bims-medebr 2024-09-08 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024‒09‒08
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

Unraveling brain palmitic acid: Origin, levels and metabolic fate.
A neurometabolic mechanism involving dmPFC/dACC lactate in physical effort-based decision-making.
Impaired energy metabolism and altered brain histoarchitecture characterized by inhibition of glycolysis and mitochondrial electron transport-linked enzymes in rats exposed to diisononyl phthalate.
The Uncoupling Effect of 17β-Estradiol Underlies the Resilience of Female-Derived Mitochondria to Damage after Experimental TBI.
Aged Brain Metabolomics Study by Metabolic Profiling Analysis of Amino Acids, Organic Acids, and Fatty Acids in Cortex, Cerebellum, Hypothalamus, and Hippocampus of Rats.
A Potential Role for the Amyloid Precursor Protein in the Regulation of Interferon Signaling, Cholesterol Homeostasis, and Tau Phosphorylation in Niemann-Pick Disease Type C.
A novel PDHK inhibitor restored cognitive dysfunction and limited neurodegeneration without affecting amyloid pathology in 5xFAD mouse, a model of Alzheimer's disease.
Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.
Concentrations of glutamate and N-acetylaspartate detected by magnetic resonance spectroscopy in the rat hippocampus correlate with hippocampal-dependent spatial memory performance.
Astrocyte involvement in metabolic regulation and disease.
Mitochondrial dysfunction and increased reactive oxygen species production in MECP2 mutant astrocytes and their impact on neurons.
Role of Cholesterol Metabolic Enzyme CYP46A1 and Its Metabolite 24S-Hydroxycholesterol in Ischemic Stroke.
Recent Advances of Mitochondrial Alterations in Alzheimer's Disease: A Perspective of Mitochondrial Basic Events.
Endo-Lysosomal Network Disorder Reprograms Energy Metabolism in SorL1-Null Rat Hippocampus.
Remote ischemic preconditioning prevents high-altitude cerebral edema by enhancing glucose metabolic reprogramming.
Lactate dehydrogenase-1 may play a key role in the brain energy disturbance caused by cryptococcal meningitis.
Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
Development of a Multiplexed Sphingolipids Method for Diagnosis of Inborn Errors of Ceramide Metabolism.
Impacts beyond the brain: Unraveling molecular mechanisms linking psychiatric, metabolic, and inflammatory conditions.
Mitochondrial transplants to treat mitochondrial dysfunction.
Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism.

Prog Lipid Res. 2024 Aug 31. pii: S0163-7827(24)00033-X. [Epub ahead of print] 101300

Unraveling brain palmitic acid: Origin, levels and metabolic fate.

Mackenzie E Smith, Richard P Bazinet.

  In the human brain, palmitic acid (16:0; PAM) comprises nearly half of total brain saturates and has been identified as the third most abundant fatty acid overall. Brain PAM supports the structure of membrane phospholipids, provides energy, and regulates protein stability. Sources underlying the origin of brain PAM are both diet and endogenous synthesis via de novo lipogenesis (DNL), primarily from glucose. However, studies investigating the origin of brain PAM are limited to tracer studies utilizing labelled (14C/11C/3H/2H) PAM, and results vary based on the model and tracer used. Nevertheless, there is evidence PAM is synthesized locally in the brain, in addition to obtained directly from the diet. Herein, we provide an overview of brain PAM origin, entry to the brain, metabolic fate, and factors influencing brain PAM kinetics and levels, the latter in the context of age, as well as neurological diseases and psychiatric disorders. Additionally, we briefly summarize the role of PAM in signaling at the level of the brain. We add to the literature a rudimentary summary on brain PAM metabolism.

Keywords:  Brain; Levels; Metabolic fate; Neurological disease; Origin; Palmitic acid

DOI:  https://doi.org/10.1016/j.plipres.2024.101300
Mol Psychiatry. 2024 Aug 30.

A neurometabolic mechanism involving dmPFC/dACC lactate in physical effort-based decision-making.

Nicolas Clairis, Arthur Barakat, Jules Brochard, Lijing Xin, Carmen Sandi.

Motivation levels vary across individuals, yet the underlying mechanisms driving these differences remain elusive. The dorsomedial prefrontal cortex/dorsal anterior cingulate cortex (dmPFC/dACC) and the anterior insula (aIns) play crucial roles in effort-based decision-making. Here, we investigate the influence of lactate, a key metabolite involved in energy metabolism and signaling, on decisions involving both physical and mental effort, as well as its effects on neural activation. Using proton magnetic resonance spectroscopy and functional MRI in 63 participants, we find that higher lactate levels in the dmPFC/dACC are associated with reduced motivation for physical effort, a relationship mediated by neural activity within this region. Additionally, plasma and dmPFC/dACC lactate levels correlate, suggesting a systemic influence on brain metabolism. Supported by path analysis, our results highlight lactate's role as a modulator of dmPFC/dACC activity, hinting at a neurometabolic mechanism that integrates both peripheral and central metabolic states with brain function in effort-based decision-making.

