bims-medebr 2023-08-20 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒08‒20
fourteen papers selected by
Regina F. Fernández, Johns Hopkins University

Metabolic aspects of genetic ion channel epilepsies.
Nutritional Intervention Through Ketogenic Diet in GLUT1 Deficiency Syndrome.
ApoE4 exacerbates the senescence of hippocampal neurons and spatial cognitive impairment by downregulating acetyl-CoA level.
GHRH Neurons from the Ventromedial Hypothalamic Nucleus Provide Dynamic and Sex-Specific Input to the Brain Glucose-Regulatory Network.
Lipidomic analysis identifies long-chain acylcarnitine as a target for ischemic stroke.
In utero and post-natal opioid exposure followed by mild traumatic brain injury contributes to cortical neuroinflammation, mitochondrial dysfunction, and behavioral deficits in juvenile rats.
Systemic alterations of tricarboxylic acid cycle enzymes in Alzheimer's disease.
Early brain metabolic disturbances associated with delayed cerebral ischemia in patients with severe subarachnoid hemorrhage.
Long chain acyl-CoA synthetase 6 facilitates the local distribution of di-docosahexaenoic acid- and ultra-long-chain-PUFA-containing phospholipids in the retina to support normal visual function in mice.
Hyperpolarized [1-13C]Acetyl-l-Carnitine Probes Tricarboxylic Acid Cycle Activity In Vivo.
Glucose oxidation drives trunk neural crest cell development and fate.
Glutamine metabolism in diseases associated with mitochondrial dysfunction.
PCSK9 and the nervous system: a no-brainer?
IF1 promotes oligomeric assemblies of sluggish ATP synthase and outlines the heterogeneity of the mitochondrial membrane potential.

J Neurochem. 2023 Aug 18.

Metabolic aspects of genetic ion channel epilepsies.

Elliott S Neal, Weizhi Xu, Karin Borges.

  Nowadays, particularly in countries with high incomes, individual mutations in people affected by genetic epilepsies are identified, and genetic therapies are being developed. In addition, drugs are being screened to directly target specific mutations, and personalised medicine is possible. However, people with epilepsy do not yet benefit from these advances, and many types of epilepsies are medication-resistant, including Dravet syndrome. Thus, in the meantime, alternative and effective treatment options are needed. There is increasing evidence that metabolic deficits contribute to epileptic seizures and that such metabolic impairments may be amenable to treatment, with metabolic treatment options like the ketogenic diet being employed with some success. However, the brain metabolic alterations that occur in ion channel epilepsies are not well-understood, nor how these may differ from epilepsies that are of acquired and unknown origins. Here, we provide an overview of studies investigating metabolic alterations in epilepsies caused by mutations in the SCN1A and KCNA1 genes, which are currently the most studied ion channel epilepsies in animal models. The metabolic changes found in these models are likely to contribute to seizures. A metabolic basis of these ion channel epilepsies is supported by human and/or animal studies that show beneficial effects of the ketogenic diet, which may be mediated by the provision of auxiliary brain fuel in the form of ketone bodies. Other potentially more preferred dietary therapies including medium-chain triglycerides and triheptanoin have also been tested in a limited number of studies, but their efficacies remain to be clearly established. The extent to which brain metabolism is affected in people with Dravet syndrome, KCNA1 epilepsy and the models thereof still requires clarification. This requires more experiments that yield functional insight into metabolism.

Keywords:  Dravet syndrome; KCNA1; Kv1.1; Nav1.1; SCN1A; brain energy metabolism

DOI:  https://doi.org/10.1111/jnc.15938
Clin Nutr Res. 2023 Jul;12(3): 169-176

Nutritional Intervention Through Ketogenic Diet in GLUT1 Deficiency Syndrome.

Young-Sun Kim, Woojeong Kim, Ji-Hoon Na, Young-Mock Lee.

