bims-medebr 2023-06-11 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒06‒11
twenty-one papers selected by
Regina F. Fernández
Johns Hopkins University

Targeted metabolomic analysis in Parkinson's disease brain frontal cortex and putamen with relation to cognitive impairment.
Systematic review of 31P-magnetic resonance spectroscopy studies of brain high energy phosphates and membrane phospholipids in aging and Alzheimer's disease.
Expression and subcellular localization of mitochondrial docking protein, syntaphilin, in oligodendrocytes and CNS myelin sheath.
ATP-Gated Potassium Channels Contribute to Ketogenic Diet-Mediated Analgesia in Mice.
Research Advances of Mitochondrial Dysfunction in Perioperative Neurocognitive Disorders.
Resolvin D1 reprograms energy metabolism to promote microglia to phagocytize neutrophils after ischemic stroke.
Mitochondrial dysfunction and oxidative stress in Alzheimer's disease, and Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis -An updated review.
NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport.
The Hypothalamus as a Key Regulator of Glucose Homeostasis: Emerging Roles of the Brain Renin-Angiotensin System.
Long-term follow-up of nutritional status in children with GLUT1 Deficiency Syndrome treated with classic ketogenic diet: a 5-year prospective study.
Mitophagy and long-term neuronal homeostasis.
Chronic stress-induced apoptosis is mitigated by young mitochondria transplantation in the prefrontal cortex of aged rats.
Apolipoprotein E intersects with amyloid-β within neurons.
Triheptanoin for the treatment of long-chain fatty acid oxidation disorders: Final results of an open-label, long-term extension study.
Spatiotemporal topological correspondence between blood oxygenation and glucose metabolism revealed by simultaneous fPET-fMRI in brain's white matter.
Role of 2-hydroxy acyl-CoA lyase HACL2 in odd-chain fatty acid production via α-oxidation in vivo.
PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport.
Lipids in Extracellular Vesicles: What Can Be Learned about Membrane Structure and Function?
Lactate Improves Long-term Cognitive Impairment Induced By Repeated Neonatal Sevoflurane Exposures Through SIRT1-mediated Regulation of Adult Hippocampal Neurogenesis and Synaptic Plasticity in Male Mice.
The cellular supply-side economics for phospholipids.
Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration.

NPJ Parkinsons Dis. 2023 Jun 03. 9(1): 84

Targeted metabolomic analysis in Parkinson's disease brain frontal cortex and putamen with relation to cognitive impairment.

Karel Kalecký, Teodoro Bottiglieri.

We performed liquid chromatography tandem mass spectrometry analysis with the targeted metabolomic kit Biocrates MxP Quant 500, in human brain cortex (Brodmann area 9) and putamen, to reveal metabolic changes characteristic of Parkinson's disease (PD) and PD-related cognitive decline. This case-control study involved 101 subjects (33 PD without dementia, 32 PD with dementia (cortex only), 36 controls). We found changes associated with PD, cognitive status, levodopa levels, and disease progression. The affected pathways include neurotransmitters, bile acids, homocysteine metabolism, amino acids, TCA cycle, polyamines, β-alanine metabolism, fatty acids, acylcarnitines, ceramides, phosphatidylcholines, and several microbiome-derived metabolites. Previously reported levodopa-related homocysteine accumulation in cortex still best explains the dementia status in PD, which can be modified by dietary supplementation. Further investigation is needed to reveal the exact mechanisms behind this pathological change.

DOI: https://doi.org/10.1038/s41531-023-00531-y
Front Aging Neurosci. 2023 ;15 1183228

Systematic review of 31P-magnetic resonance spectroscopy studies of brain high energy phosphates and membrane phospholipids in aging and Alzheimer's disease.

Steven Jett, Camila Boneu, Camila Zarate, Caroline Carlton, Vibha Kodancha, Matilde Nerattini, Michael Battista, Silky Pahlajani, Schantel Williams, Jonathan P Dyke, Lisa Mosconi.

  Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial dysfunction, cerebral energy dysmetabolism and oxidative damage increase with age, and are early event in AD pathophysiology and may precede amyloid beta (Aβ) plaques. In vivo probes of mitochondrial function and energy metabolism are therefore crucial to characterize the bioenergetic abnormalities underlying AD risk, and their relationship to pathophysiology and cognition. A majority of the research conducted in humans have used 18F-fluoro-deoxygluose (FDG) PET to image cerebral glucose metabolism (CMRglc), but key information regarding oxidative phosphorylation (OXPHOS), the process which generates 90% of the energy for the brain, cannot be assessed with this method. Thus, there is a crucial need for imaging tools to measure mitochondrial processes and OXPHOS in vivo in the human brain. 31Phosphorus-magnetic resonance spectroscopy (31P-MRS) is a non-invasive method which allows for the measurement of OXPHOS-related high-energy phosphates (HEP), including phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi), in addition to potential of hydrogen (pH), as well as components of phospholipid metabolism, such as phosphomonoesters (PMEs) and phosphodiesters (PDEs). Herein, we provide a systematic review of the existing literature utilizing the 31P-MRS methodology during the normal aging process and in patients with mild cognitive impairment (MCI) and AD, with an additional focus on individuals at risk for AD. We discuss the strengths and limitations of the technique, in addition to considering future directions toward validating the use of 31P-MRS measures as biomarkers for the early detection of AD.

