bims-medebr 2024-10-13 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–10–13
sixteen papers selected by
Regina F. Fernández, Johns Hopkins University

Exploring the role of mitochondrial uncoupling protein 4 in brain metabolism: implications for Alzheimer's disease.
Impaired brain glucose metabolism in glucagon-like peptide-1 receptor knockout mice.
Increased ketone levels as a key magnetic resonance spectroscopic findings during acute exacerbation in ECHS1-related Leigh syndrome.
Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.
LDHB-deficient brain exhibits resistance to ischemic neuronal cell death due to increased vasodilation.
Synaptic Mitochondria: a crucial factor in the aged hippocampus.
Analysis of the brain transcriptome, microbiome and metabolome in ketogenic diet and experimental stroke.
Schizophrenia, a disease of impaired dynamic metabolic flexibility: A new mechanistic framework.
Fueling Recovery: The Therapeutic Role of Ketogenic Diet in Neurological Pathologies.
Sex-specific decline in prefrontal cortex mitochondrial bioenergetics in aging baboons correlates with walking speed.
25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation.
Mapping Age Differences in Brain Energy Metabolites and Metabolic Markers of Cellular Membrane Production and Degradation With 31P Magnetic Resonance Spectroscopy.
Brain hypoxia and metabolic crisis are common in patients with acute brain injury despite a normal intracranial pressure.
Upstream and downstream pathways of diacylglycerol kinase : Novel phosphatidylinositol turnover-independent signal transduction pathways.
Genetic analysis of the X-linked Adrenoleukodystrophy ABCD1 gene in Drosophila uncovers a role in Peroxisomal dynamics.
Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in Italy.

Front Neurosci. 2024 ;18 1483708

Exploring the role of mitochondrial uncoupling protein 4 in brain metabolism: implications for Alzheimer's disease.

Simone M Crivelli, Aisylu Gaifullina, Jean-Yves Chatton.

  The brain's high demand for energy necessitates tightly regulated metabolic pathways to sustain physiological activity. Glucose, the primary energy substrate, undergoes complex metabolic transformations, with mitochondria playing a central role in ATP production via oxidative phosphorylation. Dysregulation of this metabolic interplay is implicated in Alzheimer's disease (AD), where compromised glucose metabolism, oxidative stress, and mitochondrial dysfunction contribute to disease progression. This review explores the intricate bioenergetic crosstalk between astrocytes and neurons, highlighting the function of mitochondrial uncoupling proteins (UCPs), particularly UCP4, as important regulators of brain metabolism and neuronal function. Predominantly expressed in the brain, UCP4 reduces the membrane potential in the inner mitochondrial membrane, thereby potentially decreasing the generation of reactive oxygen species. Furthermore, UCP4 mitigates mitochondrial calcium overload and sustains cellular ATP levels through a metabolic shift from mitochondrial respiration to glycolysis. Interestingly, the levels of the neuronal UCPs, UCP2, 4 and 5 are significantly reduced in AD brain tissue and a specific UCP4 variant has been associated to an increased risk of developing AD. Few studies modulating the expression of UCP4 in astrocytes or neurons have highlighted protective effects against neurodegeneration and aging, suggesting that pharmacological strategies aimed at activating UCPs, such as protonophoric uncouplers, hold promise for therapeutic interventions in AD and other neurodegenerative diseases. Despite significant advances, our understanding of UCPs in brain metabolism remains in its early stages, emphasizing the need for further research to unravel their biological functions in the brain and their therapeutic potential.

Keywords:  Alzheimer’s disease; UCP4; astrocytes; mitochondria; neurons; uncoupling agent; uncoupling protein

DOI:  https://doi.org/10.3389/fnins.2024.1483708
Nutr Diabetes. 2024 Oct 10. 14(1): 86

Impaired brain glucose metabolism in glucagon-like peptide-1 receptor knockout mice.

Hui Li, Yujiao Fang, Da Wang, Bowen Shi, Garth J Thompson.