  Glucose transporter type 1 (GLUT1) deficiency syndrome (DS) is a metabolic brain disorder caused by a deficiency resulting from SLC2A1 gene mutation and is characterized by abnormal brain metabolism and associated metabolic encephalopathy. Reduced glucose supply to the brain leads to brain damage, resulting in delayed neurodevelopment in infancy and symptoms such as eye abnormalities, microcephaly, ataxia, and rigidity. Treatment options for GLUT1 DS include ketogenic diet (KD), pharmacotherapy, and rehabilitation therapy. Of these, KD is an essential and the most important treatment method as it promotes brain neurodevelopment by generating ketone bodies to produce energy. This case is a focused study on intensive KD nutritional intervention for an infant diagnosed with GLUT1 DS at Gangnam Severance Hospital from May 2022 to January 2023. During the initial hospitalization, nutritional intervention was performed to address poor intake via the use of concentrated formula and an attempt was made to introduce complementary feeding. After the second hospitalization and diagnosis of GLUT1 DS, positive effects on the infant's growth and development, nutritional status, and seizure control were achieved with minimal side effects by implementing KD nutritional intervention and adjusting the type and dosage of anticonvulsant medications. In conclusion, for patients with GLUT1 DS, it is important to implement a KD with an appropriate ratio of ketogenic to nonketogenic components to supply adequate energy. Furthermore, individualized and intensive nutritional management is necessary to improve growth, development, and nutritional status.

Keywords:  Diet, carbohydrate-restricted; Diet, ketogenic; Epilepsy; Glut1 deficiency syndrome; Seizures

DOI:  https://doi.org/10.7762/cnr.2023.12.3.169
Aging Cell. 2023 Aug 18. e13932

ApoE4 exacerbates the senescence of hippocampal neurons and spatial cognitive impairment by downregulating acetyl-CoA level.

Shuixin Lv, Yusi Zhang, Yingbin Lin, Wenting Fang, Yu Wang, Zihang Li, Anlan Lin, Xiaoman Dai, Qinyong Ye, Jing Zhang, Xiaochun Chen.

  Although aging and apolipoprotein E (APOE) ε4 allele have been documented as two major risk factors for late-onset Alzheimer's disease (LOAD), their interaction and potential underlying mechanisms remain unelucidated. Using humanized ApoE4- and ApoE3- target replacement mice, we found the accumulation of senescent neurons and the activation of mTOR and endosome-lysosome-autophagy (ELA) system in the hippocampus of aged ApoE4 mice. Further analyses revealed that ApoE4 aggravated the profile change of hippocampal transcription and metabolism in an age-dependent manner, accompanying with an disruption of metabolism, which is presented with the downregulating activity of citrate synthase, the level of ATP and, most importantly, the level of acetyl coenzyme A (Ac-CoA); GTA supplement, an Ac-CoA substrate, reversed the senescent characteristics, decreased the activation of mTOR and ELA system, and enhanced the synaptic structure and increasing level of pre-/post-synaptic plasticity-related protein, leading to cognitive improvement in aged ApoE4 mice. These data suggest that ApoE4 exacerbates neuronal senescence due to a deficiency of acetyl-CoA, which can be ameliorated by GTA supplement. The findings provide novel insights into the potential therapeutic value of GTA supplement for the cognitive improvement in aged APOE4 carriers.

Keywords:  Alzheimer's disease; ApoE4; acetate; acetyl-CoA; synaptic plasticity

DOI:  https://doi.org/10.1111/acel.13932
Neuroscience. 2023 Aug 10. pii: S0306-4522(23)00350-0. [Epub ahead of print]

GHRH Neurons from the Ventromedial Hypothalamic Nucleus Provide Dynamic and Sex-Specific Input to the Brain Glucose-Regulatory Network.

Subash Sapkota, Md Haider Ali, Ayed A Alshamrani, Prabhat R Napit, Sagor C Roy, Madhu Babu Pasula, Karen P Briski.