Keywords:  APOE; Alzheimer's disease; aging; brain metabolic imaging; dementia; phosphorous-31 magnetic resonance spectroscopy; sex difference; systematic review

DOI:  https://doi.org/10.3389/fnagi.2023.1183228
Glia. 2023 Jun 05.

Expression and subcellular localization of mitochondrial docking protein, syntaphilin, in oligodendrocytes and CNS myelin sheath.

Diane S Nakamura, Jean-David M Gothié, Samantha F Kornfeld, Rashmi Kothary, Timothy E Kennedy.

  Oligodendrocytes produce lipid-rich myelin sheaths that provide metabolic support to the underlying axon and facilitate saltatory conduction. Oligodendrocyte mitochondria supply the bulk of energy and carbon-chain backbones required for lipid synthesis. The sparsity of mitochondria in the myelin sheath suggests that tight regulation of mitochondrial trafficking is crucial for their efficient distribution in the cell. In particular, retention of mitochondria at axoglial junctions would support local lipid synthesis and membrane remodeling during myelination. How mitochondrial docking in oligodendrocytes is regulated is not known. Our findings indicate that syntaphilin (SNPH), a mitochondrial docking protein that has been characterized in neurons, is expressed by oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes in vitro and present in the myelin sheath in vivo. We have previously reported that bath application of netrin-1 promotes the elaboration of myelin basic protein-positive membranes, and that localized presentation of a netrin-1 coated microbead results in rapid accumulation of mitochondria at the site of oligodendrocyte-bead adhesion. Here we show that netrin-1 increases the redistribution of SNPH to oligodendrocyte processes during the expansion of myelin basic protein-positive membranes and that SNPH clusters at the oligodendrocyte plasma membrane at sites of adhesion with netrin-1-coated beads where mitochondria are retained. These findings suggest roles for SNPH in oligodendrocytes regulating netrin-1-mediated mitochondrial docking and myelin membrane expansion.

Keywords:  docking; mitochondria; myelin; netrin; oligodendrocyte; syntaphilin; trafficking

DOI:  https://doi.org/10.1002/glia.24425
bioRxiv. 2023 May 24. pii: 2023.05.22.541799. [Epub ahead of print]

ATP-Gated Potassium Channels Contribute to Ketogenic Diet-Mediated Analgesia in Mice.

Jonathan D Enders, Sarah Thomas, Paige Lynch, Jarrid Jack, Janelle M Ryals, Patrycja Puchalska, Peter Crawford, Douglas E Wright.

Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (K ATP ) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a K ATP channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of K ATP channels with the K ATP channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK + cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of K ATP channels to provide ketogenic diet-related analgesia. This study also identifies K ATP channels as a new target to mimic the antinociceptive effects of a ketogenic diet.

DOI: https://doi.org/10.1101/2023.05.22.541799
Neurochem Res. 2023 Jun 09.

Research Advances of Mitochondrial Dysfunction in Perioperative Neurocognitive Disorders.

Mengjie Chen, Ruyu Yan, Lingling Ding, Jiansheng Luo, Jiaqi Ning, Ruiling Zhou.

  Perioperative neurocognitive disorders (PND) increases postoperative dementia and mortality in patients and has no effective treatment. Although the detailed pathogenesis of PND is still elusive, a large amount of evidence suggests that damaged mitochondria may play an important role in the pathogenesis of PND. A healthy mitochondrial pool not only provides energy for neuronal metabolism but also maintains neuronal activity through other mitochondrial functions. Therefore, exploring the abnormal mitochondrial function in PND is beneficial for finding promising therapeutic targets for this disease. This article summarizes the research advances of mitochondrial energy metabolism disorder, inflammatory response and oxidative stress, mitochondrial quality control, mitochondria-associated endoplasmic reticulum membranes, and cell death in the pathogenesis of PND, and briefly describes the application of mitochondria-targeted therapies in PND.