BACKGROUND: Quantitative mapping of the brain's metabolism is a critical tool in studying and diagnosing many conditions, from obesity to neurodegenerative diseases. In particular, noninvasive approaches are urgently required. Recently, there have been promising drug development approaches for the treatment of disorders related to glucose metabolism in the brain and, therefore, against obesity-associated diseases. One of the most important drug targets to emerge has been the Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R). GLP and GLP-1R play an important role in regulating blood sugar and maintaining energy homeostasis. However, the macroscopic effects on brain metabolism and function due to the presence of GLP-1R are unclear.
METHODS: To explore the physiological role of GLP-1R in mouse brain glucose metabolism, and its relationship to brain function, we used three methods. We used deuterium magnetic resonance spectroscopy (DMRS) to provide quantitative information about metabolic flux, fluorodeoxyglucose positron emission tomography (FDG-PET) to measure brain glucose metabolism, and resting state-functional MRI (rs-fMRI) to measure brain functional connectivity. We used these methods in both mice with complete GLP-1R knockout (GLP-1R KO) and wild-type C57BL/6N (WT) mice.
RESULTS: The metabolic rate of GLP-1R KO mice was significantly slower than that of WT mice (p = 0.0345, WT mice 0.02335 ± 0.057 mM/min, GLP-1R KO mice 0.01998 ± 0.07 mM/min). Quantification of the mean [18F]FDG signal in the whole brain also showed significantly reduced glucose uptake in GLP-1R KO mice versus control mice (p = 0.0314). Observing rs-fMRI, the functional brain connectivity in GLP-1R KO mice was significantly lower than that in the WT group (p = 0.0032 for gFCD, p = 0.0002 for whole-brain correlation, p < 0.0001 for ALFF).
CONCLUSIONS: GLP-1R KO mice exhibit impaired brain glucose metabolism to high doses of exogenous glucose, and they also have reduced functional connectivity. This suggests that the GLP-1R KO mouse model may serve as a model for correlated metabolic and functional connectivity loss.

DOI: https://doi.org/10.1038/s41387-024-00343-w
Radiol Case Rep. 2024 Dec;19(12): 6292-6296

Increased ketone levels as a key magnetic resonance spectroscopic findings during acute exacerbation in ECHS1-related Leigh syndrome.

Yuka Murofushi, Kenta Ochiai, Madoka Yasukochi, Kentaro Sano, Keiko Ichimoto, Kei Murayama, Yasushi Okazaki, Taku Omata, Jun-Ichi Takanashi.

  Short-chain enoyl-CoA hydratase, encoded by ECHS1, plays a major role in the valine catabolic pathway and mitochondrial fatty acid β-oxidation. Deficiency of this enzyme causes Leigh syndrome. Herein, we report a case of ECHS1-related Leigh syndrome with a prominent ketone body spectrum on magnetic resonance spectroscopy during acute exacerbation. A 6-month-old boy with mild motor developmental delay presented with disturbances of consciousness and hypercapnia without prior infection or feeding failure. Upon admission, investigations revealed prominent ketosis and elevated 2,3-dihydroxy-2-methylbutyric acid excretion. Brain magnetic resonance imaging revealed symmetrical T2 prolongation with restricted diffusion in the basal ganglia. Magnetic resonance spectroscopy showed a prominent ketone body spectrum in the cerebral white matter, and prominent ketone bodies, elevated lactate and markedly decreased N-acetylaspartate levels in the basal ganglia. Genetic analysis identified compound heterozygous variants of ECHS1. Short-chain enoyl-CoA hydratase deficiency is a disease for which a valine-restricted diet is reported to be beneficial, and early diagnosis is desirable. Severe ketosis and the ketone body magnetic resonance spectroscopy spectrum during acute exacerbation may aid in the diagnosis of this disease.

Keywords:  ECHS1; Ketosis; Leigh syndrome; Magnetic resonance spectroscopy; Metabolic encephalopathies

DOI:  https://doi.org/10.1016/j.radcr.2024.08.164
Nat Commun. 2024 Oct 07. 15(1): 8682

Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.