DOI: https://doi.org/10.1038/s41380-024-02726-y
Heliyon. 2024 Aug 30. 10(16): e36056

Impaired energy metabolism and altered brain histoarchitecture characterized by inhibition of glycolysis and mitochondrial electron transport-linked enzymes in rats exposed to diisononyl phthalate.

Samuel Abiodun Kehinde, Ayokanmi Ore, Abosede Temitope Olajide, Ebenezer Oyedele Ajiboye, Marios Papadakis, Athanasios Alexiou, Najah R Hadi, Ahmed M El-Gazzari, Farid S Ataya.

  The brain is an energy demanding organ, constituting about 20 % of the body's resting metabolic rate. An efficient energy metabolism is critical to neuronal functions. Glucose serves as the primary essential energy source for the adult brain and plays a critical role in supporting neural growth and development. Endocrine disrupting chemicals (EDCs) such as phthalates has been shown to have a negative impact on neurological functions. The impact of diisononyl phthalate (DiNP) on neural energy transduction using cellular energy metabolizing enzymes as indicators was examined. Over the course of 14 days, eighteen (18) albino rats divided into three groups (1,2 and 3) of six albino rats were given Tween-80/saline, 20 and 200 mg/kg body weight respectively. In the brain, we assessed histological changes as well as activities of selected enzymes of energy metabolism such as the glycolytic pathway, citric acid cycle and mitochondrial electron transport-linked complexes. Activities of the glycolytic and TCA cycle enzymes assayed were significantly decreased except citrate synthase activity with no statistically significant change following the administration of DiNP. Also, respiratory chain complexes (Complex I-IV) activities were significantly reduced when compared to control. DiNP exposure altered the histological integrity of various brain sections. These include degenerated Purkinje neurons, distortion of the granular layer and Purkinje cell layer. Data from this study indicated impaired brain energy metabolism via down-regulation of enzymes of cellular respiration of the glycolytic and oxidative phosphorylation pathways and altered brain histoarchitecture orchestrated by DiNP exposure.

Keywords:  Brain; Cellular respiration; Diisononyl phthalate; Glycolysis; Mitochondrial electron transport complexes; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.heliyon.2024.e36056
Life (Basel). 2024 Jul 30. pii: 961. [Epub ahead of print]14(8):

The Uncoupling Effect of 17β-Estradiol Underlies the Resilience of Female-Derived Mitochondria to Damage after Experimental TBI.

Olivia J Kalimon, Hemendra J Vekaria, Paresh Prajapati, Sydney L Short, W Brad Hubbard, Patrick G Sullivan.

  Current literature finds females have improved outcomes over their male counterparts after severe traumatic brain injury (TBI), while the opposite seems to be true for mild TBI. This begs the question as to what may be driving these sex differences after TBI. Estrogen is thought to be neuroprotective in certain diseases, and its actions have been shown to influence mitochondrial function. Mitochondrial impairment is a major hallmark of TBI, and interestingly, this dysfunction has been shown to be more severe in males than females after brain injury. This suggests estrogen could be playing a role in promoting "mitoprotection" following TBI. Despite the existence of estrogen receptors in mitochondria, few studies have examined the direct role of estrogen on mitochondrial function, and no studies have explored this after TBI. We hypothesized ex vivo treatment of isolated mitochondria with 17β-estradiol (E2) would improve mitochondrial function after experimental TBI in mice. Total mitochondria from the ipsilateral (injured) and contralateral (control) cortices of male and female mice were isolated 24 h post-controlled severe cortical impact (CCI) and treated with vehicle, 2 nM E2, or 20 nM E2 immediately before measuring reactive oxygen species (ROS) production, bioenergetics, electron transport chain complex (ETC) activities, and β-oxidation of palmitoyl carnitine. Protein expression of oxidative phosphorylation (OXPHOS) complexes was also measured in these mitochondrial samples to determine whether this influenced functional outcomes with respect to sex or injury. While mitochondrial ROS production was affected by CCI in both sexes, there were other sex-specific patterns of mitochondrial injury 24 h following severe CCI. For instance, mitochondria from males were more susceptible to CCI-induced injury with respect to bioenergetics and ETC complex activities, whereas mitochondria from females showed only Complex II impairment and reduced β-oxidation after injury. Neither concentration of E2 influenced ETC complex activities themselves, but 20 nM E2 appeared to uncouple mitochondria isolated from the contralateral cortex in both sexes, as well as the injured ipsilateral cortex of females. These studies highlight the significance of measuring mitochondrial dysfunction in both sexes after TBI and also shed light on another potential neuroprotective mechanism in which E2 may attenuate mitochondrial dysfunction after TBI in vivo.

Keywords:  bioenergetics; brain trauma; electron transport chain; neurotherapeutic; sex differences

DOI:  https://doi.org/10.3390/life14080961
Front Biosci (Landmark Ed). 2024 Aug 22. 29(8): 306

Aged Brain Metabolomics Study by Metabolic Profiling Analysis of Amino Acids, Organic Acids, and Fatty Acids in Cortex, Cerebellum, Hypothalamus, and Hippocampus of Rats.