Keywords:  Anesthesia/surgery; Inflammation; Mitochondrial dynamics; Mitochondrial dysfunction; Oxidative stress; Perioperative neurocognitive disorders

DOI:  https://doi.org/10.1007/s11064-023-03962-4
Cell Rep. 2023 Jun 06. pii: S2211-1247(23)00628-9. [Epub ahead of print]42(6): 112617

Resolvin D1 reprograms energy metabolism to promote microglia to phagocytize neutrophils after ischemic stroke.

Lei Li, Shu-Qi Cheng, Yu-Qin Sun, Jian-Bing Yu, Xin-Xin Huang, Yin-Feng Dong, Juan Ji, Xi-Yue Zhang, Gang Hu, Xiu-Lan Sun.

  Neutrophil aggregation and clearance are important factors affecting neuroinflammatory injury during acute ischemic stroke. Emerging evidence suggests that energy metabolism is essential for microglial functions, especially microglial phagocytosis, which determines the degree of brain injury. Here, we demonstrate that Resolvin D1 (RvD1), a lipid mediator derived from docosahexaenic acid (DHA), promotes the phagocytosis of neutrophils by microglia, thereby reducing neutrophil accumulation in the brain and alleviating neuroinflammation in the ischemic brain. Further studies reveal that RvD1 reprograms energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS), providing sufficient energy for microglial phagocytosis. Moreover, RvD1 enhances microglial glutamine uptake and stimulates glutaminolysis to support OXPHOS to boost ATP production depending on adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Overall, our results reveal that RvD1 reprograms energy metabolism to promote the microglial phagocytosis of neutrophils after ischemic stroke. These findings may guide perspectives for stroke therapy from modulating microglial immunometabolism.

Keywords:  CP: Immunology; Resolvin D1; immunometabolism; ischemic stroke; microglia; neutrophil; phagocytosis; reprogram energy metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.112617
Mitochondrion. 2023 Jun 01. pii: S1567-7249(23)00051-X. [Epub ahead of print]

Mitochondrial dysfunction and oxidative stress in Alzheimer's disease, and Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis -An updated review.

Taha Alqahtani, Sharada L Deore, Anjali A Kide, Bhavana A Shende, Ritika Sharma, Rita Dadarao Chakole, Lalita S Nemade, Nikita Kishor Kale, Sudarshana Borah, Savita Shrikant Deokar, Ashok Behera, Divya Dhawal Bhandari, Nikita Gaikwad, Abul Kalam Azad, Arabinda Ghosh.

  Misfolded proteins in the central nervous system can induce oxidative damage, which can contribute to neurodegenerative diseases in the mitochondria. Neurodegenerative patients face early mitochondrial dysfunction, impacting energy utilization. Amyloid-ß and tau problems both have an effect on mitochondria, which leads to mitochondrial malfunction and, ultimately, the onset of Alzheimer's disease. Cellular oxygen interaction yields reactive oxygen species within mitochondria, initiating oxidative damage to mitochondrial constituents. Parkinson's disease, linked to oxidative stress, α-synuclein aggregation, and inflammation, results from reduced brain mitochondria activity. Mitochondrial dynamics profoundly influence cellular apoptosis via distinct causative mechanisms. The condition known as Huntington's disease is characterized by an expansion of polyglutamine, primarily impactingthe cerebral cortex and striatum. Research has identified mitochondrial failure as an early pathogenic mechanism contributing to HD's selective neurodegeneration. The mitochondria are organelles that exhibit dynamism by undergoing fragmentation and fusion processes to attain optimal bioenergetic efficiency. They can also be transported along microtubules and regulateintracellular calcium homeostasis through their interaction with the endoplasmic reticulum. Additionally, the mitochondria produce free radicals. The functions of eukaryotic cells, particularly in neurons, have significantly deviated from the traditionally assigned role of cellular energy production. Most of them areimpaired in HD, which may lead to neuronal dysfunction before symptoms manifest. This article summarises the most important changes in mitochondrial dynamics that come from neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's and Amyotrophic Lateral Sclerosis. Finally, we discussed about novel techniques that can potentially treat mitochondrial malfunction and oxidative stress in four most dominating neuro disorders.

Keywords:  Alzheimer's diseases; Amyotrophic Lateral Sclerosis; Huntington's diseases; Mitochondrial dysfunction; Parkinson's diseases

DOI:  https://doi.org/10.1016/j.mito.2023.05.007
Res Sq. 2023 May 19. pii: rs.3.rs-2859584. [Epub ahead of print]

NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport.

Sen Yang, Zhen-Xian Niou, Andrea Enriquez, Jacob LaMar, Jui-Yen Huang, Karen Ling, Paymaan Jafar-Nejad, Jonathan Gilley, Michael P Coleman, Jason M Tennessen, Vidhya Rangaraju, Hui-Chen Lu.

