bims-medebr 2022-06-12 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022‒06‒12
25 papers selected by
Regina F. Fernández
Johns Hopkins University

Current Status of Our Understanding for Brain Integrated Functions and its Energetics.
Effects of Ultramicronized Palmitoylethanolamide on Mitochondrial Bioenergetics, Cerebral Metabolism, and Glutamatergic Transmission: An Integrated Approach in a Triple Transgenic Mouse Model of Alzheimer's Disease.
Glucose-sensing glucagon-like peptide-1 receptor neurons in the dorsomedial hypothalamus regulate glucose metabolism.
AMPK Modulates the Metabolic Adaptation of C6 Glioma Cells in Glucose-Deprived Conditions without Affecting Glutamate Transport.
Maternal PUFAs, Placental Epigenetics, and Their Relevance to Fetal Growth and Brain Development.
TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target.
ß-Hydroxybutyrate Improves Mitochondrial Function After Transient Ischemia in the Mouse.
Mitochondrial Dysfunction in Spinocerebellar Ataxia Type 3 Is Linked to VDAC1 Deubiquitination.
Distinct brain lipid signatures in response to low-level PM2.5 exposure in a 3xTg-Alzheimer's disease mouse inhalation model.
Processing mechanism of guanidinoacetate in choroid plexus epithelial cells: conversion of guanidinoacetate to creatine via guanidinoacetate N-methyltransferase and monocarboxylate transporter 12-mediated creatine release into the CSF.
Dietary PUFA and Exercise Dynamic Actions on Endocannabinoids in Brain - Consequences for Neural Plasticity and Neuroinflammation.
BAX regulates dendritic spine development via mitochondrial fusion.
Rapamycin ameliorates brain damage and maintains mitochondrial dynamic balance in diabetic rats subjected to middle cerebral artery occlusion.
Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease.
Addition of Prebiotics to the Ketogenic Diet Improves Metabolic Profile but Does Not Affect Seizures in a Rodent Model of Infantile Spasms Syndrome.
Structural basis of substrate recognition and translocation by human very long-chain fatty acid transporter ABCD1.
Central and peripheral regulations mediated by short-chain fatty acids on energy homeostasis.
Molecular Control of the Development of Hypothalamic Neurons Involved in Metabolic Regulation.
Elevated Serum Lactate in Glioma Patients: Associated Factors.
The "mitochondrial stress responses": the "Dr. Jekyll and Mr. Hyde" of neuronal disorders.
Lipidomics of Bioactive Lipids in Alzheimer's and Parkinson's Diseases: Where Are We?
Neuropsychological Performance Is Correlated With Tau Protein Deposition and Glucose Metabolism in Patients With Alzheimer's Disease.
GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.
Human Milk Lipids Induce Important Metabolic and Epigenetic Changes in Neonates.
Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.

Neurochem Res. 2022 Jun 11.

Current Status of Our Understanding for Brain Integrated Functions and its Energetics.

Anjani Kumar Tiwari, Anupriya Adhikari, Lokesh Chandra Mishra, Abhishek Srivastava.

  Human/animal brain is a unique organ with substantially high metabolism but it contains no energy reserve that is the reason it requires continuous supply of O2 and energy fluxes through CBF. The main source of energy remains glucose as the other biomolecules do not able to cross the blood-brain barrier. The speed of glucose metabolism is heterogeneous throughout the brain. One of the major flux consumption is Neuron-astrocyte cycling of glutamate and glutamine in glutamatergic neurons (approximately 80% of glucose metabolism in brain). The quantification of cellular glucose and other related substrate in resting, activated state can be analyzed through [18 F]FDG -positron-emission tomography (studying CMRglc) and [13 C/31P -MRS: for neuroenergetics & neurotransmitter cycling &31P-MRS: for energy induction & redox state). Merging basic in vitro studies with these techniques will help to develop new treatment paradigms for human brain diseased conditions.

Keywords:  Glucose metabolism; MRS; Neuroenergetics; PET; [18F]FDG

DOI:  https://doi.org/10.1007/s11064-022-03633-w
Front Aging Neurosci. 2022 ;14 890855

Effects of Ultramicronized Palmitoylethanolamide on Mitochondrial Bioenergetics, Cerebral Metabolism, and Glutamatergic Transmission: An Integrated Approach in a Triple Transgenic Mouse Model of Alzheimer's Disease.

Francesco Bellanti, Vidyasagar Naik Bukke, Archana Moola, Rosanna Villani, Caterina Scuderi, Luca Steardo, Gianmauro Palombelli, Rossella Canese, Sarah Beggiato, Mario Altamura, Gianluigi Vendemiale, Gaetano Serviddio, Tommaso Cassano.

  The therapeutic potential of ultramicronized palmitoylethanolamide (um-PEA) was investigated in young (6-month-old) and adult (12-month-old) 3 × Tg-AD mice, which received um-PEA for 3 months via a subcutaneous delivery system. Mitochondrial bioenergetics, ATP homeostasis, and magnetic resonance imaging/magnetic resonance spectroscopy were evaluated in the frontal cortex (FC) and hippocampus (HIPP) at the end of um-PEA treatment. Glutamate release was investigated by in vivo microdialysis in the ventral HIPP (vHIPP). We demonstrated that chronic um-PEA treatment ameliorates the decrease in the complex-I respiration rate and the FoF1-ATPase (complex V) activity, as well as ATP content depletion in the cortical mitochondria. Otherwise, the impairment in mitochondrial bioenergetics and the release of glutamate after depolarization was not ameliorated by um-PEA treatment in the HIPP of both young and adult 3 × Tg-AD mice. Moreover, progressive age- and pathology-related changes were observed in the cortical and hippocampal metabolism that closely mimic the alterations observed in the human AD brain; these metabolic alterations were not affected by chronic um-PEA treatment. These findings confirm that the HIPP is the most affected area by AD-like pathology and demonstrate that um-PEA counteracts mitochondrial dysfunctions and helps rescue brain energy metabolism in the FC, but not in the HIPP.