Byeongchan Choi, Moongi Ji, Songjin Oh, Youngbae Kim, Subin Choi, Hyun Woo Kim, Hae Young Chung, Man-Jeong Paik.

  BACKGROUND: Aging is a progressive process characterized by weakness in brain function. Although metabolomics studies on the brain related with aging have been conducted, it is not yet fully understood. A systematic metabolomics study was performed to search for biomarkers and monitor altered metabolism in various brain tissues of the cortex, cerebellum, hypothalamus, and hippocampus of young (8 months old) and old rats (22 months old).METHODS: Simultaneous profiling analysis of amino acids (AAs), organic acids (OAs), and fatty acids (FAs) in the brain tissues of young and old rats were performed by gas chromatography-tandem mass spectrometry.
RESULTS: Under optimal conditions, AA, OA, and FA profiling methods showed good linearity (r ≥0.995) with limit of detection of ≤30 and 73.2 ng and limit of quantification of ≤90.1 and 219.5 ng, respectively. Repeatability varied from 0.4 to 10.4 and 0.8 to 14.8% relative standard deviation and accuracy varied from -11.3 to 10.3 and -12.8 to 14.1% relative error, respectively. In the profiling analysis, total 32, 43, 45, and 30 metabolites were determined in cortex, cerebellum, hypothalamus, and hippocampus, respectively. In statistical analysis, eight AAs (alanine, valine, leucine, isoleucine, threonine, serine, proline, and phenylalanine) in the cortex and four metabolites (alanine, phenylalanine, 3-hydoxypropionic acid, and eicosadienoic acid) in the cerebellum were significantly evaluated (Q-value <0.05, variable importance in projection scores ≥1.0). In all brain tissues, the score plots of orthogonal partial least square discriminant analysis were clearly separated between the young and old groups.
CONCLUSIONS: Metabolomics results indicate that mechanistic targets of rapamycin complex 1, branched chain-amino acid, and energy metabolism are related to inflammation and mitochondrial dysfunction in the brain during aging. Thus, these results may explain the characteristic metabolism of brain aging.

Keywords:  aging; amino acid; fatty acid; gas chromatography-tandem mass spectrometry; metabolic profiling analysis; organic acid; rat brain tissues

DOI:  https://doi.org/10.31083/j.fbl2908306
Genes (Basel). 2024 Aug 13. pii: 1066. [Epub ahead of print]15(8):

A Potential Role for the Amyloid Precursor Protein in the Regulation of Interferon Signaling, Cholesterol Homeostasis, and Tau Phosphorylation in Niemann-Pick Disease Type C.

Kayla L Sanchez, Samuel D Shin, Naren P Rajagopal, Jacob B White, Antonio Currais, David Soriano-Castell, Pamela Maher, Salvador Soriano.

  Niemann-Pick disease type C (NPC) is a rare and fatal neurological disorder caused by mutations in Npc1 or Npc2, with Npc1 accounting for 95% of cases. These mutations result in the functional loss of their respective proteins, causing cellular abnormalities characterized by disrupted lipid dysregulation, calcium dysfunction, elevated damage associated molecular patterns (DAMPs), and a pro-inflammatory environment. This cellular pathology ultimately triggers neurodegeneration, with the cerebellum being the earliest and most affected region. We have recently shown atypical activation of interferon signaling in the presymptomatic Npc1-/- mouse cerebellum and, to a lesser extent, in the cerebral cortex. In addition, we reported that the Amyloid Precursor Protein (APP) is an NPC disease modifier. Loss of APP function leads to widespread neurodegeneration in the NPC brain, including exacerbated interferon signaling in the cerebellum. To better understand the role of APP as a disease modifier throughout the NPC brain, here we carried out a transcriptomic analysis of the cerebral cortex and cerebellum from 3-week-old Npc1-/- mice as well as age-matched controls in the presence and absence of APP. We report differential effects of APP loss of function in the cerebral cortex and cerebellum, including cholesterol and tau dysregulation, in both brain regions. Our findings demonstrate a novel link between APP loss and early pathogenic mechanisms in NPC.

Keywords:  Amyloid Precursor Protein; Niemann-Pick disease type C; neurodegeneration

DOI:  https://doi.org/10.3390/genes15081066
Alzheimers Res Ther. 2024 Sep 05. 16(1): 197

A novel PDHK inhibitor restored cognitive dysfunction and limited neurodegeneration without affecting amyloid pathology in 5xFAD mouse, a model of Alzheimer's disease.

Katsuya Sakimura, Takashi Kawai, Reiko Nashida, Yuji Ishida, Kana Harada, Takashi Suzuki, Chihiro Okuma, Gregory M Cole.

  BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Although drugs focusing on reducing amyloid β slow progression, they fail to improve cognitive function. Deficits in glucose metabolism are reflected in FDG-PET and parallel the neurodegeneration and synaptic marker loss closely preceding cognitive decline, but the role of metabolic deficits as a cause or consequence of neurodegeneration is unclear. Pyruvate dehydrogenase (PDH) is lost in AD and an important enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle by converting pyruvate into acetyl-CoA. It is negatively regulated by pyruvate dehydrogenase kinase (PDHK) through phosphorylation.METHODS: In the present study, we assessed the in vitro/ in vivo pharmacological profile of the novel PDHK inhibitor that we discovered, Compound A. We also assessed the effects of Compound A on AD-related phenotypes including neuron loss and cognitive impairment using 5xFAD model mice.
RESULTS: Compound A inhibited human PDHK1, 2 and 3 but had no inhibitory activity on PDHK4. In primary neurons, Compound A enhanced pyruvate and lactate utilization, but did not change glucose levels. In contrast, in primary astrocytes, Compound A enhanced pyruvate and glucose utilization and enhanced lactate production. In an efficacy study using 5xFAD mice, Compound A ameliorated the cognitive dysfunction in the novel object recognition test and Morris water maze. Moreover, Compound A prevented neuron loss in the hippocampus and cerebral cortex of 5xFAD without affecting amyloid β deposits.
CONCLUSIONS: These results suggest ameliorating metabolic deficits by activating PDH by Compound A can limit neurodegeneration and is a promising therapeutic strategy for treating AD.

Keywords:  5xFAD; Aerobic glycolysis; Alzheimer’s disease; Glucose metabolism; Pyruvate dehydrogenase (PDH); Pyruvate dehydrogenase kinase (PDHK)

DOI:  https://doi.org/10.1186/s13195-024-01552-2
Biochemistry (Mosc). 2024 Jul;89(7): 1336-1348

Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.

Veronika V Nesterova, Polina I Babenkova, Anna A Brezgunova, Natalia A Samoylova, Irina S Sadovnikova, Dmitry S Semenovich, Nadezda V Andrianova, Artem P Gureev, Egor Y Plotnikov.

  One of the therapeutic approaches to age-related diseases is modulation of body cell metabolism through certain diets or their pharmacological mimetics. The ketogenic diet significantly affects cell energy metabolism and functioning of mitochondria, which has been actively studied in various age-related pathologies. Here, we investigated the effect of the ketogenic diet mimetic beta-hydroxybutyrate (BHB) on the expression of genes regulating mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam), quality control (Sqstm1), functioning of the antioxidant system (Nfe2l2, Gpx1, Gpx3, Srxn1, Txnrd2, Slc6a9, Slc7a11), and inflammatory response (Il1b, Tnf, Ptgs2, Gfap) in the brain, lungs, heart, liver, kidneys, and muscles of young and old rats. We also analyzed mitochondrial DNA (mtDNA) copy number, accumulation of mtDNA damage, and levels of oxidative stress based on the concentration of reduced glutathione and thiobarbituric acid-reactive substances (TBARS). In some organs, aging disrupted mitochondrial biogenesis and functioning of cell antioxidant system, which was accompanied by the increased oxidative stress and inflammation. Administration of BHB for 2 weeks had different effects on the organs of young and old rats. In particular, BHB upregulated expression of genes coding for proteins associated with the mitochondrial biogenesis and antioxidant system, especially in the liver and muscles of young (but not old) rats. At the same time, BHB contributed to the reduction of TBARS in the kidneys of old rats. Therefore, our study has shown that administration of ketone bodies significantly affected gene expression in organs, especially in young rats, by promoting mitochondrial biogenesis, improving the functioning of the antioxidant defense system, and partially reducing the level of oxidative stress. However, these changes were much less pronounced in old animals.

Keywords:  aging; beta-hydroxybutyrate; ketogenic diet; mitochondria; mitochondrial DNA; oxidative stress

DOI:  https://doi.org/10.1134/S0006297924070149
Front Mol Neurosci. 2024 ;17 1458070

Concentrations of glutamate and N-acetylaspartate detected by magnetic resonance spectroscopy in the rat hippocampus correlate with hippocampal-dependent spatial memory performance.

João M N Duarte.

  Magnetic resonance spectroscopy (MRS) has been employed to investigate brain metabolite concentrations in vivo, and they vary during neuronal activation, across brain activity states, or upon disease with neurological impact. Whether resting brain metabolites correlate with functioning in behavioral tasks remains to be demonstrated in any of the widely used rodent models. This study tested the hypothesis that, in the absence of neurological disease or injury, the performance in a hippocampal-dependent memory task is correlated with the hippocampal levels of metabolites that are mainly synthesized in neurons, namely N-acetylaspartate (NAA), glutamate and GABA. Experimentally naïve rats were tested for hippocampal-dependent spatial memory performance by measuring spontaneous alternation in the Y-maze, followed by anatomical magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in the hippocampus and cortex. Memory performance correlated with hippocampal concentrations of NAA (p = 0.024) and glutamate (p = 0.014) but not GABA. Concentrations of glutamate in the cortex also correlated with spatial memory (p = 0.035). In addition, memory performance was also correlated with the relative volume of the hippocampus (p = 0.041). Altogether, this exploratory study suggests that levels of the neuronal maker NAA and the main excitatory neurotransmitter glutamate are associated with physiological functional capacity.