Background Bioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) in CNS neurons. NMNAT2 mRNA levels are reduced in the brains of Alzheimer's, Parkinson's, and Huntington's disease. Here we addressed whether NMNAT2 is required for axonal health of cortical glutamatergic neurons, whose long-projecting axons are often vulnerable in neurodegenerative conditions. We also tested if NMNAT2 maintains axonal health by ensuring axonal ATP levels for axonal transport, critical for axonal function. Methods We generated mouse and cultured neuron models to determine the impact of NMNAT2 loss from cortical glutamatergic neurons on axonal transport, energetic metabolism, and morphological integrity. In addition, we determined if exogenous NAD supplementation or inhibiting a NAD hydrolase, sterile alpha and TIR motif-containing protein 1 (SARM1), prevented axonal deficits caused by NMNAT2 loss. This study used a combination of genetics, molecular biology, immunohistochemistry, biochemistry, fluorescent time-lapse imaging, live imaging with optical sensors, and anti-sense oligos. Results We provide in vivo evidence that NMNAT2 in glutamatergic neurons is required for axonal survival. Using in vivo and in vitro studies, we demonstrate that NMNAT2 maintains the NAD-redox potential to provide "on-board" ATP via glycolysis to vesicular cargos in distal axons. Exogenous NAD + supplementation to NMNAT2 KO neurons restores glycolysis and resumes fast axonal transport. Finally, we demonstrate both in vitro and in vivo that reducing the activity of SARM1, an NAD degradation enzyme, can reduce axonal transport deficits and suppress axon degeneration in NMNAT2 KO neurons. Conclusion NMNAT2 ensures axonal health by maintaining NAD redox potential in distal axons to ensure efficient vesicular glycolysis required for fast axonal transport.

DOI: https://doi.org/10.21203/rs.3.rs-2859584/v1
Am J Physiol Cell Physiol. 2023 Jun 05.

The Hypothalamus as a Key Regulator of Glucose Homeostasis: Emerging Roles of the Brain Renin-Angiotensin System.

Shiyue Pan, Caleb J Worker, Yumei Feng Earley.

  The regulation of plasma glucose levels is a complex and multifactorial process involving a network of receptors and signaling pathways across numerous organs that act in concert to ensure homeostasis. However, much about the mechanisms and pathways by which the brain regulates glycemic homeostasis remains poorly understood. Understanding the precise mechanisms and circuits employed by the central nervous system to control glucose is critical to resolving the diabetes epidemic. The hypothalamus, a key integrative center within the central nervous system, has recently emerged as a critical site in the regulation of glucose homeostasis. Here, we review the current understanding of the role of the hypothalamus in regulating glucose homeostasis, with an emphasis on the paraventricular nucleus, the arcuate nucleus, the ventromedial hypothalamus, and lateral hypothalamus. In particular, we highlight the emerging role of the brain renin-angiotensin system in the hypothalamus in regulating energy expenditure and metabolic rate, as well as its potential importance in the regulation of glucose homeostasis.

Keywords:  (pro)renin receptor; central nervous system; glucose; type 2 diabetes mellitus

DOI:  https://doi.org/10.1152/ajpcell.00533.2022
Front Nutr. 2023 ;10 1148960

Long-term follow-up of nutritional status in children with GLUT1 Deficiency Syndrome treated with classic ketogenic diet: a 5-year prospective study.

Ramona De Amicis, Alessandro Leone, Marta Pellizzari, Andrea Foppiani, Alberto Battezzati, Chiara Lessa, Anna Tagliabue, Cinzia Ferraris, Valentina De Giorgis, Sara Olivotto, Roberto Previtali, Pierangelo Veggiotti, Simona Bertoli.

  Introduction: The classic ketogenic diet (cKD) is an isocaloric, high fat, low-carbohydrate diet that induces the production of ketone bodies. High consumption of dietary fatty acids, particularly long-chain saturated fatty acids, could impair nutritional status and increase cardiovascular risk. The purpose of this study was to evaluate the long-term effects of a 5-year cKD on body composition, resting energy expenditure, and biochemical parameters in children affected by Glucose Transporter 1 Deficiency Syndrome (GLUT1DS).Methods: This was a prospective, multicenter, 5-year longitudinal study of children with GLUT1DS treated with a cKD. The primary outcome was to assess the change in nutritional status compared with pre-intervention, considering anthropometric measurements, body composition, resting energy expenditure, and biochemical parameters such as glucose and lipid profiles, liver enzymes, uric acid, creatinine, and ketonemia. Assessments were conducted at pre-intervention and every 12 months of cKD interventions.
Results: Ketone bodies increased significantly in children and adolescents, and remained stable at 5 years, depending on the diet. No significant differences were reported in anthropometric and body composition standards, as well as in resting energy expenditure and biochemical parameters. Bone mineral density increased significantly over time according to increasing age. Body fat percentage significantly and gradually decreased in line with the increase in body weight and the consequent growth in lean mass. As expected, we observed a negative trend in respiratory quotient, while fasting insulin and insulin resistance were found to decrease significantly after cKD initiation.
Conclusion: Long-term adherence to cKD showed a good safety profile on anthropometric measurements, body composition, resting energy expenditure, and biochemical parameters, and we found no evidence of potential adverse effects on the nutritional status of children and adolescents.