  The ventromedial hypothalamic nucleus (VMN) controls glucose counter-regulation, including pituitary growth hormone (GH) secretion. VMN neurons that express the transcription factor steroidogenic factor-1/NR5A1 (SF-1) participate in glucose homeostasis. Research utilized in vivo gene knockdown tools to determine if VMN growth hormone-releasing hormone (Ghrh) regulates hypoglycemic patterns of glucagon, corticosterone, and GH outflow according to sex. Intra-VMN Ghrh siRNA administration blunted hypoglycemic hypercorticosteronemia in each sex, but abolished elevated GH release in males only. Single-cell multiplex qPCR shows that dorsomedial VMN (VMNdm) Ghrh neurons express mRNAs encoding Ghrh, SF-1, and protein markers for glucose-inhibitory (γ-aminobutyric acid) or -stimulatory (nitric oxide; glutamate) neurotransmitters. Hypoglycemia decreased glutamate decarboxylase67 (GAD67) transcripts in male, not female VMNdm Ghrh/SF-1 neurons, a response that was refractory to Ghrh siRNA. Ghrh gene knockdown prevented, in each sex, hypoglycemic down-regulation of Ghrh/SF-1 nerve cell GAD65 transcription. Ghrh siRNA amplified hypoglycemia-associated amplification of Ghrh/SF-1 neuron nitric oxide synthase mRNA in male and female, without affecting glutaminase gene expression. Ghrh gene knockdown altered Ghrh/SF-1 neuron estrogen receptor-alpha (ERα) and ER-beta transcripts in hypoglycemic male, not female rats, but up-regulated GPR81 lactate receptor mRNA in both sexes. Outcomes infer that VMNdm Ghrh/SF-1 neurons are an effector of SF-1 control of counter-regulation, and document Ghrh modulation of hypoglycemic patterns of glucose-regulatory neurotransmitter along with estradiol and lactate receptor gene transcription in these cells. Co-transmission of glucose-inhibitory and -stimulatory neurochemicals of diverse chemical structure, spatial, and temporal profiles may enable VMNdm Ghrh neurons to provide complex dynamic, sex-specific input to the brain glucose-regulatory network.

Keywords:  GAD65; Ghrh; SF-1; glutaminase; insulin-induced hypoglycemia; sex differences

DOI:  https://doi.org/10.1016/j.neuroscience.2023.08.006
J Adv Res. 2023 Aug 11. pii: S2090-1232(23)00223-0. [Epub ahead of print]

Lipidomic analysis identifies long-chain acylcarnitine as a target for ischemic stroke.

Xin-Xin Huang, Lei Li, Run-Hao Jiang, Jian-Bing Yu, Yu-Qin Sun, Jinjun Shan, Jin Yang, Juan Ji, Shu-Qi Cheng, Yin-Feng Dong, Xi-Yue Zhang, Hai-Bin Shi, Sheng Liu, Xiu-Lan Sun.

  INTRODUCTION: Lipid metabolism dysfunction is widely involved in the pathological process of acute ischemic stroke (AIS). The coordination of lipid metabolism between neurons and astrocytes is of great significance. However, the full scope of lipid dynamic changes and the function of key lipids during AIS remain unknown. Hence, identifying lipid alterations and characterizing their key roles in AIS is of great importance.METHODS: Untargeted and targeted lipidomic analyses were applied to profile lipid changes in the ischemic penumbra and peripheral blood of transient middle cerebral artery occlusion (tMCAO) mice as well as the peripheral blood of AIS patients. Infarct volume and neurological deficits were assessed after tMCAO. The cell viability and dendritic complexity of primary neurons were evaluated by CCK8 assay and Sholl analysis. Seahorse, MitoTracker Green, tetramethyl rhodamine methyl ester (TMRM), 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSOX were used as markers of mitochondrial health. Fluorescent and isotopic free fatty acid (FFA) pulse-chase assays were used to track FFA flux in astrocytes.
RESULTS: Long-chain acylcarnitines (LCACs) were the lipids with the most dramatic changes in the ischemic penumbra and peripheral blood of tMCAO mice. LCACs were significantly elevated on admission in AIS patients and associated with poor outcomes in AIS patients. Increasing LCACs through a bolus administration of palmitoylcarnitine amplified stroke injury, while decreasing LCACs by overexpressing carnitine palmitoyltransferase 2 (CPT2) ameliorated stroke injury. Palmitoylcarnitine aggravated astrocytic mitochondrial damage after OGD/R, while CPT2 overexpression in astrocytes ameliorated cocultured neuron viability. Further study revealed that astrocytes stimulated by OGD/R liberated FFAs from lipid droplets into mitochondria to form LCACs, resulting in mitochondrial damage and lowered astrocytic metabolic support and thereby aggravated neuronal damage.
CONCLUSION: LCACs could accumulate and damage neurons by inducing astrocytic mitochondrial dysfunction in AIS. LCACs play a crucial role in the pathology of AIS and are novel promising diagnostic and prognostic biomarkers for AIS.