Lucia Del Prado, Myriam Jaraíz-Rodríguez, Mauro Agro, Marcos Zamora-Dorta, Natalia Azpiazu, Manuel Calleja, Mario Lopez-Manzaneda, Jaime de Juan-Sanz, Alba Fernández-Rodrigo, José A Esteban, Mònica Girona, Albert Quintana, Eduardo Balsa.

Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management.

DOI: https://doi.org/10.1038/s41467-024-52968-1
Biochem Biophys Res Commun. 2024 Sep 29. pii: S0006-291X(24)01302-0. [Epub ahead of print]734 150766

LDHB-deficient brain exhibits resistance to ischemic neuronal cell death due to increased vasodilation.

Jin Soo Lee, Bok Seon Yoon, Yihyang Kim, Chan Bae Park.

  Ischemic stroke triggers a cascade of metabolic and inflammatory events leading to neuronal death, particularly in the hippocampus. Here, we investigate the role of lactate metabolism in ischemic resistance using LDHB-deficient mice, which exhibit impaired lactate utilization. Contrary to expectations of severe neuronal damage due to metabolic defects, LDHB-deficient mice displayed significantly increased neuronal survival following ischemic insult. Magnetic resonance spectroscopy revealed elevated lactate levels in LDHB-deficient brains, which correlated with enhanced vasodilation of the posterior communicating artery (PComA) and increased extracellular PGE2 levels. These findings suggest that elevated lactate inhibits PGE2 reabsorption, promoting vasodilation and neuronal protection. Our results highlight lactate's potential role in neuroprotection and its therapeutic promise for ischemic stroke.

Keywords:  Ischemic stroke; Lactate; Lactate dehydrogenase B; Vasodilation

DOI:  https://doi.org/10.1016/j.bbrc.2024.150766
Ageing Res Rev. 2024 Oct 04. pii: S1568-1637(24)00342-8. [Epub ahead of print] 102524

Synaptic Mitochondria: a crucial factor in the aged hippocampus.

Karina A Cicali, Cheril Tapia-Rojas.

  Aging is a multifaceted biological process characterized by progressive molecular and cellular damage accumulation. The brain hippocampus undergoes functional deterioration with age, caused by cellular deficits, decreased synaptic communication, and neuronal death, ultimately leading to memory impairment. One of the factors contributing to this dysfunction is the loss of mitochondrial function. In neurons, mitochondria are categorized into synaptic and non-synaptic pools based on their location. Synaptic mitochondria, situated at the synapses, play a crucial role in maintaining neuronal function and synaptic plasticity, whereas non-synaptic mitochondria are distributed throughout other neuronal compartments, supporting overall cellular metabolism and energy supply. The proper function of synaptic mitochondria is essential for synaptic transmission as they provide the energy required and regulate calcium homeostasis at the communication sites between neurons. Maintaining the structure and functionality of synaptic mitochondria involves intricate processes, including mitochondrial dynamics such as fission, fusion, transport, and quality control mechanisms. These processes ensure that mitochondria remain functional, replace damaged organelles, and sustain cellular homeostasis at synapses. Notably, deficiencies in these mechanisms have been increasingly associated with aging and the onset of age-related neurodegenerative diseases. Synaptic mitochondria from the hippocampus are particularly vulnerable to age-related changes, including alterations in morphology and a decline in functionality, which significantly contribute to decreased synaptic activity during aging. This review comprehensively explores the critical roles that mitochondrial dynamics and quality control mechanisms play in preserving synaptic activity and neuronal function. It emphasizes the emerging evidence linking the deterioration of synaptic mitochondria to the aging process and the development of neurodegenerative diseases, highlighting the importance of these organelles from hippocampal neurons as potential therapeutic targets for mitigating cognitive decline and synaptic degeneration associated with aging. The novelty of this review lies in its focus on the unique vulnerability of hippocampal synaptic mitochondria to aging, underscoring their importance in maintaining brain function across the lifespan.

Keywords:  Aging; Cognitive Decline; Mitochondria; Mitochondrial Dysfunction; Non-synaptic; Synaptic

DOI:  https://doi.org/10.1016/j.arr.2024.102524
Brain Behav Immun. 2024 Oct 06. pii: S0889-1591(24)00645-7. [Epub ahead of print]

Analysis of the brain transcriptome, microbiome and metabolome in ketogenic diet and experimental stroke.