Keywords:  GLUT1-Deficiency Syndrome; body composition; energy expenditure; ketogenic diet; long-term effect; nutritional status

DOI:  https://doi.org/10.3389/fnut.2023.1148960
J Cell Sci. 2023 Jun 01. pii: jcs260638. [Epub ahead of print]136(11):

Mitophagy and long-term neuronal homeostasis.

Maria Markaki, Dikaia Tsagkari, Nektarios Tavernarakis.

  Neurons are highly polarized, post-mitotic cells that are characterized by unique morphological diversity and complexity. As highly differentiated cells that need to survive throughout organismal lifespan, neurons face exceptional energy challenges in time and space. Therefore, neurons are heavily dependent on a healthy mitochondrial network for their proper function and maintenance under both physiological and stress conditions. Multiple quality control systems have evolved to fine-tune mitochondrial number and quality, thus preserving neuronal energy homeostasis. Here, we review the contribution of mitophagy, a selective form of autophagy that targets dysfunctional or superfluous mitochondria for degradation, in maintaining nervous system homeostasis. In addition, we discuss recent evidence implicating defective or dysregulated mitophagy in the pathogenesis of neurodegenerative diseases.

Keywords:  Autophagy; Energy homeostasis; Mitochondria; Mitophagy; Nervous system; Neurodegeneration; Neurodegenerative diseases; Neuron; Non-neuronal cells

DOI:  https://doi.org/10.1242/jcs.260638
Iran J Basic Med Sci. 2023 ;26(6): 725-730

Chronic stress-induced apoptosis is mitigated by young mitochondria transplantation in the prefrontal cortex of aged rats.

Gonja Javani, Arshad Ghaffari-Nasab, Fereshteh Farajdokht, Gisou Mohaddes.

  Objectives: Apoptosis is common and often comorbid with aging and stress-related mood disorders. Evidence suggests that fresh mitochondria could reverse age-related dysfunctions in organs, especially in the brain. Therefore, this study investigated the effect of young mitochondria administration on the apoptosis process in the prefrontal cortex (PFC) of aged rats exposed to chronic stress.Materials and Methods: Aged (22 months old) male rats were randomly assigned into four groups: aged control (AC), aged rats treated with young mitochondria (A+M), aged rats subjected to chronic stress for four weeks (A+St), and aged rats subjected to chronic stress and treated with young mitochondria (A+St+M). A+M and A+St+M groups received a single ICV injection (10 μl) of fresh mitochondria isolated from the brain of young rats for five minutes (2 µl/min). Finally, the levels of Malondialdehyde (MDA), Cytochrome c (Cyt c), Bax, Bcl-2, and Caspase-3 expression were investigated in the PFC.
Results: Young mitochondria administration reduced neuronal apoptosis in the PFC, associated with down-regulation of MDA, Bax, and Caspase-3 and up-regulation of Bcl-2. Moreover, fresh mitochondria partially improved the chronic stress-induced mitochondrial dysfunction in aged rats, as indicated by reduced cytochrome c (Cyt c) release from the mitochondria.
Conclusion: These results suggest mitotherapy could reverse cell viability and mitochondrial dysfunction-induced apoptosis in the PFC tissue of aged rats subjected to stressful stimuli.

Keywords:  Aging; Apoptosis; Chronic stress; Mitochondria; Oxidative stress; Rats

DOI:  https://doi.org/10.22038/IJBMS.2023.69551.15145
Life Sci Alliance. 2023 Aug;pii: e202201887. [Epub ahead of print]6(8):

Apolipoprotein E intersects with amyloid-β within neurons.

Sabine C Konings, Emma Nyberg, Isak Martinsson, Laura Torres-Garcia, Oxana Klementieva, Claudia Guimas Almeida, Gunnar K Gouras.