Keywords:  GABA; NAA; glutamate; metabolites; neurochemicals; neurotransmitters

DOI:  https://doi.org/10.3389/fnmol.2024.1458070
Trends Endocrinol Metab. 2024 Aug 29. pii: S1043-2760(24)00220-0. [Epub ahead of print]

Astrocyte involvement in metabolic regulation and disease.

Muhammad Naveed, Kathryn Smedlund, Qi-Gang Zhou, Weikang Cai, Jennifer W Hill.

  Astrocytes, the predominant glial cell type in the mammalian brain, influence a wide variety of brain parameters including neuronal energy metabolism. Exciting recent studies have shown that obesity and diabetes can impact on astrocyte function. We review evidence that dysregulation of astrocytic lipid metabolism and glucose sensing contributes to dysregulation of whole-body energy balance, thermoregulation, and insulin sensitivity. In addition, we consider the overlooked topic of the sex-specific roles of astrocytes and their response to hormonal fluctuations that provide insights into sex differences in metabolic regulation. Finally, we provide an update on potential ways to manipulate astrocyte function, including genetic targeting, optogenetic and chemogenetic techniques, transplantation, and tailored exosome-based therapies, which may lead to improved treatments for metabolic disease.

Keywords:  astrocytes; diabetes; metabolic disease; obesity; sex-specific

DOI:  https://doi.org/10.1016/j.tem.2024.08.001
Sci Rep. 2024 09 04. 14(1): 20565

Mitochondrial dysfunction and increased reactive oxygen species production in MECP2 mutant astrocytes and their impact on neurons.

Danielle L Tomasello, M Inmaculada Barrasa, David Mankus, Katia I Alarcon, Abigail K R Lytton-Jean, X Shawn Liu, Rudolf Jaenisch.

  Studies on MECP2 function and its implications in Rett Syndrome (RTT) have traditionally centered on neurons. Here, using human embryonic stem cell (hESC) lines, we modeled MECP2 loss-of-function to explore its effects on astrocyte (AST) development and dysfunction in the brain. Ultrastructural analysis of RTT hESC-derived cerebral organoids revealed significantly smaller mitochondria compared to controls (CTRs), particularly pronounced in glia versus neurons. Employing a multiomics approach, we observed increased gene expression and accessibility of a subset of nuclear-encoded mitochondrial genes upon mutation of MECP2 in ASTs compared to neurons. Analysis of hESC-derived ASTs showed reduced mitochondrial respiration and altered key proteins in the tricarboxylic acid cycle and electron transport chain in RTT versus CTRs. Additionally, RTT ASTs exhibited increased cytosolic amino acids under basal conditions, which were depleted upon increased energy demands. Notably, mitochondria isolated from RTT ASTs exhibited increased reactive oxygen species and influenced neuronal activity when transferred to cortical neurons. These findings underscore MECP2 mutation's differential impact on mitochondrial and metabolic pathways in ASTs versus neurons, suggesting that dysfunctional AST mitochondria may contribute to RTT pathophysiology by affecting neuronal health.

Keywords:  Amino acid metabolism; Astrocyte; Electrophysiology; MECP2; Mitochondrial transplantation; Neurodevelopment; Rett syndrome; Single nuclei ATAC-seq; Single nuclei RNA-seq; Stem cells

DOI:  https://doi.org/10.1038/s41598-024-71040-y
Stroke. 2024 Sep 03.

Role of Cholesterol Metabolic Enzyme CYP46A1 and Its Metabolite 24S-Hydroxycholesterol in Ischemic Stroke.

Huawei Sun, Tao Yang, Roger P Simon, Zhi-Gang Xiong, Tiandong Leng.

  BACKGROUND: For several decades, it has been recognized that overactivation of the glutamate-gated N-methyl-D-aspartate receptors (NMDARs) and subsequent Ca2+ toxicity play a critical role in ischemic brain injury. 24S-hydroxycholesterol (24S-HC) is a major cholesterol metabolite in the brain, which has been identified as a potent positive allosteric modulator of NMDAR in rat hippocampal neurons. We hypothesize that 24S-HC worsens ischemic brain injury via its potentiation of the NMDAR, and reducing the production of 24S-HC by targeting its synthetic enzyme CYP46A1 provides neuroprotection.METHODS: We tested this hypothesis using electrophysiological, pharmacological, and transgenic approaches and in vitro and in vivo cerebral ischemia models.
RESULTS: Our data show that 24S-HC potentiates NMDAR activation in primary cultured mouse cortical neurons in a concentration-dependent manner. At 10 µmol/L, it dramatically increases the steady-state currents by 51% and slightly increases the peak currents by 20%. Furthermore, 24S-HC increases NMDA and oxygen-glucose deprivation-induced cortical neuronal injury. The increased neuronal injury is largely abolished by NMDAR channel blocker MK-801, suggesting an NMDAR-dependent mechanism. Pharmacological inhibition of CYP46A1 by voriconazole or gene knockout of Cyp46a1 dramatically reduces ischemic brain injury.
CONCLUSIONS: These results identify a new mechanism and signaling cascade that critically impacts stroke outcome: CYP46A1 → 24S-HC → NMDAR → ischemic brain injury. They offer proof of principle for further development of new strategies for stroke intervention by targeting CYP46A1 or its metabolite 24S-HC.

