bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2022–05–01
23 papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Proton MRS Assessment of Neonatal Brain Metabolism During Cardiopulmonary Bypass (CPB) Surgery.
  2. Riluzole restores memory and brain energy metabolism in AβPP-PS1 mouse model of Alzheimer's disease.
  3. Oxidative phosphorylation mediated pathogenesis of Parkinson's disease and its implication via Akt signaling.
  4. Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairment.
  5. Where functional MRI stops, metabolism starts.
  6. Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease.
  7. Indolylbenzothiadiazoles as highly tunable fluorophores for imaging lipid droplet accumulation in astrocytes and glioblastoma cells.
  8. Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion.
  9. Brain Metabolism and Amyloid Load in Individuals With Subjective Cognitive Decline or Pre-Mild Cognitive Impairment.
  10. Autonomic control of energy balance and glucose homeostasis.
  11. Comparative analysis of CI- and CIV-containing respiratory supercomplexes at single-cell resolution.
  12. trans-2-Enoyl-CoA Reductase Tecr-Driven Lipid Metabolism in Endothelial Cells Protects against Transcytosis to Maintain Blood-Brain Barrier Homeostasis.
  13. Role of the gut-brain axis in energy and glucose metabolism.
  14. Altered glucose metabolism and its association with carbonic anhydrase 8 in Machado-Joseph Disease.
  15. Mitochondrial Complex I deficiency: guilty in Parkinson's disease.
  16. Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy.
  17. Alteration of Glycerophospholipid Metabolism in Hippocampus of Post-stroke Depression Rats.
  18. Cerebrospinal fluid lactate levels along the Alzheimer's disease continuum and associations with blood-brain barrier integrity, age, cognition, and biomarkers.
  19. Lipid level alteration in human and cellular models of alpha synuclein mutations.
  20. Connecting the Dots Between Hypercholesterolemia and Alzheimer's Disease: A Potential Mechanism Based on 27-Hydroxycholesterol.
  21. CURRENT PERSPECTIVES ON MITOCHONDRIAL DYSFUNCTION IN MIGRAINE.
  22. Mitochondrial stroke-like episodes: the search for new therapies.
  23. LIS1 and NDEL1 Regulate Axonal Trafficking of Mitochondria in Mature Neurons.
  1. NMR Biomed. 2022 Apr 28.
    Proton MRS Assessment of Neonatal Brain Metabolism During Cardiopulmonary Bypass (CPB) Surgery.
    D M Spielman, M Gu, R E Hurd, K Riemer, K Okamura, F L Hanley.
       PURPOSE: Here we report on the development and performance of a robust 3T single-voxel proton magnetic resonance spectroscopy (1 H-MRS) experimental protocol and data analysis pipeline for quantifying brain metabolism during cardiopulmonary bypass (CPB) surgery in a neonatal porcine model, with an overall goal of elucidating primary mechanisms of brain injury associated with these procedures. The specific aims were to assess which metabolic processes can be reliably interrogated by 1 H MRS on a 3T clinical scanner and to provide an initial assessment of brain metabolism during deep hypothermia cardiac arrest (DHCA) surgery and recovery.
    METHODS: 14 neonatal pigs underwent CPB surgery while placed in a 3T MRI scanner for 18°C, 28°C, and 37°C DHCA studies under hyperglycemic, euglycemic, and hypoglycemic conditions. Total imaging times, including baseline measurements, circulatory arrest (CA), and recovery averaged 3 hrs/animal, during which 30 - 40 single-voxel 1 H MRS spectra (sLASER pulse sequence, TR/TE = 2000/30 ms, 64 or 128 averages) were acquired from a 2.2 cc right midbrain voxel.
    RESULTS: 1 H MRS at 3T was able to reliably quantify 1) anaerobic metabolism via depletion of brain glucose and the associate build-up of lactate during CA, 2) phosphocreatine (PCr) to creatine (Cr) conversion during CA and subsequent recovery upon reperfusion, 3) a robust increase in the glutamine-to-glutamate (Gln/Glu) ratio during the post-CA recovery period, and 4) a broadening of the water peak during CA.
    CONCLUSIONS: In vivo 1 H MRS at 3T can reliably quantify subtle metabolic brain changes previously deemed challenging to interrogate, including brain glucose concentrations even under hypoglycemic conditions, ATP usage via the conversion of PCr to Cr, and differential changes in Glu and Gln. Observed metabolic changes during CPB surgery of a neonatal porcine model provide new insights into possible mechanisms for prevention of neuronal injury.