Anastasia A Zharikova, Nadezda V Andrianova, Denis N Silachev, Vladimir O Nebogatikov, Irina B Pevzner, Ciara I Makievskaya, Ljubava D Zorova, Grigoriy V Maleev, Galina V Baydakova, Dmitry V Chistyakov, Sergey V Goriainov, Marina G Sergeeva, Inna Y Burakova, Artem P Gureev, Vasily A Popkov, Aleksey A Ustyugov, Egor Y Plotnikov.

  The ketogenic diet (KD) has been shown to be effective in treating various brain pathologies. In this study, we conducted detailed transcriptomic and metabolomic profiling of rat brains after KD and ischemic stroke in order to investigate the effects of KD and its underlying mechanisms. We evaluated the effect of a two-month KD on gene expression in intact brain tissue and after middle cerebral artery occlusion (MCAO). We analyzed the effects of KD on gut microbiome composition and blood metabolic profile as well as investigated the correlation between severity of neurological deficits and KD-induced changes. We found transcriptional reprogramming in the brain after stroke and KD treatment. The KD altered the expression of genes involved in the regulation of glucose and fatty acid metabolism, mitochondrial function, the immune response, Wnt-associated signaling, stem cell development, and neurotransmission, both in intact rats and after MCAO. The KD led to a significant change in the composition of gut microbiome and the levels of amino acids, acylcarnitines, polyunsaturated fatty acids, and oxylipins in the blood. However, the KD slightly worsened the neurological functions after MCAO, so that the therapeutic effect of the diet remained unproven.

Keywords:  Intestine microbiota; Ketogenic diet; Metabolism; Neurologic deficit; RNA sequencing; Stroke

DOI:  https://doi.org/10.1016/j.bbi.2024.10.004
Psychiatry Res. 2024 Oct 02. pii: S0165-1781(24)00505-5. [Epub ahead of print]342 116220

Schizophrenia, a disease of impaired dynamic metabolic flexibility: A new mechanistic framework.

Zoltán Sarnyai, Dorit Ben-Shachar.

  Schizophrenia is a chronic, neurodevelopmental disorder with unknown aetiology and pathophysiology that emphasises the role of neurotransmitter imbalance and abnormalities in synaptic plasticity. The currently used pharmacological approach, the antipsychotic drugs, which have limited efficacy and an array of side-effects, have been developed based on the neurotransmitter hypothesis. Recent research has uncovered systemic and brain abnormalities in glucose and energy metabolism, focusing on altered glycolysis and mitochondrial oxidative phosphorylation. These findings call for a re-conceptualisation of schizophrenia pathophysiology as a progressing bioenergetics failure. In this review, we provide an overview of the fundamentals of brain bioenergetics and the changes identified in schizophrenia. We then propose a new explanatory framework positing that schizophrenia is a disease of impaired dynamic metabolic flexibility, which also reconciles findings of abnormal glucose and energy metabolism in the periphery and in the brain along the course of the disease. This evidence-based framework and testable hypothesis has the potential to transform the way we conceptualise this debilitating condition and to develop novel treatment approaches.

Keywords:  Aerobic glycolysis; Brain and periphery; Dynamic energy metabolism; Mitochondrial oxidative phosphorylation; Schizophrenia

DOI:  https://doi.org/10.1016/j.psychres.2024.116220
Cureus. 2024 Sep;16(9): e68697

Fueling Recovery: The Therapeutic Role of Ketogenic Diet in Neurological Pathologies.

Allah Yar Yahya Khan, Muhammad Asadullah Khalid Rana, Haseeb Mehmood Qadri, Arham Amir.