Keywords:  Alzheimer's disease; frontal cortex; glutamate; hippocampus; microdialysis; mitochondria

DOI:  https://doi.org/10.3389/fnagi.2022.890855
Sci Adv. 2022 Jun 10. 8(23): eabn5345

Glucose-sensing glucagon-like peptide-1 receptor neurons in the dorsomedial hypothalamus regulate glucose metabolism.

Zhaohuan Huang, Ling Liu, Jian Zhang, Kristie Conde, Jay Phansalkar, Zhongzhong Li, Lei Yao, Zihui Xu, Wei Wang, Jiangning Zhou, Guoqiang Bi, Feng Wu, Randy J Seeley, Michael M Scott, Cheng Zhan, Zhiping P Pang, Ji Liu.

Glucagon-like peptide-1 (GLP-1) regulates energy homeostasis via activation of the GLP-1 receptors (GLP-1Rs) in the central nervous system. However, the mechanism by which the central GLP-1 signal controls blood glucose levels, especially in different nutrient states, remains unclear. Here, we defined a population of glucose-sensing GLP-1R neurons in the dorsomedial hypothalamic nucleus (DMH), by which endogenous GLP-1 decreases glucose levels via the cross-talk between the hypothalamus and pancreas. Specifically, we illustrated the sufficiency and necessity of DMHGLP-1R in glucose regulation. The activation of the DMHGLP-1R neurons is mediated by a cAMP-PKA-dependent inhibition of a delayed rectifier potassium current. We also dissected a descending control of DMHGLP-1R -dorsal motor nucleus of the vagus nerve (DMV)-pancreas activity that can regulate glucose levels by increasing insulin release. Thus, our results illustrate how central GLP-1 action in the DMH can induce a nutrient state-dependent reduction in blood glucose level.

DOI: https://doi.org/10.1126/sciadv.abn5345
Cells. 2022 May 31. pii: 1800. [Epub ahead of print]11(11):

AMPK Modulates the Metabolic Adaptation of C6 Glioma Cells in Glucose-Deprived Conditions without Affecting Glutamate Transport.

Inês Belo do Nascimento, Marie Verfaillie, Gamze Ates, Pauline Beckers, Virginie Joris, Nathalie Desmet, Ann Massie, Emmanuel Hermans.

  Energy homeostasis in the central nervous system largely depends on astrocytes, which provide metabolic support and protection to neurons. Astrocytes also ensure the clearance of extracellular glutamate through high-affinity transporters, which indirectly consume ATP. Considering the role of the AMP-activated protein kinase (AMPK) in the control of cell metabolism, we have examined its implication in the adaptation of astrocyte functions in response to a metabolic stress triggered by glucose deprivation. We genetically modified the astrocyte-like C6 cell line to silence AMPK activity by overexpressing a dominant negative mutant of its catalytic subunit. Upon glucose deprivation, we found that C6 cells maintain stable ATP levels and glutamate uptake capacity, highlighting their resilience during metabolic stress. In the same conditions, cells with silenced AMPK activity showed a reduction in motility, metabolic activity, and ATP levels, indicating that their adaptation to stress is compromised. The rate of ATP production remained, however, unchanged by AMPK silencing, suggesting that AMPK mostly influences energy consumption during stress conditions in these cells. Neither AMPK modulation nor prolonged glucose deprivation impaired glutamate uptake. Together, these results indicate that AMPK contributes to the adaptation of astrocyte metabolism triggered by metabolic stress, but not to the regulation of glutamate transport.

Keywords:  ATP; astrocyte; glucose deprivation; glutamate transporter; metabolic stress

DOI:  https://doi.org/10.3390/cells11111800
Reprod Sci. 2022 Jun 08.

Maternal PUFAs, Placental Epigenetics, and Their Relevance to Fetal Growth and Brain Development.

Sanjay Basak, Asim K Duttaroy.

  Dietary polyunsaturated fatty acids (PUFAs), especially omega-3 (n-3) and n-6 long-chain (LC) PUFAs, are indispensable for the fetus' brain supplied by the placenta. Despite being highly unsaturated, n-3 LCPUFA-docosahexaenoic acid (DHA) plays a protective role as an antioxidant in the brain. Deficiency of DHA during fetal development may cause irreversible damages in neurodevelopment programming. Dietary PUFAs can impact placental structure and functions by regulating early placentation processes, such as angiogenesis. They promote remodeling of uteroplacental architecture to facilitate increased blood flow and surface area for nutrient exchange. The placenta's fatty acid transfer depends on the uteroplacental vascular development, ensuring adequate maternal circulatory fatty acids transport to fulfill the fetus' rapid growth and development requirements. Maternal n-3 PUFA deficiency predominantly leads to placental epigenetic changes than other fetal developing organs. A global shift in DNA methylation possibly transmits epigenetic instability in developing fetuses due to n-3 PUFA deficiency. Thus, an optimal level of maternal omega-3 (n-3) PUFAs may protect the placenta's structural and functional integrity and allow fetal growth by controlling the aberrant placental epigenetic changes. This narrative review summarizes the recent advances and underpins the roles of maternal PUFAs on the structure and functions of the placenta and their relevance to fetal growth and brain development.