    Keywords:  Brain metabolism; Cardiopulmonary bypass; Deep hyperthermia cardiac arrest; Hypothermia; Magnetic resonance spectroscopy; Neonatal
    DOI:  https://doi.org/10.1002/nbm.4752
  2. Biochem Biophys Res Commun. 2022 Apr 14. pii: S0006-291X(22)00574-5. [Epub ahead of print]610 140-146
    Riluzole restores memory and brain energy metabolism in AβPP-PS1 mouse model of Alzheimer's disease.
    Kamal Saba, Anant B Patel.
      Alzheimer's disease (AD) is a neurodegenerative disorder leading to memory loss and impaired cognition. Despite several decades of research, AD therapeutic is not available. In this study, we have investigated the impact of a chronic intervention of riluzole on memory and neurometabolism in the AβPP-PS1 mouse model of AD. The 10-month-old AβPP-PS1 mice were administered 30 doses of riluzole (6 mg/kg, intragastrically) on an alternate day for two months. The memory was assessed using Morris Water Maze, while neurometabolism was evaluated by 1H-[13C]-NMR spectroscopy together with an intravenous infusion of [1,6-13C2]glucose. The normal saline-treated AβPP-PS1 mice exhibited a decrease in learning and memory that were restored to the control level following riluzole treatment. Most interestingly, the reduced 13C labeling of GluC4 and AspC3 from [1,6-13C]glucose in the AβPP-PS1 mice was restored to the control level following riluzole intervention. As a consequence, chronic riluzole treatment improved metabolic activity of glutamatergic neurons in AβPP-PS1 mice. Together these data suggest that riluzole may be useful for improving cognition in AD.
    Keywords:  (1)H-[(13)C]-NMR; AD Drug; Glucose; Glutamate
    DOI:  https://doi.org/10.1016/j.bbrc.2022.04.051
  3. Neurochem Int. 2022 Apr 25. pii: S0197-0186(22)00069-9. [Epub ahead of print] 105344
    Oxidative phosphorylation mediated pathogenesis of Parkinson's disease and its implication via Akt signaling.
    Md Zainul Ali, Pankaj Singh Dholaniya.
      Substantia Nigra Pars-compacta (SNpc), in the basal ganglion region, is a primary source of dopamine release. These dopaminergic neurons require more energy than other neurons, as they are highly arborized and redundant. Neurons meet most of their energy demand (∼90%) from mitochondria. Oxidative phosphorylation (OxPhos) is the primary pathway for energy production. Many genes involved in Parkinson's disease (PD) have been associated with OxPhos, especially complex I. Abrogation in complex I leads to reduced ATP formation in these neurons, succumbing to death by inducing apoptosis. This review discusses the interconnection between complex I-associated PD genes and specific mitochondrial metabolic factors (MMFs) of OxPhos. Interestingly, all the complex I-associated PD genes discussed here have been linked to the Akt signaling pathway; thus, neuron survival is promoted and smooth mitochondrial function is ensured. Any changes in these genes disrupt the Akt pathway, which hampers the opening of the permeability transition pore (PTP) via GSK3β dephosphorylation; promotes destabilization of OxPhos; and triggers the release of pro-apoptotic factors.
    Keywords:  Akt signaling pathway; Mitochondria; Mitochondrial metabolic factors; Neurodegeneration; Oxidative phosphorylation; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.neuint.2022.105344
  4. Cell Death Dis. 2022 Apr 25. 13(4): 406
    Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairment.
    Manman Zhang, Wenliang Gong, Dianjun Zhang, Ming Ji, Binjie Chen, Beina Chen, Xinyu Li, Yuefei Zhou, Chengyi Dong, Gehua Wen, Xiaoni Zhan, Xiafang Wu, Lulu Cui, Yuliang Feng, Siman Wang, Huiya Yuan, Enyu Xu, Maosheng Xia, Alexei Verkhratsky, Baoman Li.
      Alzheimer's disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking ApoE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered a significant increase in the ApoE4 content of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with healthy adults. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum level of thyroid hormones and cognitive function. We analysed effects of ApoE4-containing peripheral exosomes on neural cells and neurological outputs in aged or thyroidectomised young mice. Ageing-associated hypothyroidism as well as acute thyroidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activated nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing cholesterol level in neural cells. This, in turn, affected cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, this process can represent potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-022-04858-x
  5. Elife. 2022 Apr 25. pii: e78327. [Epub ahead of print]11
    Where functional MRI stops, metabolism starts.
    Polytimi Frangou, William T Clarke.
      Combining techniques that track blood oxygenation and biochemicals during neuronal activity reveals how the brain computes perceived and unperceived stimuli.
    Keywords:  BOLD fMRI; human; human brain metabolism; lactate; magnetic resonance spectroscopy; neuroscience; perception
    DOI:  https://doi.org/10.7554/eLife.78327
  6. Alzheimers Dement. 2022 Apr 28.
    Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease.