  The ketogenic diet (KD) has gained a lot of attraction in the management of neurological disorders. KD therapies are high-fat, low-carbohydrate diets intended to shift energy consumption and metabolism from carbohydrates to fat in ketogenesis. The oxidative phosphorylation of ketone bodies generates energy packets for body cells, especially the central nervous system, replacing the role of glucose. KD can benefit multiple neurologic disorders like migraine, motor neuron disease, autism, multiple sclerosis, neuro-oncology, drug-resistant epilepsy, and neurotrauma. KD can provide significant adjuncts to limited conventional therapies, highlighting the feasibility, safety, and potential efficacy in neurology and neurosurgical disease management.

Keywords:  brain; cancer; epilepsy; fat; keto diet; ketogenic; migraine; spine; traumatic brain injury; tumor

DOI:  https://doi.org/10.7759/cureus.68697
bioRxiv. 2024 Sep 24. pii: 2024.09.19.613684. [Epub ahead of print]

Sex-specific decline in prefrontal cortex mitochondrial bioenergetics in aging baboons correlates with walking speed.

Daniel A Adekunbi, Hillary F Huber, Gloria A Benavides, Ran Tian, Cun Li, Peter W Nathanielsz, Jianhua Zhang, Victor Darley-Usmar, Laura A Cox, Adam B Salmon.

Mitochondria play a crucial role in brain aging due to their involvement in bioenergetics, neuroinflammation and brain steroid synthesis. Mitochondrial dysfunction is linked to age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. We investigated changes in the activities of the electron transport chain (ETC) complexes in normally aging baboon brains and determined how these changes relate to donor sex, morning cortisol levels, and walking speed. Using a novel approach, we assessed mitochondrial bioenergetics from frozen prefrontal cortex (PFC) tissues from a large cohort (60 individuals) of well-characterized aging baboons (6.6-22.8 years, approximately equivalent to 26.4-91.2 human years). Aging was associated with a decline in mitochondrial ETC complexes in the PFC, which was more pronounced when activities were normalized for citrate synthase activity, suggesting that the decline in respiration is predominantly driven by changes in the specific activity of individual complexes rather than changes in mitochondrial number. Moreover, when donor sex was used as a covariate, we found that mitochondrial respiration was preserved with age in females, whereas males showed significant loss of ETC activity with age. Males had higher activities of each individual ETC complex and greater lactate dehydrogenase activity relative to females. Circulating cortisol levels correlated only with complex II-linked respiration in males. We also observed a robust positive predictive relationship between walking speed and respiration linked to complexes I, III, and IV in males but not in females. This data reveals a previously unknown link between aging and bioenergetics across multiple tissues linking frailty and bioenergetic function. This study highlights a potential molecular mechanism for sexual dimorphism in brain resilience and suggests that in males changes in PFC bioenergetics contribute to reduced motor function with age.

DOI: https://doi.org/10.1101/2024.09.19.613684
J Neuroinflammation. 2024 Oct 05. 21(1): 251

25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation.

Johnathan Romero, Danira Toral-Rios, Jinsheng Yu, Steven M Paul, Anil G Cashikar.

  Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers of neuroinflammation and, in response to different inflammatory stimuli, overexpress a proinflammatory signature of genes. Among these, Ch25h is a gene overexpressed in brain tissue from Alzheimer's disease as well as various mouse models of neuroinflammation. Ch25h encodes cholesterol 25-hydroxylase, an enzyme upregulated in activated microglia under conditions of neuroinflammation, that hydroxylates cholesterol to form 25-hydroxycholesterol (25HC). 25HC can be further metabolized to 7α,25-dihydroxycholesterol, which is a potent chemoattractant of leukocytes. We have previously shown that 25HC increases the production and secretion of the proinflammatory cytokine, IL-1β, by primary mouse microglia treated with lipopolysaccharide (LPS). In the present study, wildtype (WT) and Ch25h-knockout (KO) mice were peripherally administered LPS to induce an inflammatory state in the brain. In LPS-treated WT mice, Ch25h expression and 25HC levels increased in the brain relative to vehicle-treated WT mice. Among LPS-treated WT mice, females produced significantly higher levels of 25HC and showed transcriptomic changes reflecting higher levels of cytokine production and leukocyte migration than WT male mice. However, females were similar to males among LPS-treated KO mice. Ch25h-deficiency coincided with decreased microglial activation in response to systemic LPS. Proinflammatory cytokine production and intra-parenchymal infiltration of leukocytes were significantly lower in KO compared to WT mice. Amounts of IL-1β and IL-6 in the brain strongly correlated with 25HC levels. Our results suggest a proinflammatory role for 25HC in the brain following peripheral administration of LPS.