Keywords:  Angiogenesis; Brain; DNA methylation; Epigenetics; PUFA; Placenta

DOI:  https://doi.org/10.1007/s43032-022-00989-w
Mol Neurodegener. 2022 Jun 03. 17(1): 40

TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target.

Rui-Yang Li, Qi Qin, Han-Chen Yang, Ying-Ying Wang, Ying-Xin Mi, Yun-Si Yin, Meng Wang, Chao-Ji Yu, Yi Tang.

  Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane immune receptor that is mainly expressed on microglia in the brain and macrophages in the periphery. Recent studies have identified TREM2 as a risk factor for Alzheimer's disease (AD). Increasing evidence has shown that TREM2 can affect lipid metabolism both in the central nervous system (CNS) and in the periphery. In the CNS, TREM2 affects the metabolism of cholesterol, myelin, and phospholipids and promotes the transition of microglia into a disease-associated phenotype. In the periphery, TREM2 influences lipid metabolism by regulating the onset and progression of obesity and its complications, such as hypercholesterolemia, atherosclerosis, and nonalcoholic fatty liver disease. All these altered lipid metabolism processes could influence the pathogenesis of AD through several means, including affecting inflammation, insulin resistance, and AD pathologies. Herein, we will discuss a potential pathway that TREM2 mediates lipid metabolism to influence the pathogenesis of AD in both the CNS and periphery. Moreover, we discuss the possibility that TREM2 may be a key factor that links central and peripheral lipid metabolism under disease conditions, including AD. This link may be due to impacts on the integrity of the blood-brain barrier, and we introduce potential pathways by which TREM2 affects the blood-brain barrier. Moreover, we discuss the role of lipids in TREM2-associated treatments for AD. We propose some potential therapies targeting TREM2 and discuss the prospect and limitations of these therapies.

Keywords:  Alzheimer’s disease; Central nervous system; Lipid metabolism; Peripheral system; TREM2; Therapeutic target

DOI:  https://doi.org/10.1186/s13024-022-00542-y
Neurochem Res. 2022 Jun 08.

ß-Hydroxybutyrate Improves Mitochondrial Function After Transient Ischemia in the Mouse.

Alina Lehto, Konrad Koch, Johanna Barnstorf-Brandes, Christian Viel, Marius Fuchs, Jochen Klein.

  ß-Hydroxybutyrate (BHB) is a ketone body formed in high amounts during lipolysis and fasting. Ketone bodies and the ketogenic diet were suggested as neuroprotective agents in neurodegenerative disease. In the present work, we induced transient ischemia in mouse brain by unilaterally occluding the middle cerebral artery for 90 min. BHB (30 mg/kg), given immediately after reperfusion, significantly improved the neurological score determined after 24 h. In isolated mitochondria from mouse brain, oxygen consumption by the complexes I, II and IV was reduced immediately after ischemia but recovered slowly over 1 week. The single acute BHB administration after reperfusion improved complex I and II activity after 24 h while no significant effects were seen at later time points. After 24 h, plasma and brain BHB concentrations were strongly increased while mitochondrial intermediates (citrate, succinate) were unchanged in brain tissue. Our data suggest that a single administration of BHB may improve mitochondrial respiration for 1-2 days but not for later time points. Endogenous BHB formation seems to complement the effects of exogenous BHB administration.

Keywords:  Complex I; Complex II; Glucose; Microdialysis; Oxidative phosphorylation; Stroke

DOI:  https://doi.org/10.1007/s11064-022-03637-6
Int J Mol Sci. 2022 May 25. pii: 5933. [Epub ahead of print]23(11):

Mitochondrial Dysfunction in Spinocerebellar Ataxia Type 3 Is Linked to VDAC1 Deubiquitination.

Tina Harmuth, Jonasz J Weber, Anna J Zimmer, Anna S Sowa, Jana Schmidt, Julia C Fitzgerald, Ludger Schöls, Olaf Riess, Jeannette Hübener-Schmid.

  Dysfunctional mitochondria are linked to several neurodegenerative diseases. Metabolic defects, a symptom which can result from dysfunctional mitochondria, are also present in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, the most frequent, dominantly inherited neurodegenerative ataxia worldwide. Mitochondrial dysfunction has been reported for several neurodegenerative disorders and ataxin-3 is known to deubiquitinylate parkin, a key protein required for canonical mitophagy. In this study, we analyzed mitochondrial function and mitophagy in a patient-derived SCA3 cell model. Human fibroblast lines isolated from SCA3 patients were immortalized and characterized. SCA3 patient fibroblasts revealed circular, ring-shaped mitochondria and featured reduced OXPHOS complexes, ATP production and cell viability. We show that wildtype ataxin-3 deubiquitinates VDAC1 (voltage-dependent anion channel 1), a member of the mitochondrial permeability transition pore and a parkin substrate. In SCA3 patients, VDAC1 deubiquitination and parkin recruitment to the depolarized mitochondria is inhibited. Increased p62-linked mitophagy, autophagosome formation and autophagy is observed under disease conditions, which is in line with mitochondrial fission. SCA3 fibroblast lines demonstrated a mitochondrial phenotype and dysregulation of parkin-VDAC1-mediated mitophagy, thereby promoting mitochondrial quality control via alternative pathways.

Keywords:  Machado–Joseph disease; VDAC1 ubiquitination; ataxin-3; mitochondria dysfunction; spinocerebellar ataxia type 3

DOI:  https://doi.org/10.3390/ijms23115933
Sci Total Environ. 2022 Jun 02. pii: S0048-9697(22)03553-7. [Epub ahead of print] 156456

Distinct brain lipid signatures in response to low-level PM2.5 exposure in a 3xTg-Alzheimer's disease mouse inhalation model.