    Alzheimer's Disease Neuroimaging Initiative† and the Alzheimer's Disease Metabolomics Consortium
       INTRODUCTION: Late-onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease characterized by multiple progressive stages, glucose metabolic dysregulation, Alzheimer's disease (AD) pathology, and inexorable cognitive decline. Discovery of metabolic profiles unique to sex, apolipoprotein E (APOE) genotype, and stage of disease progression could provide critical insights for personalized LOAD medicine.
    METHODS: Sex- and APOE-specific metabolic networks were constructed based on changes in 127 metabolites of 656 serum samples from the Alzheimer's Disease Neuroimaging Initiative cohort.
    RESULTS: Application of an advanced analytical platform identified metabolic drivers and signatures clustered with sex and/or APOE ɛ4, establishing patient-specific biomarkers predictive of disease state that significantly associated with cognitive function. Presence of the APOE ɛ4 shifts metabolic signatures to a phosphatidylcholine-focused profile overriding sex-specific differences in serum metabolites of AD patients.
    DISCUSSION: These findings provide an initial but critical step in developing a diagnostic platform for personalized medicine by integrating metabolomic profiling and cognitive assessments to identify targeted precision therapeutics for AD patient subgroups through computational network modeling.
    Keywords:  Alzheimer's Disease Neuroimaging Initiative; apolipoprotein E ε4; computational systems biology; late-onset Alzheimer's disease; metabolic biomarkers; metabolic network; metabolomics; precision medicine; sex-specific metabolic changes
    DOI:  https://doi.org/10.1002/alz.12675
  7. RSC Adv. 2021 Jul 06. 11(39): 23960-23967
    Indolylbenzothiadiazoles as highly tunable fluorophores for imaging lipid droplet accumulation in astrocytes and glioblastoma cells.
    Kilian Colas, Karl O Holmberg, Linus Chiang, Susanne Doloczki, Fredrik J Swartling, Christine Dyrager.
      We present an extensive photophysical study of a series of fluorescent indolylbenzothiadiazole derivatives and their ability to specifically image lipid droplets in astrocytes and glioblastoma cells. All compounds in the series displayed positive solvatochromism together with large Stokes shifts, and π-extended derivatives exhibited elevated brightness. It was shown that the fluorescence properties were highly tunable by varying the electronic character or size of the N-substituent on the indole motif. Three compounds proved capable as probes for detecting small quantities of lipid deposits in healthy and cancerous brain cells. In addition, all twelve compounds in the series were predicted to cross the blood-brain barrier, which raises the prospect for future in vivo studies for exploring the role of lipid droplets in the central nervous system.
    DOI:  https://doi.org/10.1039/d1ra04419b
  8. Mol Metab. 2022 Apr 22. pii: S2212-8778(22)00057-6. [Epub ahead of print] 101488
    Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion.
    Alison D McNeilly, Adonis Yianakas, Jennifer G Gallagher, Jamie Tarlton, Michael Lj Ashford, Rory J McCrimmon.
       OBJECTIVE: IL-6 is an important contributor to glucose and energy homeostasis through changes in whole-body glucose disposal, insulin sensitivity, food intake and energy expenditure. However, the relative contributions of peripheral versus central IL-6 signaling to these metabolic actions are presently unclear. A conditional mouse model with reduced brain IL-6Ra expression was used to explore how blunted central IL-6 signaling alters metabolic status in lean and obese mice.
    METHODS: Transgenic mice with reduced levels of central IL-6 receptor alpha (IL-6Ra) levels (IL-6Ra KD mice) and Nestin Cre controls (Cre+/- mice) were fed standard chow or high-fat diet for 20 weeks. Obese and lean mouse cohorts underwent metabolic phenotyping with various measures of energy and glucose homeostasis determined. Glucose-stimulated insulin secretion was assessed in vivo and ex vivo in both mouse groups.
    RESULTS: IL-6Ra KD mice exhibited altered body fat mass, liver steatosis, plasma insulin, IL-6 and NEFA levels versus Cre+/- mice in a diet-dependent manner. IL-6Ra KD mice had increased food intake, higher RER, decreased energy expenditure with diminished cold tolerance compared to Cre+/- controls. Standard chow-fed IL-6Ra KD mice displayed reduced plasma insulin and glucose-stimulated insulin secretion with impaired glucose disposal and unchanged insulin sensitivity. Isolated pancreatic islets from standard chow-fed IL-6Ra KD mice showed comparable morphology and glucose-stimulated insulin secretion to Cre+/- controls. The diminished in vivo insulin secretion exhibited by IL-6Ra KD mice was recovered by blockade of autonomic ganglia.