Keywords:  Astrocytic mitochondrial; Biomarker; Ischemic stroke; Lipid droplet; Long-chain acylcarnitine

DOI:  https://doi.org/10.1016/j.jare.2023.08.007
Brain Behav Immun Health. 2023 Oct;32 100669

In utero and post-natal opioid exposure followed by mild traumatic brain injury contributes to cortical neuroinflammation, mitochondrial dysfunction, and behavioral deficits in juvenile rats.

Austin M Gowen, Jina Yi, Kelly Stauch, Luke Miles, Sanjay Srinivasan, Katherine Odegaard, Gurudutt Pendyala, Sowmya V Yelamanchili.

  Maternal opioid use poses a significant health concern not just to the expectant mother but also to the fetus. Notably, increasing numbers of children born suffering from neonatal opioid withdrawal syndrome (NOWS) further compounds the crisis. While epidemiological research has shown the heightened risk factors associated with NOWS, little research has investigated what molecular mechanisms underly the vulnerabilities these children carry throughout development and into later life. To understand the implications of in utero and post-natal opioid exposure on the developing brain, we sought to assess the response to one of the most common pediatric injuries: minor traumatic brain injury (mTBI). Using a rat model of in utero and post-natal oxycodone (IUO) exposure and a low force weight drop model of mTBI, we show that not only neonatal opioid exposure significantly affects neuroinflammation, brain metabolites, synaptic proteome, mitochondrial function, and altered behavior in juvenile rats, but also, in conjunction with mTBI these aberrations are further exacerbated. Specifically, we observed long term metabolic dysregulation, neuroinflammation, alterations in synaptic mitochondria, and impaired behavior were impacted severely by mTBI. Our research highlights the specific vulnerability caused by IUO exposure to a secondary stressor such as later life brain injury. In summary, we present a comprehensive study to highlight the damaging effects of prenatal opioid abuse in conjunction with mild brain injury on the developing brain.

Keywords:  Cortex; Minor traumatic brain injury; Mitochondria; Neonatal opioid withdrawal syndrome; Neuroinflammation; Opioid; Synaptosome

DOI:  https://doi.org/10.1016/j.bbih.2023.100669
Front Neurosci. 2023 ;17 1206688

Systemic alterations of tricarboxylic acid cycle enzymes in Alzheimer's disease.

Dongdong Jia, Fangzhou Wang, Haitao Yu.

  Mitochondrial dysfunction, especially tricarboxylic acid (TCA) cycle arrest, is strongly associated with Alzheimer's disease (AD), however, its systemic alterations in the central and peripheral of AD patients are not well defined. Here, we performed an integrated analysis of AD brain and peripheral blood cells transcriptomics to reveal the expression levels of nine TCA cycle enzymes involving 35 genes. The results showed that TCA cycle related genes were consistently down-regulated in the AD brain, whereas 11 genes were increased and 16 genes were decreased in the peripheral system. Pearson analysis of the TCA cycle genes with Aβ, Tau and mini-mental state examination (MMSE) revealed several significant correlated genes, including pyruvate dehydrogenase complex subunit (PDHB), isocitrate dehydrogenase subunits (IDH3B, IDH3G), 2-oxoglutarate dehydrogenase complex subunit (DLD), succinyl-CoA synthetase subunit (SUCLA2), malate dehydrogenase subunit (MDH1). In addition, SUCLA2, MDH1, and PDHB were also uniformly down-regulated in peripheral blood cells, suggesting that they may be candidate biomarkers for the early diagnosis of AD. Taken together, TCA cycle enzymes were systemically altered in AD progression, PDHB, SUCLA2, and MDH1 may be potential diagnostic and therapeutic targets.