Keywords:  25-hydroxycholesterol; Alzheimer’s disease; Cholesterol-25-hydroxylase; Cytokines; Lipopolysaccharide; Microglial activation; Neuroinflammation; Neutrophil infiltration; Toll-like receptor-4

DOI:  https://doi.org/10.1186/s12974-024-03233-1
Hum Brain Mapp. 2024 Oct;45(14): e70039

Mapping Age Differences in Brain Energy Metabolites and Metabolic Markers of Cellular Membrane Production and Degradation With 31P Magnetic Resonance Spectroscopy.

Naftali Raz, Ana M Daugherty, Dalal Khatib, Cheryl L Dahle, Usha Rajan, Caroline Zajac-Benitez, Jeffrey A Stanley.

Using Phosphorus Magnetic Resonance Spectroscopy (31P MRS), we examined five metabolites associated with brain energy cycle, and cellular membrane production and degradation in 11 brain regions of 48 children (age 6-15), and 80 middle-aged and older adults (age 52-87). Levels of phosphomonoesters (PMEs) and phosphodiesters (PDEs), gamma plus alpha adenosine triphosphate (γαATP), phosphocreatine (PCr) and inorganic phosphate (Pi), were residualized on the total amplitude value. PMEs were greater in children compared to adults, whereas PDEs showed the opposite age difference. Higher γαATP and lower Pi were found in children compared to adults. The age group differences were particularly salient in the association cortices and anterior white matter. Among children, age correlated negatively with PMEs and positively with PDEs in association cortices. Compared to children, adults had lower intracellular pH. The results suggest reduction in membrane synthesis and increase in membrane degradation in adolescents and to a greater degree in adults compared to younger children. Concomitant reduction in γαATP and increase in Pi are consistent with reduced energy consumption in adolescents and further drop in middle-aged and older adults, although it is impossible to distinguish declines in energy supply from reduced demand due to shrinking neuropil, without longitudinal studies.

DOI: https://doi.org/10.1002/hbm.70039
Sci Rep. 2024 Oct 11. 14(1): 23828

Brain hypoxia and metabolic crisis are common in patients with acute brain injury despite a normal intracranial pressure.

Anton Lund, Anna Forsberg Madsen, Tenna Capion, Helene Ravnholt Jensen, Axel Forsse, John Hauerberg, Sigurður Þor Sigurðsson, Tiit Illimar Mathiesen, Kirsten Møller, Markus Harboe Olsen.

  Patients with acute brain injury are vulnerable to secondary deterioration, which may go undetected by traditional monitoring. However, multimodal neuromonitoring of brain tissue oxygen tension (PbtO2) and energy metabolism may be able to detect such episodes. We report a retrospective, observational study of 94 patients with aneurysmal subarachnoid haemorrhage (SAH) or traumatic brain injury (TBI) who underwent multimodal neuromonitoring during admission. We examined the co-occurrence of pathological neuromonitoring values: elevated intracranial pressure (ICP, > 20 mmHg), inadequate cerebral perfusion pressure (CPP, < 60 mmHg), brain hypoxia (PbtO2 < 20 mmHg), and metabolic crisis (lactate/pyruvate ratio > 40 and a glucose level < 0.2 mmol/L in cerebral microdialysate). Mixed effects linear regression demonstrated significant associations between abnormal ICP/CPP, cerebral hypoxia and metabolic crisis. However, brain hypoxia occurred in 40% and 31% of observations in patients with SAH and TBI, respectively, despite normal concurrent values of ICP. Similarly, metabolic crisis was observed in 8% and 16% of measurements for SAH and TBI, respectively, despite a normal ICP. The pattern was identical for CPP. In conclusion, although all neuromonitoring variables are interrelated, brain hypoxia and metabolic crisis are common despite an absence of abnormalities in conventional monitoring. Multimodal neuromonitoring may help identify such episodes and guide individualised treatment.