    CONCLUSIONS: This study shows that central IL-6Ra signaling contributes to glucose and energy control mechanisms by regulating food intake, energy expenditure, fuel flexibility and insulin secretion. A plausible mechanism linking central IL-6Ra signaling and pancreatic insulin secretion is through the modulation of autonomic output activity. Thus, brain IL-6 signaling may contribute to the central adaptive mechanisms engaged in response to metabolic stress.
    Keywords:  Autonomic output; Energy expenditure; Food intake; Insulin secretion; Interleukin-6
    DOI:  https://doi.org/10.1016/j.molmet.2022.101488
  9. Neurology. 2022 Apr 29. pii: 10.1212/WNL.0000000000200351. [Epub ahead of print]
    Brain Metabolism and Amyloid Load in Individuals With Subjective Cognitive Decline or Pre-Mild Cognitive Impairment.
    Network-AD project
       BACKGROUND AND OBJECTIVE: Multicenter study aiming at investigating the characteristics of cognitive decline, neuropsychiatric symptoms, and brain imaging in individuals with subjective cognitive decline (SCD) and subtle cognitive decline (pre-Mild Cognitive Impairment, pre-MCI).
    METHODS: Data were obtained from the Network-AD project (NET-2011-02346784). The included subjects underwent baseline cognitive and neurobehavioral evaluation, FDG-PET, and, amyloid-PET. We used Principal Component Analysis (PCA) to identify independent neuropsychological and neuropsychiatric dimensions and their association with brain metabolism.
    RESULTS: A total of 105 subjects (SCD=49, pre-MCI=56) were included. FDG-PET was normal in 45% of subjects and revealed brain hypometabolism in 55%, with a frontal-like pattern as the most frequent finding (28%). Neuropsychiatric symptoms emerging from the Neuropsychiatric Inventory and the Starkstein Apathy Scale were highly prevalent in the whole sample (78%). An abnormal amyloid load was detected in the 18% of the subjects that underwent amyloid-PET (n=60). PCA resulted in three neuropsychological factors: 1) executive/visuo-motor, correlating with hypometabolism in frontal, occipital cortices and basal ganglia; 2) memory, correlating with hypometabolism in temporo-parietal regions; 3) visuo-spatial/constructional, correlating with hypometabolism in fronto-parietal cortices. Two factors emerged from the neuropsychiatric PCA: 1) affective, correlating with hypometabolism in orbito-frontal, cingulate cortex, insula; 2) hyperactive/psychotic, correlating with hypometabolism in frontal, temporal and parietal regions.
    DISCUSSION: FDG-PET evidence suggests either normal brain function or different patterns of brain hypometabolism in SCD and pre-MCI subjects. These results indicate that SCD and pre-MCI represent heterogeneous populations. Consistently, different neuropsychological and neuropsychiatric profiles emerged, which correlated with neuronal dysfunction in specific brain regions. Long-term follow-up studies are needed to assess the risk of progression to dementia in these conditions.
    DOI:  https://doi.org/10.1212/WNL.0000000000200351
  10. Exp Mol Med. 2022 Apr 26.
    Autonomic control of energy balance and glucose homeostasis.
    Uisu Hyun, Jong-Woo Sohn.
      Neurons in the central nervous system (CNS) communicate with peripheral organs largely via the autonomic nervous system (ANS). Through such communications, the sympathetic and parasympathetic efferent divisions of the ANS may affect thermogenesis and blood glucose levels. In contrast, peripheral organs send feedback to the CNS via hormones and autonomic afferent nerves. These humoral and neural feedbacks, as well as neural commands from higher brain centers directly or indirectly shape the metabolic function of autonomic neurons. Notably, recent developments in mouse genetics have enabled more detailed studies of ANS neurons and circuits, which have helped elucidate autonomic control of metabolism. Here, we will summarize the functional organization of the ANS and discuss recent updates on the roles of neural and humoral factors in the regulation of energy balance and glucose homeostasis by the ANS.
    DOI:  https://doi.org/10.1038/s12276-021-00705-9
  11. Cell Rep Methods. 2021 May 24. 1(1): 100002
    Comparative analysis of CI- and CIV-containing respiratory supercomplexes at single-cell resolution.
    Fabio Bertan, Lena Wischhof, Enzo Scifo, Mihaela Guranda, Joshua Jackson, Anaïs Marsal-Cots, Antonia Piazzesi, Miriam Stork, Michael Peitz, Jochen Herbert Martin Prehn, Dan Ehninger, Pierluigi Nicotera, Daniele Bano.