Sheng-Han Lee, Ching-Yu Lin, Ta-Fu Chen, Charles C-K Chou, Ming-Jang Chiu, Boon Lead Tee, Hao-Jan Liang, Tsun-Jen Cheng.

  Fine particulate matter (PM2.5) poses a significant risk to human health. The molecular mechanisms underlying low-level PM2.5-induced neurotoxicity in the central nervous system remain unclear. In addition, changes in lipids in response to PM2.5 exposure have not yet been fully elucidated. In this study, 3xTg-Alzheimer's disease (AD) mice experienced continuous whole-body exposure to non-concentrated PM2.5 for three consecutive months, while control mice inhaled particulate matter-filtered air over the same time span. A liquid chromatography-mass spectrometry-based lipidomic platform was used to determine the distinct lipid profiles of various brain regions. The average PM2.5 concentration during the exposure was 11.38 μg/m3, which was close to the regulation limits of USA and Taiwan. The partial least squares discriminant analysis model showed distinct lipid profiles in the cortex, hippocampus, and olfactory bulb, but not the cerebellum, of mice in the exposure group. Increased levels of fatty acyls, glycerolipids, and sterol lipids, as well as the decreased levels of glycerophospholipids and sphingolipids in PM2.5-exposed mouse brains may be responsible for the increased energy demand, membrane conformation, neuronal loss, antioxidation, myelin function, and cellular signaling pathways associated with AD development. Our research suggests that subchronic exposure to low levels of PM2.5 may cause neurotoxicity by changing the lipid profiles in a susceptible model. Lipidomics is a powerful tool to study the early effects of PM2.5-induced AD toxicity.

Keywords:  Alzheimer's disease; Ambient fine particulate matter; Lipidomics; Neurotoxicity; Transgenic mouse model

DOI:  https://doi.org/10.1016/j.scitotenv.2022.156456
Fluids Barriers CNS. 2022 Jun 03. 19(1): 42

Processing mechanism of guanidinoacetate in choroid plexus epithelial cells: conversion of guanidinoacetate to creatine via guanidinoacetate N-methyltransferase and monocarboxylate transporter 12-mediated creatine release into the CSF.

Ryuta Jomura, Shin-Ichi Akanuma, Yoshiyuki Kubo, Masanori Tachikawa, Ken-Ichi Hosoya.

  BACKGROUND: Guanidinoacetate (GAA) induces epileptogenesis and neurotoxicity in the brain. As epileptic animal models have been reported to show elevated cerebral GAA levels, the processing mechanism of GAA in the brain is important for maintaining brain homeostasis. We have revealed that GAA in the cerebrospinal fluid (CSF) is removed by incorporation into the choroid plexus epithelial cells (CPxEpic), which form the blood-CSF barrier (BCSFB). However, the processing mechanism of GAA incorporated into CPxEpic remains unknown. We have reported that monocarboxylate transporter 12 (MCT12) functions as an efflux transporter of GAA and creatine, a metabolite of GAA, in the kidneys and liver. Therefore, we aimed to clarify the role of MCT12 in GAA dynamics in CPxEpic.METHODS: Protein expression and localization in CPxEpic were evaluated using immunohistochemistry. Metabolic analysis was performed using high-performance liquid chromatography (HPLC) 24 h after the addition of [14C]GAA to TR-CSFB3 cells, which are conditionally immortalized rat CPxEpic. The efflux transport of [14C]creatine was evaluated in TR-CSFB3 cells after transfection with MCT12 small interfering RNA (siRNA). The CSF-to-brain parenchyma transfer of creatine was measured after intracerebroventricular injection in rats.
RESULTS: Immunohistochemical staining revealed that MCT12-derived signals merged with those of the marker protein at the apical membrane of CPxEpic, suggesting that MCT12 is localized on the apical membrane of CPxEpic. The expression levels of guanidinoacetate N-methyltransferase (GAMT), which catalyzes the conversion of GAA to creatine, in TR-CSFB3 cells was also indicated, and GAA was considered to be metabolized to creatine after influx transport into CPxEpic, after which creatine was released into the CSF. Creatine release from TR-CSFB3 cells decreased following MCT12 knockdown. The contribution ratio of MCT12 to the release of creatine was more than 50%. The clearance of CSF-to-brain parenchyma transfer of creatine was 4.65 µL/(min·g brain), suggesting that biosynthesized creatine in CPxEpic is released into the CSF and supplied to the brain parenchyma.
CONCLUSIONS: In CPxEpic, GAA is metabolized to creatine via GAMT. Biosynthesized creatine is then released into the CSF via MCT12 and supplied to the brain parenchyma.

Keywords:  Blood-cerebrospinal fluid barrier (BCSFB); Choroid plexus epithelial cells; Creatine; Guanidinoacetate (GAA); Guanidinoacetate N-methyltransferase (GAMT); MCT12 (SLC16A12); Monocarboxylate transporter (MCT/SLC16A)

DOI:  https://doi.org/10.1186/s12987-022-00328-w
Adv Nutr. 2022 Jun 08. pii: nmac064. [Epub ahead of print]

Dietary PUFA and Exercise Dynamic Actions on Endocannabinoids in Brain - Consequences for Neural Plasticity and Neuroinflammation.

Yongsoon Park, Bruce A Watkins.