Apolipoprotein E4 (ApoE4) is the most important genetic risk factor for Alzheimer's disease (AD). Among the earliest changes in AD is endosomal enlargement in neurons, which was reported as enhanced in ApoE4 carriers. ApoE is thought to be internalized into endosomes of neurons, whereas β-amyloid (Aβ) accumulates within neuronal endosomes early in AD. However, it remains unknown whether ApoE and Aβ intersect intracellularly. We show that internalized astrocytic ApoE localizes mostly to lysosomes in neuroblastoma cells and astrocytes, whereas in neurons, it preferentially localizes to endosomes-autophagosomes of neurites. In AD transgenic neurons, astrocyte-derived ApoE intersects intracellularly with amyloid precursor protein/Aβ. Moreover, ApoE4 increases the levels of endogenous and internalized Aβ42 in neurons. Taken together, we demonstrate differential localization of ApoE in neurons, astrocytes, and neuron-like cells, and show that internalized ApoE intersects with amyloid precursor protein/Aβ in neurons, which may be of considerable relevance to AD.

DOI: https://doi.org/10.26508/lsa.202201887
J Inherit Metab Dis. 2023 Jun 05.

Triheptanoin for the treatment of long-chain fatty acid oxidation disorders: Final results of an open-label, long-term extension study.

Jerry Vockley, Barbara K Burton, Gerard Berry, Nicola Longo, John Phillips, Amarilis Sanchez-Valle, Kimberly A Chapman, Pranoot Tanpaiboon, Stephanie Grunewald, Elaine Murphy, Xiaoxiao Lu, Syeda Rahman, Kathryn Ray, Bridget Reineking, Laura Pisani, Antonio Nino Ramirez.

  Long-chain fatty acid oxidation disorders (LC-FAODs) result in life-threatening energy metabolism deficiencies/energy source depletion. Triheptanoin is an odd-carbon, medium chain triglyceride (that is an anaplerotic substrate of calories and fatty acids) for treating pediatric and adult patients with LC-FAODs. Study CL202 (NCT02214160), an open-label extension study of study CL201 (NCT01886378), evaluated the long-term safety/efficacy of triheptanoin in patients with LC-FAODs (N = 94), including cohorts who were triheptanoin naïve (n = 33) or had received triheptanoin in study CL201 (n = 24) or in investigator-sponsored trials/expanded access programs (IST/EAPs; n = 37). Primary endpoint was the annualized rate of LC-FAOD major clinical events (MCEs; rhabdomyolysis, hypoglycemia, cardiomyopathy). Mean±standard deviation (SD) triheptanoin treatment durations were 27.4±19.9, 46.9±13.6, and 49.6±21.4 months for the triheptanoin-naïve, CL201 rollover, and IST/EAP cohorts, respectively. In the triheptanoin-naïve cohort, median (interquartile range [IQR]) MCE rate significantly decreased from 2.00 (0.67-3.33) events/patient/year pre-triheptanoin to 0.28 (0.00-1.43) events/patient/year with triheptanoin (p = 0.0343), a reduction of 86%. In the CL201 rollover cohort, mean±SD MCE rate significantly decreased from 1.76±1.64 events/patient/year pre-triheptanoin to 1.00±1.00 events/patient/year with triheptanoin (p = 0.0347), a reduction of 43%. In the IST/EAP cohort, mean±SD MCE rate was 1.40±2.37 (median [IQR] 0.57 [0.00-1.67]) events/patient/year with triheptanoin. Safety data were consistent with previous observations. Treatment-related treatment-emergent adverse events (TEAEs) occurred in 68.1% of patients and were mostly mild/moderate in severity. Five patients had 7 serious treatment-related TEAEs; all resolved. Our results confirm the long-term efficacy of triheptanoin for patients with LC-FAOD. This article is protected by copyright. All rights reserved.

Keywords:  cardiomyopathy; hypoglycemia; long-chain fatty acid oxidation disorders; rhabdomyolysis; triheptanoin (Dojolvi®)

DOI:  https://doi.org/10.1002/jimd.12640
Cereb Cortex. 2023 Jun 06. pii: bhad201. [Epub ahead of print]

Spatiotemporal topological correspondence between blood oxygenation and glucose metabolism revealed by simultaneous fPET-fMRI in brain's white matter.

Jiao Li, Guo-Rong Wu, Mengyuan Shi, Jie Xia, Yao Meng, Siqi Yang, Huafu Chen, Wei Liao.