      Mitochondria sustain the energy demand of the cell. The composition and functional state of the mitochondrial oxidative phosphorylation system are informative indicators of organelle bioenergetic capacity. Here, we describe a highly sensitive and reproducible method for a single-cell quantification of mitochondrial CI- and CIV-containing respiratory supercomplexes (CI∗CIV-SCs) as an alternative means of assessing mitochondrial respiratory chain integrity. We apply a proximity ligation assay (PLA) and stain CI∗CIV-SCs in fixed human and mouse brains, tumorigenic cells, induced pluripotent stem cells (iPSCs) and iPSC-derived neural precursor cells (NPCs), and neurons. Spatial visualization of CI∗CIV-SCs enables the detection of mitochondrial lesions in various experimental models, including complex tissues undergoing degenerative processes. We report that comparative assessments of CI∗CIV-SCs facilitate the quantitative profiling of even subtle mitochondrial variations by overcoming the confounding effects that mixed cell populations have on other measurements. Together, our PLA-based analysis of CI∗CIV-SCs is a sensitive and complementary technique for detecting cell-type-specific mitochondrial perturbations in fixed materials.
    Keywords:  brain; in-situ imaging analysis; mitochondria; mitochondrial diseases; mitochondrial dysfunction; mitochondrial respiratory supercomplexes; proximity ligation assay
    DOI:  https://doi.org/10.1016/j.crmeth.2021.100002
  12. Research (Wash D C). 2022 ;2022 9839368
    trans-2-Enoyl-CoA Reductase Tecr-Driven Lipid Metabolism in Endothelial Cells Protects against Transcytosis to Maintain Blood-Brain Barrier Homeostasis.
    Jinxuan Wang, Jianxiong Xu, Guangchao Zang, Tao Zhang, Qi Wu, Hongping Zhang, Yidan Chen, Yi Wang, Weixi Qin, Shuang Zhao, Erdai Qin, Juhui Qiu, Xiaojuan Zhang, Lin Wen, Yeqi Wang, Guixue Wang.
      The transport and metabolism of lipids in cerebrovascular endothelial cells (ECs) have been hypothesized to regulate blood-brain barrier (BBB) maturation and homeostasis. Long-chain polyunsaturated fatty acids (LCPUFAs) as the important lipids components of cell membranes are essential for the development and function of BBB, but the direct links of lipid metabolism and ECs barrier function remain to be established. Here, we comprehensively characterize the transcriptomic phenotype of developmental cerebrovascular ECs in single-cell resolution and firstly find that trans-2-enoyl-CoA reductase (Tecr), a very-long-chain fatty acid synthesis, is highly expressed during barriergenesis and decreased after BBB maturation. EC-specific knockout of Tecr compromises angiogenesis due to delayed vascular sprouting. Importantly, EC-specific deletion of Tecr loss restrictive quality of vascular permeability from neonatal stages to adulthood, with high levels of transcytosis, but maintains the vascular tight junctions. Moreover, lipidomic analysis shows that the expression of Tecr in ECs is associated with the containing of omega-3 fatty acids, which directly suppresses caveolae vesicles formation. These results reveal a protective role for Tecr in BBB integrity and suggest that Tecr as a novel therapeutic target in the central nervous system (CNS) diseases associated with BBB dysfunction.
    DOI:  https://doi.org/10.34133/2022/9839368
  13. Exp Mol Med. 2022 Apr 26.
    Role of the gut-brain axis in energy and glucose metabolism.
    Hallie R Wachsmuth, Savanna N Weninger, Frank A Duca.
      The gastrointestinal tract plays a role in the development and treatment of metabolic diseases. During a meal, the gut provides crucial information to the brain regarding incoming nutrients to allow proper maintenance of energy and glucose homeostasis. This gut-brain communication is regulated by various peptides or hormones that are secreted from the gut in response to nutrients; these signaling molecules can enter the circulation and act directly on the brain, or they can act indirectly via paracrine action on local vagal and spinal afferent neurons that innervate the gut. In addition, the enteric nervous system can act as a relay from the gut to the brain. The current review will outline the different gut-brain signaling mechanisms that contribute to metabolic homeostasis, highlighting the recent advances in understanding these complex hormonal and neural pathways. Furthermore, the impact of the gut microbiota on various components of the gut-brain axis that regulates energy and glucose homeostasis will be discussed. A better understanding of the gut-brain axis and its complex relationship with the gut microbiome is crucial for the development of successful pharmacological therapies to combat obesity and diabetes.
    DOI:  https://doi.org/10.1038/s12276-021-00677-w
  14. Metab Brain Dis. 2022 Apr 30.
    Altered glucose metabolism and its association with carbonic anhydrase 8 in Machado-Joseph Disease.