  The brain and peripheral nervous system provide oversight to muscle physiology and metabolism. Muscle is the largest organ in the body and critical for glucose sensitivity, prevention of diabetes, and control of obesity. The CNS produces endocannabinoids (eCBs) that play a role in brain neurobiology, such as inflammation and pain. Interestingly, studies in humans and rodents show that moderate duration of exercise increases eCBs in the brain and blood and influences cannabinoid receptors. Cannabinoid actions in the nervous system have advanced our understanding of pain, well-being, and disease. Nutrition is an important aspect of brain and eCB physiology because polyunsaturated fatty acids (PUFAs) are biosynthesized to the eCBs. The primary eCB metabolites are derived from arachidonic acid, an n-6 PUFAs, and the n-3 PUFAs, eicosapentaenoic and docosahexaenoic acids. The eCBs bind to cannabinoid receptors CB1 and CB2 to exert a wide range of activities, such as stimulate appetite, influence energy metabolism, support the immune system, and facilitate neuroplasticity. A diet containing different essential n-6 and n-3 PUFAs will dominate the formation of specific eCBs, and subsequently, their actions as ligands to CB1 and CB2. The eCB also function in a substrate role for COX enzymes, including potential substrates for the oxylipins (OxLs), which can be pro-inflammatory. Together, the eCBs and OxLs act as modulators of neuroinflammation. Thus, dietary PUFAs have implications in exercise responses as in the synthesis of eCBs and their effects on neuroinflammation. Neurotrophins are another participant in the diet and eCB interactions, specifically the brain-derived neurotrophic factor (BDNF). Particularly, BDNF supports neuroplasticity in cooperation with the endocannabinoid system (ECS). This review will present the role of PUFA in eCB biosynthesis, discuss the ECS and OxLs in neuroinflammation, highlight the evidence of exercise effects on eCBs, and describe eCBs and BDNF actions on neuroplasticity.

Keywords:  cannabinoid receptors; endocannabinoids; exercise; neuroinflammation; neuroplasticity; oxylipins; polyunsaturated fatty acids

DOI:  https://doi.org/10.1093/advances/nmac064
Neurosci Res. 2022 Jun 07. pii: S0168-0102(22)00172-9. [Epub ahead of print]

BAX regulates dendritic spine development via mitochondrial fusion.

Qinhua Gu, Kaizheng Duan, Ronald S Petralia, Ya-Xian Wang, Zheng Li.

  BAX is a Bcl-2 family protein acting on apoptosis. It also promotes mitochondrial fusion by interacting with the mitochondrial fusion protein Mitofusin (Mfn1 and Mfn2). Neuronal mitochondria are important for the development and modification of dendritic spines, which are subcellular compartments accommodating excitatory synapses in postsynaptic neurons. The abundance of dendritic mitochondria influences dendritic spine development. Mitochondrial fusion is essential for mitochondrial homeostasis. Here, we show that in the hippocampal neuron of BAX knockout mice, mitochondrial fusion is impaired, leading to decreases in mitochondrial length and total mitochondrial mass in dendrites. Notably, BAX knockout mice also have fewer dendritic spines and less cellular Adenosine 5'triphosphate (ATP) in dendrites. The spine and ATP changes are abolished by restoring mitochondria fusion via overexpressing Mfn1 and Mfn2. These findings indicate that BAX-mediated mitochondrial fusion in neurons is crucial for the development of dendritic spines and the maintenance of cellular ATP levels.

Keywords:  ATP; Mfn; mitochondria; spine

DOI:  https://doi.org/10.1016/j.neures.2022.06.002
Metab Brain Dis. 2022 Jun 07.

Rapamycin ameliorates brain damage and maintains mitochondrial dynamic balance in diabetic rats subjected to middle cerebral artery occlusion.

Changchun Hei, Yujia Zhou, Chenyang Zhang, Furong Gao, Meiling Cao, Shilin Yuan, Yixin Qin, P Andy Li, Xiao Yang.

  To investigate the effect of rapamycin on mitochondrial dynamic balance in diabetic rats subjected to cerebral ischemia-reperfusion injury. Male Sprague Dawley (SD) rats (n = 78) were treated with high fat diet combined with streptozotocin injection to construct diabetic model in rats. Transient middle cerebral artery occlusion (MCAO) of 2 hours was induced and the brains were harvested after 1 and 3 days of reperfusion. Rapamycin was injected intraperitoneally for 3 days prior to and immediately after operation, once a day. The neurological function was assessed, infarct volumes were measured and HE staining as well as immunohistochemistry were performed. The protein of hippocampus was extracted and Western blotting were performed to detect the levels of mTOR, mitochondrial dynamin related proteins (DRP1, p-DRP1, OPA1), SIRT3, and Nix/BNIP3L. Diabetic hyperglycemia worsened the neurological function performance (p < 0.01), enlarged infarct size (p < 0.01) and increased ischemic neuronal cell death (p < 0.01). The increased damage was associated with elevations of p-mTOR, p-S6, and p-DRP1; and suppressions of SIRT3 and Nix/BNIP3L. Rapamycin ameliorated diabetes-enhanced ischemic brain damage and reversed the biomarker alterations caused by diabetes. High glucose activated mTOR pathway and caused mitochondrial dynamics toward fission. The protective effect of rapamycin against diabetes-enhanced ischemic brain damage was associated with inhibiting mTOR pathway, redressing mitochondrial dynamic imbalance, and elevating SIRT3 and Nix/BNIP3L expression.

Keywords:  Cerebral ischemia; Diabetes; Mitochondrial dynamics; Mitochondrial fission and fusion; Rapamycin; SIRT3

DOI:  https://doi.org/10.1007/s11011-022-01020-6
Cells. 2022 Jun 04. pii: 1840. [Epub ahead of print]11(11):

Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease.

Stefano Doccini, Maria Marchese, Federica Morani, Nicola Gammaldi, Serena Mero, Francesco Pezzini, Rabah Soliymani, Melissa Santi, Giovanni Signore, Asahi Ogi, Silvia Rocchiccioli, Katja M Kanninen, Alessandro Simonati, Maciej M Lalowski, Filippo M Santorelli.

  CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach, followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5-/- mice, to unravel affected pathways and modifying factors involved in this disease scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments.

Keywords:  CLN5 disease; NCL; lysosomal proteomics; lysosomes; miglustat; trehalose

DOI:  https://doi.org/10.3390/cells11111840
Nutrients. 2022 May 26. pii: 2210. [Epub ahead of print]14(11):

Addition of Prebiotics to the Ketogenic Diet Improves Metabolic Profile but Does Not Affect Seizures in a Rodent Model of Infantile Spasms Syndrome.

Chunlong Mu, Angela Pochakom, Raylene A Reimer, Anamika Choudhary, Melinda Wang, Jong M Rho, Morris H Scantlebury, Jane Shearer.

  The ketogenic diet (KD) is an effective treatment for infantile spasms syndrome (IS). However, the KD has implications for somatic growth, development, and the gut microbiota. The impact of incorporating a prebiotic fiber (PRE, oligofructose-enriched inulin, 0.8 g/dL) into a KD diet on spasms, developmental milestones, fecal gut microbiota, metabolites, and hippocampal mitochondrial metabolism were examined. Following IS induction, animals were randomized to KD or KD + PRE diets. A third group without IS and suckled by dams was included as a normally developing reference group (R). PRE inclusion decreased ketones and increased circulating glucose levels but had no impact on spasms. In the liver, PRE increased triglyceride concentrations, decreased carnitine levels, and downregulated genes encoding enzymes responsible for ketogenesis. In the hippocampus, PRE increased glutathione levels but did not affect the maximal respiratory capacity of mitochondria. Analysis of the gut microbiota showed that KD + PRE increased microbial richness and the relative abundance of Bifidobacterium pseudolongum and Lactobacillus johnsonii. No differences in developmental milestones (i.e., surface righting, negative geotaxis, and open field behavior) were observed between KD and KD + PRE, except for ultrasonic vocalizations that were more frequent in KD + PRE. In summary, PRE did not impact spasms or developmental outcomes, but was effective in improving both metabolic parameters and gut microbiota diversity.

Keywords:  epilepsy; ketogenic diet; metabolism; nutrition; prebiotic fiber

DOI:  https://doi.org/10.3390/nu14112210
Nat Commun. 2022 Jun 08. 13(1): 3299

Structural basis of substrate recognition and translocation by human very long-chain fatty acid transporter ABCD1.

Zhi-Peng Chen, Da Xu, Liang Wang, Yao-Xu Mao, Yang Li, Meng-Ting Cheng, Cong-Zhao Zhou, Wen-Tao Hou, Yuxing Chen.

Human ABC transporter ABCD1 transports very long-chain fatty acids from cytosol to peroxisome for β-oxidation, dysfunction of which usually causes the X-linked adrenoleukodystrophy (X-ALD). Here, we report three cryogenic electron microscopy structures of ABCD1: the apo-form, substrate- and ATP-bound forms. Distinct from what was seen in the previously reported ABC transporters, the two symmetric molecules of behenoyl coenzyme A (C22:0-CoA) cooperatively bind to the transmembrane domains (TMDs). For each C22:0-CoA, the hydrophilic 3'-phospho-ADP moiety of CoA portion inserts into one TMD, with the succeeding pantothenate and cysteamine moiety crossing the inter-domain cavity, whereas the hydrophobic fatty acyl chain extends to the opposite TMD. Structural analysis combined with biochemical assays illustrates snapshots of ABCD1-mediated substrate transport cycle. It advances our understanding on the selective oxidation of fatty acids and molecular pathology of X-ALD.

DOI: https://doi.org/10.1038/s41467-022-30974-5
Transl Res. 2022 Jun 07. pii: S1931-5244(22)00135-9. [Epub ahead of print]

Central and peripheral regulations mediated by short-chain fatty acids on energy homeostasis.

Pei Luo, Kristen Lednovich, Kai Xu, Chioma Nnyamah, Brian T Layden, Pingwen Xu.

  The human gut microbiota influences obesity, insulin resistance, and the subsequent development of type 2 diabetes (T2D). The gut microbiota digests and ferments nutrients resulting in the production of short-chain fatty acids (SCFAs), which generate various beneficial metabolic effects on energy and glucose homeostasis. However, their roles in the central nervous system (CNS)-mediated outputs on the metabolism have only been minimally studied. Here, we explore what is known and future directions that may be worth exploring in this emerging area. Specifically, we searched studies or data in English by using PubMed, Google Scholar, and the Human Metabolome Database. Studies were filtered by time from 1978 to March 2022. As a result, 195 studies, 53 reviews, 1 website, and 1 book were included. One hundred and sixty-five of 195 studies describe the production and metabolism of SCFAs or the effects of SCFAs on energy homeostasis, glucose balance, and mental diseases through the gut-brain axis or directly by a central pathway. Thirty of 195 studies show that inappropriate metabolism and excessive of SCFAs are metabolically detrimental. Most studies suggest that SCFAs exert beneficial metabolic effects by acting as the energy substrate in the TCA cycle, regulating the hormones related to satiety regulation and insulin secretion, and modulating immune cells and microglia. These functions have been linked with AMPK signaling, GPCRs-dependent pathways, and inhibition of HDACs. However, the studies focusing on the central effects of SCFAs are still limited. The mechanisms by which central SCFAs regulate appetite, energy expenditure, and blood glucose during different physiological conditions warrant further investigation.

Keywords:  CNS; SCFAs; energy balance; glucose homeostasis

DOI:  https://doi.org/10.1016/j.trsl.2022.06.003
J Chem Neuroanat. 2022 Jun 06. pii: S0891-0618(22)00047-3. [Epub ahead of print] 102117

Molecular Control of the Development of Hypothalamic Neurons Involved in Metabolic Regulation.

