive impairment; mitochondria; synaptic dysfunction; α-synuclein neurons

DOI:  https://doi.org/10.3390/ijms252111490
J Cereb Blood Flow Metab. 2024 Nov 14. 271678X241300223

Molecular and cellular mechanisms of mitochondria transfer in models of central nervous system disease.

Takafumi Nakano, Keiichi Irie, Koichi Matsuo, Kenichi Mishima, Yoshihiko Nakamura.

  In the central nervous system (CNS), neuronal function and dysfunction are critically dependent on mitochondrial integrity and activity. In damaged or diseased brains, mitochondrial dysfunction reduces adenosine triphosphate (ATP) levels and impairs ATP-dependent neural firing and neurotransmitter dynamics. Restoring mitochondrial capacity to generate ATP may be fundamental in restoring neuronal function. Recent studies in animals and humans have demonstrated that endogenous mitochondria may be released into the extracellular environment and transported or exchanged between cells in the CNS. Under pathological conditions in the CNS, intercellular mitochondria transfer contributes to new classes of signaling and multifunctional cellular activities, thereby triggering deleterious effects or promoting beneficial responses. Therefore, to take full advantage of the beneficial effects of mitochondria, it may be useful to transplant healthy and viable mitochondria into damaged tissues. In this review, we describe recent findings on the mechanisms of mitochondria transfer and provide an overview of experimental methodologies, including tissue sourcing, mitochondrial isolation, storage, and modification, aimed at optimizing mitochondria transplantation therapy for CNS disorders. Additionally, we examine the clinical relevance and potential strategies for the therapeutic application of mitochondria transplantation.

Keywords:  Central nervous system; experimental disease models; mitochondria transplantation; therapeutic strategies; transfer mechanism

DOI:  https://doi.org/10.1177/0271678X241300223