    Guan-Yu Lin, Chung-Yung Ma, Li-Chung Kuo, Benjamin Y Hsieh, Hanbing Wang, Chin-San Liu, Mingli Hsieh.
      Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disease. This disorder is caused by polyglutamine (polyQ)-containing mutant ataxin-3, which tends to misfold and aggregate in neuron cells. We previously demonstrated a protective function of carbonic anhydrase 8 (CA8) in MJD disease models and a decreased glycolytic activity associated with down-regulated CA8 in a human osteosarcoma (OS) cell model. Given that a reduction in body weight accompanied by gait and balance instability was observed in MJD patients and transgenic (Tg) mice, in this study, we aimed to examine whether metabolic defects are associated with MJD and whether CA8 expression is involved in metabolic dysfunction in MJD. Our data first showed that glucose uptake ability decreases in cells harboring mutant ataxin-3, but increases in cells overexpressing CA8. In addition, the expressions of glucose transporter 3 (GLUT3) and phosphofructokinase-1 (PFK1) were significantly decreased in the presence of mutant ataxin-3. Consistently, immunohistochemistry (IHC) showed that GLUT3 was less expressed in cerebella of aged MJD Tg mice, indicating that the dysfunction of GLUT3 may be associated with late-stage disease. On the other hand, transient down-regulation of CA8 revealed decreased expressions of GLUT3 and PFK1 in HEK293 cells harboring wild-type (WT) ataxin-3, but no further reduction of GLUT3 and PFK1 expressions were observed in HEK293 cells harboring mutant ataxin-3. Moreover, immunoprecipitation (IP) and immunofluorescence (IF) demonstrated that interactions exist between ataxin-3, CA8 and GLUT3 in MJD cellular and Tg models. These lines of evidence suggest that CA8 plays an important role in glucose metabolism and has different impacts on cells with or without mutant ataxin-3. Interestingly, the decreased relative abundance of Firmicutes/Bacteroidetes (F/B) ratio in the feces of aged MJD Tg mice coincided with weight loss and metabolic dysfunction in MJD. Taken together, our results are the first to demonstrate the effects of CA8 on glucose metabolism and its involvement in the metabolic defects in MJD disease. Further investigations will be required to clarify the underlying mechanisms for the metabolic defects associated with MJD.
    Keywords:  Carbonic anhydrase 8; Glucose metabolism; Glucose transporter 3; Machado-Joseph Disease; Phosphofructokinase-1
    DOI:  https://doi.org/10.1007/s11011-022-00994-7
  15. Signal Transduct Target Ther. 2022 Apr 23. 7(1): 136
    Mitochondrial Complex I deficiency: guilty in Parkinson's disease.
    Melissa Vos.
      
    DOI:  https://doi.org/10.1038/s41392-022-00983-3
  16. Autophagy. 2022 Apr 26.
    Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy.
    Angelika B Harbauer, Thomas L Schwarz.
      Mitostasis, the process of mitochondrial maintenance by biogenesis and degradative mechanisms, is challenged by the extreme length of axons. PINK1 (PTEN induced putative kinase 1) is a mitochondrial protein that targets damaged mitochondria for mitophagy. In reconciling the short half-life of PINK1 with the need for mitophagy of damaged axonal mitochondria, we found that axonal mitophagy depends on local translation of the Pink1 mRNA. Using live-cell imaging, we detected co-transport of the Pink1 mRNA on mitochondria in neurons, which is crucial for mitophagy in distal parts of the cell. Here we discuss how the coupling of the transcript of a short-lived mitochondrial protein to the movement of its target organelles contributes to our understanding of mitostasis in neurons.
    Keywords:  Axonal biology; RNA transport; local translation; mitochondria; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2070332
  17. Neurochem Res. 2022 Apr 25.
    Alteration of Glycerophospholipid Metabolism in Hippocampus of Post-stroke Depression Rats.
    Wenxia Jiang, Jianjun Chen, Lei Gong, Fang Liu, Huan Zhao, Jun Mu.
      Post-stroke depression (PSD) is the most common mental disorder in stroke survivors. However, its specific pathophysiology remains largely unknown. Previous studies suggested a role of hippocampus in PSD. Therefore, we conducted this study to investigate the lipid metabolic signatures in hippocampus of PSD rats. Here, the liquid chromatography mass spectrometry was used to identify the lipid metabolic signatures in the hippocampus of PSD, control and stroke rats. Then, correlations between behavior indices and differential lipid metabolites in PSD rats were explored. Pathway and enrichment analysis were further conducted to uncover the crucial metabolic pathways related to PSD. Finally, we found that the lipid metabolic phenotype in hippocampus of PSD rats was substantially different from that in control and stroke rats, and identified 50 key lipid metabolites that were significantly decreased in PSD rats. These differential metabolites were mainly involved in glycerophospholipid metabolism. Meanwhile, the sucrose preference and immobility time were found to be significantly positively and negatively, respectively, correlated with glycerophospholipid metabolites. The pathway and enrichment analysis showed that the glycerophospholipid metabolism, especially cardiolipin metabolism, was significantly disturbed in PSD rats. These results suggested that the down-regulated glycerophospholipids in hippocampus, especially cardiolipin, might participate in the pathophysiology of PSD. Our findings would be helpful for future exploring the pathophysiology of PSD.