Keywords:  Brain hypoxia; Energy Metabolism; Intracranial hypertension; Intracranial pressure; Microdialysis; Oxygen; Subarachnoid hemorrhage; Traumatic brain Injury

DOI:  https://doi.org/10.1038/s41598-024-75129-2
Adv Biol Regul. 2024 Oct 01. pii: S2212-4926(24)00042-3. [Epub ahead of print] 101054

Upstream and downstream pathways of diacylglycerol kinase : Novel phosphatidylinositol turnover-independent signal transduction pathways.

Fumio Sakane, Chiaki Murakami, Hiromichi Sakai.

  Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprise ten isozymes (α-κ) that regulate a wide variety of physiological and pathological events. Recently, we revealed that DGK isozymes use saturated fatty acid (SFA)/monosaturated fatty acid (MUFA)-containing and docosahexaenoic acid (22:6)-containing DG species, but not phosphatidylinositol (PI) turnover-derived 18:0/20:4-DG. For example, DGKδ, which is involved in the pathogenesis of type 2 diabetes, preferentially uses SFA/MUFA-containing DG species, such as 16:0/16:0- and 16:0/18:1-DG species, in high glucose-stimulated skeletal muscle cells. Moreover, DGKδ, which destabilizes the serotonin transporter (SERT) and regulates the serotonergic system in the brain, primarily generates 18:0/22:6-PA. Furthermore, 16:0/16:0-PA is produced by DGKζ in Neuro-2a cells during neuronal differentiation. We searched for SFA/MUFA-PA- and 18:0/22:6-PA-selective binding proteins (candidate downstream targets of DGKδ) and found that SFA/MUFA-PA binds to and activates the creatine kinase muscle type, an energy-metabolizing enzyme, and that 18:0/22:6-PA interacts with and activates Praja-1, an E3 ubiquitin ligase acting on SERT, and synaptojanin-1, a key player in the synaptic vesicle cycle. Next, we searched for SFA/MUFA-DG-generating enzymes upstream of DGKδ. We found that sphingomyelin synthase (SMS)1, SMS2, and SMS-related protein (SMSr) commonly act as phosphatidylcholine (PC)-phospholipase C (PLC) and phosphatidylethanolamine (PE)-PLC, generating SFA/MUFA-DG species, in addition to SMS and ceramide phosphoethanolamine synthase. Moreover, the orphan phosphatase PHOSPHO1 showed PC- and PE-PLC activities that produced SFA/MUFA-DG. Although PC- and PE-PLC activities were first described 70-35 years ago, their proteins and genes were not identified for a long time. We found that DGKδ interacts with SMSr and PHOSPHO1, and that DGKζ binds to SMS1 and SMSr. Taken together, these results strongly suggest that there are previously unrecognized signal transduction pathways that include DGK isozymes and generate and utilize SFA/MUFA-DG/PA or 18:0/22:6-DG/PA but not PI-turnover-derived 18:0/20:4-DG/PA.

Keywords:  Cancer; Diabetes; Diacylglycerol kinase; PHOSPHO1; Parkinson's disease; Phosphatidic acid; Phosphatidylcholine-specific phospholipase C; Phosphatidylethanolamine-specific phospholipase C; Phosphatidylinositol turnover; Serotonin transporter; Sphingomyelin synthase

DOI:  https://doi.org/10.1016/j.jbior.2024.101054
bioRxiv. 2024 Sep 25. pii: 2024.09.23.614586. [Epub ahead of print]

Genetic analysis of the X-linked Adrenoleukodystrophy ABCD1 gene in Drosophila uncovers a role in Peroxisomal dynamics.

Joshua Manor, Sharayu V Jangam, Hyung-Lok Chung, Pranjali Bhagwat, Jonathan Andrews, Hillary Chester, Shu Kondo, Saurabh Srivastav, Juan Botas, Ann B Moser, Suzette M Huguenin, Michael F Wangler.