Sophie Croizier, Sebastien G Bouret.

  The hypothalamus is a large brain region made of nuclei and areas involved in the control of behaviors and physiological regulations. Among them, the arcuate nucleus (ARH) and the lateral hypothalamic area (LHA) contain key neuronal populations expressing the pro-opiomelanocortin (POMC), the agouti-related peptide (AgRP), and the melanin-concentrating hormone (MCH), respectively, that are involved in goal-oriented behaviors (such as feeding behavior) and glucose homeostasis. These neuronal populations are generated from distinct parts of the germinative neuroepithelium during embryonic life, and acquire their cell fate under the influence of morphogen proteins, specific transcription factors, and epigenetic modulators. POMC and MCH neuronal development continues by sending long descending axonal projections before birth under the control of axon guidance molecules such as Netrin1 and Slit2. Later, during the postnatal period, POMC and AgRP neurons develop intra-hypothalamic projections notably to the paraventricular nucleus of the hypothalamus through the influence of other axon guidance cues such as the class3 Semaphorins. Other cellular processes, such as autophagy and primary cilia function, and hormonal cues also appear critical for the proper development of POMC neurons.

Keywords:  development; hypothalamus; melanin-concentrating hormone; melanocortin; neuropeptide Y; pro-opiomelanocortin

DOI:  https://doi.org/10.1016/j.jchemneu.2022.102117
Front Oncol. 2022 ;12 831079

Elevated Serum Lactate in Glioma Patients: Associated Factors.

Beathe Sitter, Annamaria Forsmark, Ole Solheim.

  Introduction: Serum lactate levels in brain cancer patients correlate with tumor malignancy grading, and serum lactate has been suggested as a potential biomarker and prognostic factor. The purpose of this study was to identify potential sources of elevated serum lactate in patients with brain gliomas by examining factors of importance for serum lactate production and clearance.Methods: In this cross-sectional study, data were collected from 261 glioma patients who underwent surgery from March 2011 to June 2015. We recorded patient gender, age, blood serum measures of lactate, glucose, pH, hemoglobin and base excess, patient health status, medications, and tumor characteristics. Patients with elevated and normal serum lactate levels were compared, and we explored if there were correlations between the variables. The association of serum lactate with the measured variables was investigated by simple and multivariable linear regression models.
Results and Discussion: Patients with elevated serum lactate had higher blood glucose, larger tumor volumes, and more tumor edema; more often needed pressor medication during surgery; and more often received corticosteroid treatment. The investigated variables were highly correlated. Multivariable linear regression indicated that gender, tumor volume, Charlson Comorbidity Index, hyperglycemia, and corticosteroid treatment were associated with serum lactate levels. Histopathology was not an independent factor. In conclusion, comorbidities, hyperglycemia, and presurgical corticosteroid treatment exhibited the strongest association with serum lactate in glioma patients.

Keywords:  biomarker; corticosteroid; glioma; hyperlactatemia; lactate

DOI:  https://doi.org/10.3389/fonc.2022.831079
Neural Regen Res. 2022 Dec;17(12): 2563-2575

The "mitochondrial stress responses": the "Dr. Jekyll and Mr. Hyde" of neuronal disorders.

Simone Patergnani, Giampaolo Morciano, Marianna Carinci, Sara Leo, Paolo Pinton, Alessandro Rimessi.

  Neuronal disorders are associated with a profound loss of mitochondrial functions caused by various stress conditions, such as oxidative and metabolic stress, protein folding or import defects, and mitochondrial DNA alteration. Cells engage in different coordinated responses to safeguard mitochondrial homeostasis. In this review, we will explore the contribution of mitochondrial stress responses that are activated by the organelle to perceive these dangerous conditions, keep them under control and rescue the physiological condition of nervous cells. In the sections to come, particular attention will be dedicated to analyzing how compensatory mitochondrial hyperfusion, mitophagy, mitochondrial unfolding protein response, and apoptosis impact human neuronal diseases. Finally, we will discuss the relevance of the new concept: the "mito-inflammation", a mitochondria-mediated inflammatory response that is recently found to cover a relevant role in the pathogenesis of diverse inflammatory-related diseases, including neuronal disorders.

Keywords:  Alzheimer’s disease; Parkinson’s disease; UPR mt; apoptosis; mito-inflammation; mitochondrial dynamics; mitophagy; multiple sclerosis; neurodegeneration

DOI:  https://doi.org/10.4103/1673-5374.339473
Int J Mol Sci. 2022 Jun 02. pii: 6235. [Epub ahead of print]23(11):

Lipidomics of Bioactive Lipids in Alzheimer's and Parkinson's Diseases: Where Are We?

Valerio Chiurchiù, Marta Tiberi, Alessandro Matteocci, Federico Fazio, Hasibullah Siffeti, Stefano Saracini, Nicola Biagio Mercuri, Giuseppe Sancesario.

  Lipids are not only constituents of cellular membranes, but they are also key signaling mediators, thus acting as "bioactive lipids". Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation, and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between the immune and nervous systems, and lipids can interact particularly with the aggregation and propagation of many pathogenic proteins that are well-renowned hallmarks of several neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's (PD) diseases. In this review, we summarize the current knowledge about the presence and quantification of the main classes of endogenous bioactive lipids, namely glycerophospholipids/sphingolipids, classical eicosanoids, pro-resolving lipid mediators, and endocannabinoids, in AD and PD patients, as well as their most-used animal models, by means of lipidomic analyses, advocating for these lipid mediators as powerful biomarkers of pathology, diagnosis, and progression, as well as predictors of response or activity to different current therapies for these neurodegenerative diseases.