    Keywords:  Glycerophospholipid; Hippocampus; Metabolomics; Post-stroke depression
    DOI:  https://doi.org/10.1007/s11064-022-03596-y
  18. Alzheimers Res Ther. 2022 Apr 26. 14(1): 61
    Cerebrospinal fluid lactate levels along the Alzheimer's disease continuum and associations with blood-brain barrier integrity, age, cognition, and biomarkers.
    Paul Theo Zebhauser, Achim Berthele, Oliver Goldhardt, Janine Diehl-Schmid, Josef Priller, Marion Ortner, Timo Grimmer.
       BACKGROUND: Cerebrospinal fluid (CSF) lactate levels have been suggested to be associated with disease severity and progression in several neurological diseases as an indicator of impaired energy metabolism, neuronal death, or microglial activation. Few studies have examined CSF lactate levels in dementia due to Alzheimer's disease (AD) and found higher values in AD patients compared to healthy controls (HC). However, these studies were mostly small in size, the inclusion criteria were not always well defined, and the diagnostic value and pathophysiological significance of CSF lactate in AD remain unclear.
    METHODS: We examined CSF lactate levels and potentially associated factors in a large (n=312), biologically and clinically well-defined sample of patients with AD at the stage of mild cognitive impairment (MCI-AD) and dementia (ADD), HC, and patients with frontotemporal lobar degeneration (FTLD).
    RESULTS: Contrary to previous studies, patients with ADD and HC did not differ in CSF lactate levels. However, we found higher values for patients with MCI-AD compared to those with ADD and to HC in univariate analysis, as well as for MCI-AD compared to ADD when controlling for age and blood-brain barrier integrity. CSF lactate levels were associated with age and blood-brain barrier integrity but not with clinical severity or CSF biomarkers of AD.
    CONCLUSIONS: CSF lactate does not indicate biological or clinical disease severity in AD, nor does it differentiate between patients with AD and HC or patients with FTLD. However, higher CSF lactate levels were found in earlier stages of AD, which might be interpreted in the context of inflammatory processes.
    Keywords:  Alzheimer’s disease; Biomarkers; Blood-brain barrier; Cerebrospinal fluid; Lactate
    DOI:  https://doi.org/10.1186/s13195-022-01004-9
  19. NPJ Parkinsons Dis. 2022 Apr 25. 8(1): 52
    Lipid level alteration in human and cellular models of alpha synuclein mutations.
    Hila Avisar, Cristina Guardia-Laguarta, Matthew Surface, Nikos Papagiannakis, Matina Maniati, Roubina Antonellou, Dimitra Papadimitriou, Christos Koros, Aglaia Athanassiadou, Serge Przedborski, Boaz Lerner, Leonidas Stefanis, Estela Area-Gomez, Roy N Alcalay.
      Lipid profiles in biological fluids from patients with Parkinson's disease (PD) are increasingly investigated in search of biomarkers. However, the lipid profiles in genetic PD remain to be determined, a gap of knowledge of particular interest in PD associated with mutant α-synuclein (SNCA), given the known relationship between this protein and lipids. The objective of this research is to identify serum lipid composition from SNCA A53T mutation carriers and to compare these alterations to those found in cells and transgenic mice carrying the same genetic mutation. We conducted an unbiased lipidomic analysis of 530 lipid species from 34 lipid classes in serum of 30 participants with SNCA mutation with and without PD and 30 healthy controls. The primary analysis was done between 22 PD patients with SNCA+ (SNCA+/PD+) and 30 controls using machine-learning algorithms and traditional statistics. We also analyzed the lipid composition of human clonal-cell lines and tissue from transgenic mice overexpressing the same SNCA mutation. We identified specific lipid classes that best discriminate between SNCA+/PD+ patients and healthy controls and found certain lipid species, mainly from the glycerophosphatidylcholine and triradylglycerol classes, that are most contributory to this discrimination. Most of these alterations were also present in human derived cells and transgenic mice carrying the same mutation. Our combination of lipidomic and machine learning analyses revealed alterations in glycerophosphatidylcholine and triradylglycerol in sera from PD patients as well as cells and tissues expressing mutant α-Syn. Further investigations are needed to establish the pathogenic significance of these α-Syn-associated lipid changes.