  White matter (WM) makes up half of the human brain. Compelling functional MRI evidence indicates that white matter exhibits neural activation and synchronization via a hemodynamic window. However, the neurometabolic underpinnings of white matter temporal synchronization and spatial topology remain unknown. By leveraging concurrent [18F]FDG-fPET and blood-oxygenation-level-dependent-fMRI, we demonstrated the temporal and spatial correspondences between blood oxygenation and glucose metabolism in the human brain white matter. In the temporal scale, we found that blood-oxygenation-level-dependent signals shared mutual information with FDG signals in the default-mode, visual, and sensorimotor-auditory networks. For spatial distribution, the blood-oxygenation-level-dependent functional networks in white matter were accompanied by substantial correspondence of FDG functional connectivity at different topological scales, including degree centrality and global gradients. Furthermore, the content of blood-oxygenation-level-dependent fluctuations in the white matter default-mode network was aligned and liberal with the FDG graph, suggesting the freedom of default-mode network neuro-dynamics, but the constraint by metabolic dynamics. Moreover, the dissociation of the functional gradient between blood-oxygenation-level-dependent and FDG connectivity specific to the white matter default-mode network revealed functional heterogeneities. Together, the results showed that brain energy metabolism was closely coupled with blood oxygenation in white matter. Comprehensive and complementary information from fMRI and fPET might therefore help decode brain white matter functions.

Keywords:  default mode; neurometabolic; simultaneous fPET-fMRI; topological correspondence; white matter

DOI:  https://doi.org/10.1093/cercor/bhad201
Mol Biol Cell. 2023 Jun 07. mbcE23020042

Role of 2-hydroxy acyl-CoA lyase HACL2 in odd-chain fatty acid production via α-oxidation in vivo.

Keisuke Mori, Tatsuro Naganuma, Akio Kihara.

Although most fatty acids (FAs) are even chain, certain tissues, including brain, contain relatively large quantities of odd-chain FAs in their sphingolipids. One of the pathways producing odd-chain FAs is the α-oxidation of 2-hydroxy (2-OH) FAs, where 2-OH acyl-CoA lyases (HACL1 and HACL2) catalyze the key cleavage reaction. However, the contribution of each HACL to odd-chain FA production in vivo remains unknown. Here, we found that HACL2 and HACL1 play major roles in the α-oxidation of 2-OH FAs (especially very-long-chain types) and 3-methyl FAs (other α-oxidation substrates), respectively, using ectopic expression systems of human HACL2 and HACL1 in yeast and analyzing Hacl1 and/or Hacl2 knockout (KO) CHO-K1 cells. We then generated Hacl2 KO mice and measured the quantities of odd-chain and 2-OH lipids (free FAs and sphingolipids [ceramides, sphingomyelins, and monohexosylceramides]) in 17 tissues. We observed fewer odd-chain lipids and more 2-OH lipids in many tissues of Hacl2 KO mice than in wild-type mice, and of these differences the reductions were most prominent for odd-chain monohexosylceramides in the brain and ceramides in the stomach. These results indicate that HACL2-involved α-oxidation of 2-OH FAs is mainly responsible for odd-chain FA production in the brain and stomach.

DOI: https://doi.org/10.1091/mbc.E23-02-0042
Dev Cell. 2023 Jun 02. pii: S1534-5807(23)00239-3. [Epub ahead of print]

PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport.

Gregory E Miner, Christina M So, Whitney Edwards, Joey V Ragusa, Jonathan T Wine, Daniel Wong Gutierrez, Michael V Airola, Laura E Herring, Rosalind A Coleman, Eric L Klett, Sarah Cohen.

  Cells adjust their metabolism by remodeling membrane contact sites that channel metabolites to different fates. Lipid droplet (LD)-mitochondria contacts change in response to fasting, cold exposure, and exercise. However, their function and mechanism of formation have remained controversial. We focused on perilipin 5 (PLIN5), an LD protein that tethers mitochondria, to probe the function and regulation of LD-mitochondria contacts. We demonstrate that efficient LD-to-mitochondria fatty acid (FA) trafficking and ß-oxidation during starvation of myoblasts are promoted by phosphorylation of PLIN5 and require an intact PLIN5 mitochondrial tethering domain. Using human and murine cells, we further identified the acyl-CoA synthetase, FATP4 (ACSVL4), as a mitochondrial interactor of PLIN5. The C-terminal domains of PLIN5 and FATP4 constitute a minimal protein interaction capable of inducing organelle contacts. Our work suggests that starvation leads to phosphorylation of PLIN5, lipolysis, and subsequent channeling of FAs from LDs to FATP4 on mitochondria for conversion to fatty-acyl-CoAs and subsequent oxidation.

Keywords:  FATP4; PLIN5; acyl-CoA; fatty acids; lipid droplets; membrane contact sites; metabolism; mitochondria; organelles

DOI:  https://doi.org/10.1016/j.devcel.2023.05.006
Cold Spring Harb Perspect Biol. 2023 Jun 05. pii: a041415. [Epub ahead of print]

Lipids in Extracellular Vesicles: What Can Be Learned about Membrane Structure and Function?