Keywords:  24-hydroxycholesterol; brain ischemia; cholesterol; cholesterol 24-hydroxylase; stroke

DOI:  https://doi.org/10.1161/STROKEAHA.124.047803
J Alzheimers Dis. 2024 Aug 23.

Recent Advances of Mitochondrial Alterations in Alzheimer's Disease: A Perspective of Mitochondrial Basic Events.

Wenyan Wei, Ying Jiang, Guizhen Hu, Yanfang He, Huiyi Chen.

  Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and is characterized by a decrease in learning capacity, memory loss and behavioral changes. In addition to the well-recognized amyloid-β cascade hypothesis and hyperphosphorylated Tau hypothesis, accumulating evidence has led to the proposal of the mitochondrial dysfunction hypothesis as the primary etiology of AD. However, the predominant molecular mechanisms underlying the development and progression of AD have not been fully elucidated. Mitochondrial dysfunction is not only considered an early event in AD pathogenesis but is also involved in the whole course of the disease, with numerous pathophysiological processes, including disordered energy metabolism, Ca2+ homeostasis dysfunction and hyperactive oxidative stress. In the current review, we have integrated emerging evidence to summarize the main mitochondrial alterations- bioenergetic metabolism, mitochondrial inheritance, mitobiogenesis, fission- fusion dynamics, mitochondrial degradation, and mitochondrial movement- underlying AD pathogenesis; precisely identified the mitochondrial regulators; discussed the potential mechanisms and primary processes; highlighted the leading players; and noted additional incidental signaling pathway changes. This review may help to stimulate research exploring mitochondrial metabolically-oriented neuroprotection strategies in AD therapies, leading to a better understanding of the link between the mitochondrial dysfunction hypothesis and AD pathogenesis.

Keywords:  Alzheimer’s disease; aging; mitochondria; molecular therapy

DOI:  https://doi.org/10.3233/JAD-240092
Adv Sci (Weinh). 2024 Sep 03. e2407709

Endo-Lysosomal Network Disorder Reprograms Energy Metabolism in SorL1-Null Rat Hippocampus.

Yajie Wang, Yuting Yang, Ying Cai, Ayikaimaier Aobulikasimu, Yuexin Wang, Chuanwei Hu, Zhikang Miao, Yue Shao, Mengna Zhao, Yue Hu, Chang Xu, Xinjun Chen, Zhiqiang Li, Jincao Chen, Lianrong Wang, Shi Chen.

  Sortilin-related receptor 1 (SorL1) deficiency is a genetic predisposition to familial Alzheimer's disease (AD), but its pathology is poorly understood. In SorL1-null rats, a disorder of the global endosome-lysosome network (ELN) is found in hippocampal neurons. Deletion of amyloid precursor protein (APP) in SorL1-null rats could not completely rescue the neuronal abnormalities in the ELN of the hippocampus and the impairment of spatial memory in SorL1-null young rats. These in vivo observations indicated that APP is one of the cargoes of SorL1 in the regulation of the ELN, which affects hippocampal-dependent memory. When SorL1 is depleted, the endolysosome takes up more of the lysosome flux and damages lysosomal digestion, leading to pathological lysosomal storage and disturbance of cholesterol and iron homeostasis in the hippocampus. These disturbances disrupt the original homeostasis of the material-energy-subcellular structure and reprogram energy metabolism based on fatty acids in the SorL1-null hippocampus, instead of glucose. Although fatty acid oxidation increases ATP supply, it cannot reduce the levels of the harmful byproduct ROS during oxidative phosphorylation, as it does in glucose catabolism. Therefore, the SorL1-null rats exhibit hippocampal degeneration, and their spatial memory is impaired. Our research sheds light on the pathology of SorL1 deficiency in AD.

Keywords:   SorL1 ; Alzheimer's disease; endo‐lysosome network disorder; energy metabolism; hippocampus degeneration; iron homeostasis

DOI:  https://doi.org/10.1002/advs.202407709
CNS Neurosci Ther. 2024 Sep;30(9): e70026

Remote ischemic preconditioning prevents high-altitude cerebral edema by enhancing glucose metabolic reprogramming.

Rongrong Han, Xiaoyan Yang, Xunming Ji, Bing Zhou.