Keywords:  Alzheimer’s disease; brain; peripheral blood cells; transcriptomics; tricarboxylic acid (TCA) cycle

DOI:  https://doi.org/10.3389/fnins.2023.1206688
J Cereb Blood Flow Metab. 2023 Aug 12. 271678X231193661

Early brain metabolic disturbances associated with delayed cerebral ischemia in patients with severe subarachnoid hemorrhage.

Yannick Tholance, Sami Aboudhiaf, Baptiste Balança, Gleicy Keli Barcelos, Sebastien Grousson, Romain Carrillon, Thomas Lieutaud, Armand Perret-Liaudet, Frédéric Dailler, Stéphane Marinesco.

  Delayed cerebral ischemia (DCI) is a devastating complication of aneurysmal subarachnoid hemorrhage (ASAH) causing brain infarction and disability. Cerebral microdialysis (CMD) monitoring is a focal technique that may detect DCI-related neurochemical changes as an advance warning. We conducted retrospective analyses from 44 poor-grade ASAH patients and analyzed glucose, lactate, pyruvate, and glutamate concentrations in control patients without DCI (n = 19), and in patients with DCI whose CMD probe was located within (n = 17) or outside (n = 8) a new infarct. When monitored from within a lesion, DCI was preceded by a decrease in glucose and a surge in glutamate, accompanied by increases in lactate/pyruvate and lactate/glucose ratios whereas these parameters remained stable in control patients. When CMD monitoring was performed outside the lesion, the glutamate surge was absent, but glucose and L/G ratio were still significantly altered. Overall, glucose and L/G ratio were significant biomarkers of DCI (se96.0, spe73.7-68.4). Glucose and L/G predicted DCI 67 h before CT detection of a new infarct. The pathogenesis of DCI therefore induces early metabolic disturbances that can be detected by CMD as an advance warning. Glucose and L/G could provide a trigger for initiating further examination or therapy, earlier than when guided by other monitoring techniques.

Keywords:  Brain metabolism; cerebral microdialysis; glucose; lactate; multimodal monitoring

DOI:  https://doi.org/10.1177/0271678X231193661
FASEB J. 2023 09;37(9): e23151

Long chain acyl-CoA synthetase 6 facilitates the local distribution of di-docosahexaenoic acid- and ultra-long-chain-PUFA-containing phospholipids in the retina to support normal visual function in mice.

Sayoko Kuroha, Yusaku Katada, Yosuke Isobe, Haruki Uchino, Kyosuke Shishikura, Takashi Nirasawa, Kazuo Tsubota, Kazuno Negishi, Toshihide Kurihara, Makoto Arita.

  Docosahexaenoic acid (DHA) and ultra-long-chain polyunsaturated fatty acids (ULC-PUFAs) are uniquely enriched in membrane phospholipids of retinal photoreceptors. Several studies have shown that di-DHA- and ULC-PUFA-containing phospholipids in photoreceptors have an important role in maintaining normal visual function; however, the molecular mechanisms underlying the synthesis and enrichment of these unique lipids in the retina, and their specific roles in retinal function remain unclear. Long-chain acyl-coenzyme A (CoA) synthetase 6 (ACSL6) preferentially converts DHA into DHA-CoA, which is a substrate during DHA-containing lipid biosynthesis. Here, we report that Acsl6 mRNA is expressed in the inner segment of photoreceptor cells and the retinal pigment epithelial cells, and genetic deletion of ACSL6 resulted in the selective depletion of di-DHA- and ULC-PUFA-containing phospholipids, but not mono-DHA-containing phospholipids in the retina. MALDI mass spectrometry imaging (MALDI-MSI) revealed the selective distribution of di-DHA- and ULC-PUFA-containing phospholipids in the photoreceptor outer segment (OS). Electroretinogram of Acsl6-/- mice exhibited photoreceptor cell-derived visual impairment, whereas the expression levels and localization of opsin proteins were unchanged. Acsl6-/- mice exhibited an age-dependent progressive decrease of the thickness of the outer nuclear layers, whereas the inner nuclear layers and OSs were normal. These results demonstrate that ACSL6 facilitates the local enrichment of di-DHA- and ULC-PUFA-containing phospholipids in the retina, which supports normal visual function and retinal homeostasis.