Keywords:  Alzheimer’s; Parkinson’s; classical eicosanoids; endocannabinoids; glycerophospholipids; specialized pro-resolving mediators; sphingolipids

DOI:  https://doi.org/10.3390/ijms23116235
Front Aging Neurosci. 2022 ;14 841942

Neuropsychological Performance Is Correlated With Tau Protein Deposition and Glucose Metabolism in Patients With Alzheimer's Disease.

Zhen Qiao, Guihong Wang, Xiaobin Zhao, Kai Wang, Di Fan, Qian Chen, Lin Ai.

  Objective: This study characterizes glucose metabolism and tau protein deposition distribution in patients with Alzheimer's disease (AD) and to evaluate the relationships between neuropsychological performance and tau protein deposition or glucose metabolism using 18F-FDG and 18F-AV1451 positron emission tomography/computed tomography (PET/CT).Methods: Sixty-four patients with β-amyloid-positive (Aβ+) AD and twenty-five healthy participants were enrolled in this study. All participants underwent 18F-FDG and 18F-AV1451 PET/CT. Clinical data and neuropsychological scores were collected. Patients with AD were divided into mild, moderate, and severe groups according to mini-mental state examination (MMSE) scores. The standardized uptake value ratios (SUVRs) for both FDG and AV1451 PET images were calculated using the cerebellar vermis as reference. The SUVRs of the whole cerebral cortex and each brain region were calculated. The volume of interest (VOI) was obtained using automated anatomical atlas (AAL) and Brodmann regions. Student's t-test was used to perform intergroup comparisons of SUVR. The partial correlation coefficient between SUVR and neuropsychological scores was computed in an inter-subject manner using age and education as covariates.
Results: The mild subgroup showed a reduction in glucose metabolism and aggregation of tau protein in the temporoparietal cortex. With a decline in neuropsychiatric performance, the SUVR on FDG PET decreased and SUVR on tau PET increased gradually. The areas of glucose metabolism reduction and tau protein deposition appeared first in the parietal cortex, followed by the temporal and frontal cortex, successively. Both FDG and tau SUVRs significantly correlated with MMSE, Montreal cognitive assessment (MOCA), auditory verbal learning test (AVLT), Boston naming test (BNT), clock drawing task (CDT), and verbal fluency test (VFT) (p < 0.05). The SUVR on FDG PET significantly correlated with activities of daily living (ADL) and the Hamilton depression scale (HAMD). There was no significant correlation between the tau SUVRs and ADL or HAMD.
Conclusion: The extension of tau protein deposition was similar but not exactly consistent with the area of glucose metabolism reduction. Both tau and FDG SUVRs correlated with cognitive function in domain-specific patterns, and the results of FDG PET more closely correlated with neuropsychological function than tau PET results did.

Keywords:  Alzheimer’s disease; glucose metabolism; neuropsychological domain; neuropsychological scores; positron emission tomography; tau protein

DOI:  https://doi.org/10.3389/fnagi.2022.841942
Commun Biol. 2022 Jun 03. 5(1): 541

GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.

Christina Wolf, Alireza Pouya, Sara Bitar, Annika Pfeiffer, Diones Bueno, Liliana Rojas-Charry, Sabine Arndt, David Gomez-Zepeda, Stefan Tenzer, Federica Dal Bello, Caterina Vianello, Sandra Ritz, Jonas Schwirz, Kristina Dobrindt, Michael Peitz, Eva-Maria Hanschmann, Pauline Mencke, Ibrahim Boussaad, Marion Silies, Oliver Brüstle, Marta Giacomello, Rejko Krüger, Axel Methner.

Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 and beta-tubulin in a redox-dependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. GDAP1 silencing also disrupts mitochondria-ER contact sites. These changes result in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, our findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.

DOI: https://doi.org/10.1038/s42003-022-03487-6
Clin Perinatol. 2022 Jun;pii: S0095-5108(22)00020-3. [Epub ahead of print]49(2): 331-353

Human Milk Lipids Induce Important Metabolic and Epigenetic Changes in Neonates.

Keyur Donda, Akhil Maheshwari.

  Lipids are a major source of energy during the fetal/neonatal period. Most are received from the mother, transplacentally during the intrauterine period or via maternal milk after birth. However, in addition to the known nutritional roles, lipids are now known to bind a variety of cellular receptors to regulate specific patterns in metabolism and gene expression. The expression of these receptors is regulated by various genetic and environmental stimuli, and ligation can activate positive-feedback loops in the expression and the activity of downstream signaling pathways. The authors summarize the role of lipid ligands, cognate receptors, epigenetic regulation, and downstream signaling.

Keywords:  Breast milk; DNA methylation; Extrauterine growth restriction; Fatty acids; Infant nutrition; Intrauterine growth restriction; Lipid receptors; Polyunsaturated fatty acids

DOI:  https://doi.org/10.1016/j.clp.2022.02.006
EMBO Mol Med. 2022 Jun 07. e15851

Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.

Chunyue Liu, Zixing Fu, Shanshan Wu, Xiaosong Wang, Shengrong Zhang, Chu Chu, Yuan Hong, Wenbo Wu, Shengqi Chen, Yueqing Jiang, Yang Wu, Yongbo Song, Yan Liu, Xing Guo.

  Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington's disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin-related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single-stranded DNA-binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1-induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.

Keywords:  Huntington's disease; heat shock transcription factor 1; human striatal organoids; mitochondrial DNA; single-stranded DNA-binding protein 1

DOI:  https://doi.org/10.15252/emmm.202215851