  AIMS: Incidence of acute mountain sickness (AMS) ranges from 40%-90%, with high-altitude cerebral edema (HACE) representing a life-threatening end stage of severe AMS. However, practical and convenient preventive strategies for HACE are lacking. Remote ischemic preconditioning (RIPC) has demonstrated preventive effects on ischemia- or hypoxia-induced cardiovascular and cerebrovascular diseases. This study aimed to investigate the potential molecular mechanism of HACE and the application of RIPC in preventing HACE onset.METHODS: A hypobaric hypoxia chamber was used to simulate a high-altitude environment of 7000 meters. Metabolomics and metabolic flux analysis were employed to assay metabolite levels. Transcriptomics and quantitative real-time PCR (q-PCR) were used to investigate gene expression levels. Immunofluorescence staining was performed on neurons to label cellular proteins. The fluorescent probes Mito-Dendra2, iATPSnFR1.0, and CMTMRos were used to observe mitochondria, ATP, and membrane potential in cultured neurons, respectively. TUNEL staining was performed to detect and quantify apoptotic cell death. Hematoxylin and eosin (H&E) staining was utilized to analyze pathological changes, such as tissue swelling in cerebral cortex samples. The Rotarod test was performed to assess motor coordination and balance in rats. Oxygen-glucose deprivation (OGD) of cultured cells was employed as an in vitro model to simulate the hypoxia and hypoglycemia induced by RIPC in animal experiments.
RESULTS: We revealed a causative perturbation of glucose metabolism in the brain preceding cerebral edema. Ischemic preconditioning treatment significantly reprograms glucose metabolism, ameliorating cell apoptosis and hypoxia-induced energy deprivation. Notably, ischemic preconditioning improves mitochondrial membrane potential and ATP production through enhanced glucose-coupled mitochondrial metabolism. In vivo studies confirm that RIPC alleviates cerebral edema, reduces cell apoptosis induced by high-altitude hypoxia, and improves motor dysfunction resulting from cerebral edema.
CONCLUSIONS: Our study elucidates the metabolic basis of HACE pathogenesis. This study provides a new strategy for preventing HACE that RIPC reduces brain edema through reprogramming metabolism, highlighting the potential of targeting metabolic reprogramming for neuroprotective interventions in neurological diseases caused by ischemia or hypoxia.

Keywords:  high‐altitude cerebral edema; hypoxia; metabolic reprogramming; mitochondrial dysfunction; remote ischemic preconditioning

DOI:  https://doi.org/10.1111/cns.70026
J Microbiol Immunol Infect. 2024 Aug 23. pii: S1684-1182(24)00153-1. [Epub ahead of print]

Lactate dehydrogenase-1 may play a key role in the brain energy disturbance caused by cryptococcal meningitis.

Qingdong Zhu, Qian Long, Cailing Wei, Jieling Chen, Lanwei Nong, Jianglong Qin, Zhizhong Huang, Yanqing Zheng, Sijun Li.

  BACKGROUND: Cryptococcal meningitis (CM) may affect the conversion of lactate to pyruvate in the brain, resulting in abnormal levels of adenosine triphosphate (ATP) throughout the brain. Lactate conversion to pyruvate is mainly caused by lactic dehydrogenase 1 (LDH1), which is composed of four LDHB subunits. However, the underlying mechanism of LDH1 in CM remains unclear.METHODS: Cerebrospinal fluid (CSF) from 17 patients was collected, including eight patients with non-infectious diseases of the central nervous system and nine patients with CM. Based on clinical data and laboratory reports, data regarding intracranial pressure, CSF white cell counts, lactate dehydrogenase (LDH), adenosine deaminase, glucose, protein, and chloridion were collected. Meanwhile, LDH1, LDH5, lactate, pyruvate, and ATP levels were detected in CSF. Whereafter, the levels of lactate, pyruvate, ATP, and the amplitude and frequency of action potentials in the neurons with low expression of LDHB were explored.
RESULTS: Intracranial pressure and white cell count in CSF were significantly increased in patients with CM. In patients with CM, the LDH1, pyruvate, and ATP levels in the CSF were significantly decreased, and the levels of lactate were found to be increased. Furthermore, pyruvate and ATP levels were decreased, while lactate was increased in the neurons with low expression of LDHB. The amplitude and frequency of APs in the neurons with low expression of LDHB were significantly decreased.
CONCLUSION: Reduced levels of LDH1 in the brain of patients with CM may lead to increased lactate levels, decreased pyruvate and ATP levels, and negatively affect neuronal activity.

Keywords:  Adenosine triphosphate; Cryptococcal meningitis; Lactate; Lactate dehydrogenase 1; Pyruvate

DOI:  https://doi.org/10.1016/j.jmii.2024.08.009
J Biol Chem. 2024 Sep 03. pii: S0021-9258(24)02247-6. [Epub ahead of print] 107746

Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.

Antonio J Rua, Wayne Mitchell, Steven M Claypool, Nathan N Alder, Andrei T Alexandrescu.

  Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin. Mutations in tafazzin are the primary cause of Barth syndrome. Here, we investigated how defects in cardiolipin biosynthesis and remodeling impacts metabolic flux through the TCA cycle and associated yeast pathways. Nuclear magnetic resonance was used to monitor in real-time the metabolic fate of 13C3-pyruvate in isolated mitochondria from three isogenic yeast strains. We compared mitochondria from a wild-type strain to mitochondria from a Δtaz1 strain that lacks tafazzin and contains lower amounts of unremodeled cardiolipin, and mitochondria from a Δcrd1 strain that lacks cardiolipin synthase and cannot synthesize cardiolipin. We found that the 13C-label from the pyruvate substrate was distributed through twelve metabolites. Several of the metabolites were specific to yeast pathways including branched chain amino acids and fusel alcohol synthesis. While most metabolites showed similar kinetics amongst the different strains, mevalonate concentrations were significantly increased in Δtaz1 mitochondria. Additionally, the kinetic profiles of α-ketoglutarate, as well as NAD+ and NADH measured in separate experiments, displayed significantly lower concentrations for Δtaz1 and Δcrd1 mitochondria at most time points. Taken together, the results show how cardiolipin remodeling influences pyruvate metabolism, tricarboxylic acid cycle flux, and the levels of mitochondrial nucleotides.