Keywords:  docosahexaenoic acid; lipidomics; long-chain acyl-coenzyme a (CoA) synthetase 6; photoreceptor cells; ultra-long-chain polyunsaturated fatty acid

DOI:  https://doi.org/10.1096/fj.202300976R
ACS Sens. 2023 Aug 14.

Hyperpolarized [1-13C]Acetyl-l-Carnitine Probes Tricarboxylic Acid Cycle Activity In Vivo.

Jun Chen, Tamara K Singh, Sarah Al Nemri, Maheen Zaidi, Kelvin L Billingsley, Jae Mo Park.

  Mitochondrial oxidative phosphorylation (OXPHOS) is sensitive to a variety of biological factors, and dysregulated OXPHOS is observed during the development of numerous pathological conditions. ATP production via OXPHOS is intrinsically dependent on the availability of acetyl-coenzyme A (CoA), which can enter the tricarboxylic acid (TCA) cycle to drive the oxidative pathway. Acetyl-l-carnitine (ALCAR) is an interchangeable endogenous source of acetyl-CoA, and therefore, ALCAR-derived probes are uniquely positioned for the assessment of OXPHOS. In this report, we develop hyperpolarized (HP) [1-13C]ALCAR as a noninvasive probe to investigate cardiac TCA cycle activity in vivo. We initially synthesized the isotopically labeled substrate and demonstrated that the 13C nucleus maintained a suitable T1 value (50.1 ± 0.8 s at 3 T) and polarization levels (21.3 ± 5.3%) to execute in vivo metabolic measurements. HP [1-13C]ALCAR was employed for cardiac analyses of OXPHOS in rats under fed and fasted conditions. [5-13C]Glutamate was successfully detected, and the metabolite was used to analyze the TCA cycle activity in both nutritional states. These assessments were compared to analogous experiments with the HP [1-13C]pyruvate. Our report represents the first study to demonstrate that HP methods using [1-13C]ALCAR enable direct analyses of mitochondrial function and TCA cycle activity, which are fundamental to cardiac cell homeostasis.

Keywords:  acetyl-CoA; acetyl-l-carnitine; carbon-13 MRS; cardiac oxidative metabolism; hyperpolarization; oxidative phosphorylation

DOI:  https://doi.org/10.1021/acssensors.3c01046
J Cell Sci. 2023 Aug 15. pii: jcs260607. [Epub ahead of print]136(16):

Glucose oxidation drives trunk neural crest cell development and fate.

Nioosha Nekooie Marnany, Redouane Fodil, Sophie Féréol, Alwyn Dady, Marine Depp, Frederic Relaix, Roberto Motterlini, Roberta Foresti, Jean-Loup Duband, Sylvie Dufour.

  Bioenergetic metabolism is a key regulator of cellular function and signaling, but how it can instruct the behavior of cells and their fate during embryonic development remains largely unknown. Here, we investigated the role of glucose metabolism in the development of avian trunk neural crest cells (NCCs), a migratory stem cell population of the vertebrate embryo. We uncovered that trunk NCCs display glucose oxidation as a prominent metabolic phenotype, in contrast to what is seen for cranial NCCs, which instead rely on aerobic glycolysis. In addition, only one pathway downstream of glucose uptake is not sufficient for trunk NCC development. Indeed, glycolysis, mitochondrial respiration and the pentose phosphate pathway are all mobilized and integrated for the coordinated execution of diverse cellular programs, epithelial-to-mesenchymal transition, adhesion, locomotion, proliferation and differentiation, through regulation of specific gene expression. In the absence of glucose, the OXPHOS pathway fueled by pyruvate failed to promote trunk NCC adaptation to environmental stiffness, stemness maintenance and fate-decision making. These findings highlight the need for trunk NCCs to make the most of the glucose pathway potential to meet the high metabolic demands appropriate for their development.