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder caused by a loss-of-function (LOF) mutation in the ATP-binding cassette subfamily D member 1 ( ABCD1) gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). This disorder exhibits striking heterogeneity; some male patients develop an early childhood neuroinflammatory demyelination disorder, while other patients, including adult males and most affected female carriers, experience a chronic progressive myelopathy. Adrenocortical failure is observed in almost all male patients, with age of onset varying sometimes being the first diagnostic finding. The gene underlying this spectrum of disease encodes an ATP-binding cassette (ABC) transporter that localizes to peroxisomes and facilitates VLCFA transport. X-ALD is considered a single peroxisomal component defect and does not play a direct role in peroxisome assembly. Drosophila models of other peroxisomal genes have provided mechanistic insight into some of the neurodegenerative mechanisms with reduced lifespan, retinal degeneration, and VLCFA accumulation. Here, we perform a genetic analysis of the fly ABCD1 ortholog Abcd1 (CG2316). Knockdown or deficiency of Abcd1 leads to VLCFA accumulation, salivary gland defects, locomotor impairment and retinal lipid abnormalities. Interestingly, there is also evidence of reduced peroxisomal numbers. Flies overexpressing the human cDNA for ABCD1 display a wing crumpling phenotype characteristic of the pex2 loss-of-function. Surprisingly, overexpression of human ABCD1 appears to inhibit or overwhelm peroxisomal biogenesis to levels similar to null mutations in fly pex2 , pex16 and pex3 . Drosophila Abcd1 is therefore implicated in peroxisomal number, and overexpression of the human ABCD1 gene acts a potent inhibitor of peroxisomal biogenesis in flies.

DOI: https://doi.org/10.1101/2024.09.23.614586
Ital J Pediatr. 2024 Oct 07. 50(1): 204

Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in Italy.

Francesco Porta, Arianna Maiorana, Vincenza Gragnaniello, Elena Procopio, Serena Gasperini, Roberta Taurisano, Marco Spada, Carlo Dionisi-Vici, Alberto Burlina.

   BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) are rare and potentially life-threatening diseases that cause deficient energy production and accumulation of toxic metabolites. Despite dietary management, adherence to maximum fasting guidelines, restricted long-chain triglyceride intake and supplementation with medium-chain triglyceride (MCT) oil (current standard of care), most patients experience recurrent decompensation episodes that can require hospitalisation. Herein, we analysed the effectiveness and safety of triheptanoin (a highly purified, synthetic medium odd-chain triglyceride) treatment in a cohort of Italian patients with LC-FAOD.
METHODS: This retrospective, nationwide study included nine patients with LC-FAOD who switched from standard therapy with MCT oil to triheptanoin oral liquid. Data were collected between 2018 and 2022. Clinical outcome measures were the number and duration of intercurrent catabolic episodes and number and duration of metabolic decompensation episodes requiring hospitalisation. Creatine kinase (CK) levels and treatment-related adverse effects were also reported.
RESULTS: Patients were provided a mean ± standard deviation (SD) triheptanoin dose of 1.5 ± 0.9 g/kg/day in four divided administrations, which accounted for 23.9 ± 8.9% of patients' total daily caloric intake. Triheptanoin treatment was started between 2.7 and 16 years of age and was continued for 2.2 ± 0.9 years. The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014), and annualised hospitalisation rates and duration. Mean CK levels (outside metabolic decompensation episodes) were lower with triheptanoin treatment versus MCT oil for seven patients. No intensive care unit admissions were required during triheptanoin treatment. Epigastric pain and diarrhoea were recorded as adverse effects during both MCT and triheptanoin treatment.
CONCLUSIONS: The significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD. Triheptanoin was well tolerated and decreased the number of intercurrent catabolic episodes, metabolic decompensation episodes requiring hospitalisation, and the annualised rate and duration of hospitalisations.

Keywords:  Inherited metabolic disorders; Long-chain fatty acid oxidation disorders; Medium-chain triglyceride oil; Triheptanoin

DOI:  https://doi.org/10.1186/s13052-024-01782-y