Keywords:  3-methylglutaconic acid (3MGA); Barth syndrome (BTHS); Krebs cycle; adenosine triphosphate (ATP); metabolic disease; mitochondrial respiration; nuclear magnetic resonance (NMR); tricarboxylic acid (TCA) cycle

DOI:  https://doi.org/10.1016/j.jbc.2024.107746
Clin Chem. 2024 Aug 29. pii: hvae115. [Epub ahead of print]

Development of a Multiplexed Sphingolipids Method for Diagnosis of Inborn Errors of Ceramide Metabolism.

Seul Kee Byeon, Jinyong Kim, Peter Jared Wegwerth, Roman Zenka, John P George, Filippo Pinto E Vairo, Devin Oglesbee, Matthew J Schultz, Dietrich Matern, Akhilesh Pandey.

BACKGROUND: Sphingolipids play a crucial role in cellular functions and are essential components of cell membranes, signaling molecules, and lipid metabolism. In particular, ceramide is a key intermediate in sphingolipid metabolism and defects in ceramide metabolism can lead to various inborn errors of metabolism, making ceramides important targets for clinical screening and diagnosis. Detecting altered concentration patterns of sphingolipids is desirable for distinguishing related inborn errors of metabolism for diagnosis and treatment monitoring.METHODS: We developed a liquid chromatography-tandem mass spectrometry method with a pathway-oriented approach to focus on sphingolipids involved in ceramide metabolism. A total of 47 sphingolipids bearing different head groups and side chains were targeted. Precision/reproducibility, linearity, and spike recovery extraction efficiency tests were performed on plasma and serum samples from confirmed cases of sphingolipidosis.
RESULTS: Linearity of the method showed the coefficient of determination (r2) for all standards to be >0.99 with a slope of 1.00 ± 0.01. Intra- and interday reproducibility of standards spiked into plasma and serum revealed a coefficient of variation <20%. Spike and recovery assessment showed recovery values of 80%-120% for all standards. Altered levels of sphingolipids from patients with hereditary sensory and autonomic neuropathy caused by pathogenic variants in SPTLC2 and hypomyelinating leukodystrophy related to variants in DEGS1 were detected, in agreement with trends reported in earlier studies confirming the utility of this pathway-centric method.
CONCLUSIONS: This method can serve as a useful tool to simultaneously monitor sphingolipids, enabling screening and diagnosis of inborn errors of ceramide metabolism.

DOI: https://doi.org/10.1093/clinchem/hvae115
Neuron. 2024 Sep 04. pii: S0896-6273(24)00573-7. [Epub ahead of print]112(17): 2827-2829

Impacts beyond the brain: Unraveling molecular mechanisms linking psychiatric, metabolic, and inflammatory conditions.

Nathaniel Napoli, Quenten Schwarz.

By establishing semaphorin 6D expression in the amygdala as a central coordinator of brain, metabolic, and immunologic function, the Neuron publication by Nakanishi et al.1 provides new insight to how primary brain deficiency impacts physiological systems beyond the brain.

DOI: https://doi.org/10.1016/j.neuron.2024.08.001
Nat Metab. 2024 Sep 02.

Mitochondrial transplants to treat mitochondrial dysfunction.

Alessandro Bitto.

DOI: https://doi.org/10.1038/s42255-024-01124-6
Commun Biol. 2024 Sep 05. 7(1): 1088

Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism.

Hideyuki Takahashi, Azucena Perez-Canamas, Chris W Lee, Hongping Ye, Xianlin Han, Stephen M Strittmatter.

TMEM106B is an endolysosomal transmembrane protein not only associated with multiple neurological disorders including frontotemporal dementia, Alzheimer's disease, and hypomyelinating leukodystrophy but also potentially involved in COVID-19. Additionally, recent studies have identified amyloid fibrils of C-terminal TMEM106B in both aged healthy and neurodegenerative brains. However, so far little is known about physiological functions of TMEM106B in the endolysosome and how TMEM106B is involved in a wide range of human conditions at molecular levels. Here, we performed lipidomic analysis of the brain of TMEM106B-deficient mice. We found that TMEM106B deficiency significantly decreases levels of two major classes of myelin lipids, galactosylceramide and its sulfated derivative sulfatide. Subsequent co-immunoprecipitation assay showed that TMEM106B physically interacts with galactosylceramidase. We also found that galactosylceramidase activity was significantly increased in TMEM106B-deficient brains. Thus, our results suggest that TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism and have implications for TMEM106B-associated diseases.

DOI: https://doi.org/10.1038/s42003-024-06810-5