Keywords:  Bioenergetics; Cell migration; Fate decision; Glycolysis; Neural crest; Oxidative phosphorylation

DOI:  https://doi.org/10.1242/jcs.260607
Mol Cell Neurosci. 2023 Aug 15. pii: S1044-7431(23)00081-7. [Epub ahead of print]126 103887

Glutamine metabolism in diseases associated with mitochondrial dysfunction.

Rebecca Bornstein, Michael T Mulholland, Margaret Sedensky, Phil Morgan, Simon C Johnson.

  Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways involved in glutamine catabolism, anabolism, and glutamine-glutamate cycling. In recent years, altered glutamine metabolism has been found to play important roles in the pathologic consequences of mitochondrial dysfunction. Glutamine is a pleiotropic molecule, not only providing an alternate carbon source to glucose in certain conditions, but also playing unique roles in cellular communication in neurons and astrocytes. Glutamine consumption and catabolic flux can be significantly altered in settings of genetic mitochondrial defects or exposure to mitochondrial toxins, and alterations to glutamine metabolism appears to play a particularly significant role in neurodegenerative diseases. These include primary mitochondrial diseases like Leigh syndrome (subacute necrotizing encephalopathy) and MELAS (mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke-like episodes), as well as complex age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Pharmacologic interventions targeting glutamine metabolizing and catabolizing pathways appear to provide some benefits in cell and animal models of these diseases, indicating glutamine metabolism may be a clinically relevant target. In this review, we discuss glutamine metabolism, mitochondrial disease, the impact of mitochondrial dysfunction on glutamine metabolic processes, glutamine in neurodegeneration, and candidate targets for therapeutic intervention.

Keywords:  Glutamine toxicity; Mitochondrial disease; Neurodegenerative disease

DOI:  https://doi.org/10.1016/j.mcn.2023.103887
J Lipid Res. 2023 Aug 14. pii: S0022-2275(23)00099-8. [Epub ahead of print] 100426

PCSK9 and the nervous system: a no-brainer?

Ali K Jaafar, Romuald Techer, Kévin Chemello, Gilles Lambert, Steeve Bourane.

  In the past 20 years, PCSK9 has been shown to play a pivotal role in LDL cholesterol metabolism and cardiovascular health, by inducing the lysosomal degradation of the LDL receptor. PCSK9 was discovered by the cloning of genes up-regulated after apoptosis induced by serum deprivation in primary cerebellar neurons, but despite its initial identification in the brain, the precise role of PCSK9 in the nervous system remains to be clearly established. The present manuscript is a comprehensive review of studies published or in print before July 2023, that have investigated the expression pattern of PCSK9, its effects on lipid metabolism, as well as its putative roles specifically in the central and peripheral nervous systems, with a special focus on cerebrovascular and neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Brain; LDL receptor; Nervous system; PCSK9; Stroke

DOI:  https://doi.org/10.1016/j.jlr.2023.100426
Commun Biol. 2023 08 12. 6(1): 836

IF1 promotes oligomeric assemblies of sluggish ATP synthase and outlines the heterogeneity of the mitochondrial membrane potential.

Inés Romero-Carramiñana, Pau B Esparza-Moltó, Sonia Domínguez-Zorita, Cristina Nuevo-Tapioles, José M Cuezva.

The coexistence of two pools of ATP synthase in mitochondria has been largely neglected despite in vitro indications for the existence of reversible active/inactive state transitions in the F1-domain of the enzyme. Herein, using cells and mitochondria from mouse tissues, we demonstrate the existence in vivo of two pools of ATP synthase: one active, the other IF1-bound inactive. IF1 is required for oligomerization and inactivation of ATP synthase and for proper cristae formation. Immunoelectron microscopy shows the co-distribution of IF1 and ATP synthase, placing the inactive "sluggish" ATP synthase preferentially at cristae tips. The intramitochondrial distribution of IF1 correlates with cristae microdomains of high membrane potential, partially explaining its heterogeneous distribution. These findings support that IF1 is the in vivo regulator of the active/inactive state transitions of the ATP synthase and suggest that local regulation of IF1-ATP synthase interactions is essential to activate the sluggish ATP synthase.

DOI: https://doi.org/10.1038/s42003-023-05214-1