Tore Skotland, Alicia Llorente, Kirsten Sandvig.

Extracellular vesicles, such as exosomes, can be used as interesting models to study the structure and function of biological membranes as these vesicles contain only one membrane (i.e., one lipid bilayer). In addition to lipids, they contain proteins, nucleic acids, and various other molecules. The lipid composition of exosomes is here compared to HIV particles and detergent-resistant membranes, which also have a high content of sphingolipids, cholesterol, and phosphatidylserine (PS). We discuss interactions between the lipids in the two bilayers, and especially those between PS 18:0/18:1 in the inner leaflet and the very-long-chain sphingolipids in the outer leaflet, and the importance of cholesterol for these interactions. We also briefly discuss the involvement of ether-linked phospholipids (PLs) in such lipid raft-like structures, and the possible involvement of these and other lipid classes in the formation of exosomes. The urgent need to improve the quality of quantitative lipidomic studies is highlighted.

DOI: https://doi.org/10.1101/cshperspect.a041415
Mol Neurobiol. 2023 Jun 07.

Lactate Improves Long-term Cognitive Impairment Induced By Repeated Neonatal Sevoflurane Exposures Through SIRT1-mediated Regulation of Adult Hippocampal Neurogenesis and Synaptic Plasticity in Male Mice.

Li-Li Qiu, Xiao-Xiang Tan, Jiao-Jiao Yang, Mu-Huo Ji, Hui Zhang, Chunjie Zhao, Jiang-Yan Xia, Jie Sun.

  Repeated neonatal exposures to sevoflurane induce long-term cognitive impairment that has been reported to have sex-dependent differences. Exercise promotes learning and memory by releasing lactate from the muscle. The study tested the hypothesis that lactate may improve long-term cognitive impairment induced by repeated neonatal exposures to sevoflurane through SIRT1-mediated regulation of adult hippocampal neurogenesis and synaptic plasticity. C57BL/6 mice of both genders were exposed to 3% sevoflurane for 2 h daily from postnatal day 6 (P6) to P8. In the intervention experiments, mice received lactate at 1 g/kg intraperitoneally once daily from P21 to P41. Behavioral tests including open field (OF), object location (OL), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function. The number of 5-Bromo-2'- deoxyuridine positive (BrdU+) cells and BrdU+/DCX+ (doublecortin) co-labeled cells, expressions of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), early growth response 1 (Egr-1), SIRT1, PGC-1α and FNDC5, and long-term potentiation (LTP) were evaluated in the hippocampus. Repeated exposures to sevoflurane induced deficits in OL, NOR and contextual FC tests in male but not female mice. Similarly, adult hippocampal neurogenesis, synaptic plasticity-related proteins and hippocampal LTP were impaired after repeated exposures to sevoflurane in male but not female mice, which could rescue by lactate treatment. Our study suggests that repeated neonatal exposures to sevoflurane inhibit adult hippocampal neurogenesis and induce defects of synaptic plasticity in male but not female mice, which may contribute to long-term cognitive impairment. Lactate treatment rescues these abnormalities through activation of SIRT1.

Keywords:  Adult hippocampal neurogenesis; Lactate; Neonatal; SIRT1; Sevoflurane; Synaptic plasticity

DOI:  https://doi.org/10.1007/s12035-023-03413-9
Cell Metab. 2023 Jun 06. pii: S1550-4131(23)00181-X. [Epub ahead of print]35(6): 909-911

The cellular supply-side economics for phospholipids.

Alvin C Y Kuk, David L Silver.

Choline is an essential nutrient, but how cells acquire it was not known. Two studies by Kenny et al. and Tsuchiya et al. identified the plasma membrane proteins FLVCR1 and FLVCR2 to be the bona fide choline transporters mediating choline uptake for de novo synthesis of phospholipids in all cells.

DOI: https://doi.org/10.1016/j.cmet.2023.05.004
Nat Commun. 2023 Jun 08. 14(1): 3372

Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration.

Irene Molina-Gonzalez, Rebecca K Holloway, Zoeb Jiwaji, Owen Dando, Sarah A Kent, Katie Emelianova, Amy F Lloyd, Lindsey H Forbes, Ayisha Mahmood, Thomas Skripuletz, Viktoria Gudi, James A Febery, Jeffrey A Johnson, Jill H Fowler, Tanja Kuhlmann, Anna Williams, Siddharthan Chandran, Martin Stangel, Andrew J M Howden, Giles E Hardingham, Veronique E Miron.

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned male mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

DOI: https://doi.org/10.1038/s41467-023-39046-8