    DOI:  https://doi.org/10.1038/s41531-022-00313-y
  20. Front Neurosci. 2022 ;16 842814
    Connecting the Dots Between Hypercholesterolemia and Alzheimer's Disease: A Potential Mechanism Based on 27-Hydroxycholesterol.
    Mingan Wu, Yingying Zhai, Xiaoyi Liang, Weichun Chen, Ruiyi Lin, Linlin Ma, Yi Huang, Di Zhao, Yong Liang, Wei Zhao, Jiansong Fang, Shuhuan Fang, Yunbo Chen, Qi Wang, Weirong Li.
      Alzheimer's disease (AD), the most common cause of dementia, is a complex and multifactorial disease involving genetic and environmental factors, with hypercholesterolemia considered as one of the risk factors. Numerous epidemiological studies have reported a positive association between AD and serum cholesterol levels, and experimental studies also provide evidence that elevated cholesterol levels accelerate AD pathology. However, the underlying mechanism of hypercholesterolemia accelerating AD pathogenesis is not clear. Here, we review the metabolism of cholesterol in the brain and focus on the role of oxysterols, aiming to reveal the link between hypercholesterolemia and AD. 27-hydroxycholesterol (27-OHC) is the major peripheral oxysterol that flows into the brain, and it affects β-amyloid (Aβ) production and elimination as well as influencing other pathogenic mechanisms of AD. Although the potential link between hypercholesterolemia and AD is well established, cholesterol-lowering drugs show mixed results in improving cognitive function. Nevertheless, drugs that target cholesterol exocytosis and conversion show benefits in improving AD pathology. Herbs and natural compounds with cholesterol-lowering properties also have a potential role in ameliorating cognition. Collectively, hypercholesterolemia is a causative risk factor for AD, and 27-OHC is likely a potential mechanism for hypercholesterolemia to promote AD pathology. Drugs that regulate cholesterol metabolism are probably beneficial for AD, but more research is needed to unravel the mechanisms involved in 27-OHC, which may lead to new therapeutic strategies for AD.
    Keywords:  27-hydroxycholesterol; Alzheimer’s disease; drug; hypercholesterolemia; pathogenesis
    DOI:  https://doi.org/10.3389/fnins.2022.842814
  21. Eur J Neurosci. 2022 Apr 28.
    CURRENT PERSPECTIVES ON MITOCHONDRIAL DYSFUNCTION IN MIGRAINE.
    Shraman Kumar Bohra, Raghu Ram Achar, Saravana Babu Chidambaram, Christophe Pellegrino, Jerome Laurin, Mojgan Masoodi, Asha Srinivasan.
      Mitochondria is an autonomous organelle that plays a crucial role in the metabolic aspects of a cell. Cortical Spreading Depression (CSD) and fluctuations in the cerebral blood flow have for long been mechanisms underlying migraine. It is a neurovascular disorder with a unilateral manifestation of disturbing, throbbing and pulsating head pain. Migraine affects 2.6 and 21.7% of the general population and is the major cause of partial disability in the age group 15-49. Higher mutation rates, imbalance in concentration of physiologically relevant molecules, oxidative stress biomarkers have been the main themes of discussion in determining the role of mitochondrial disability in migraine. The correlation of migraine with other disorders like hemiplegic migraine, MELAS, TTH, CVS, ischemic stroke and hypertension has helped in the assessment of the physiological and morphogenetic basis of migraine. Here, we have reviewed the different nuances of mitochondrial dysfunction and migraine. The different mtDNA polymorphisms that can affect the generation and transmission of nerve impulse has been highlighted and supported with research findings. In addition to this, the genetic basis of migraine pathogenesis as a consequence of mutations in nuclear DNA that can in turn affect the synthesis of defective mitochondrial proteins is discussed along with a brief overview of epigenetic profile. This review gives an overview of the pathophysiology of migraine and explores mitochondrial dysfunction as a potential underlying mechanism. Also, therapeutic supplements for managing migraine have been discussed at different junctures in this paper.
    Keywords:  Mitochondrial dysfunction; impairment; metabolism; migraine; mitochondrial genetics
    DOI:  https://doi.org/10.1111/ejn.15676
  22. Pharmacol Res. 2022 Apr 21. pii: S1043-6618(22)00173-6. [Epub ahead of print] 106228
    Mitochondrial stroke-like episodes: the search for new therapies.
    Daniele Orsucci, Elena Caldarazzo Ienco, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso.
      A mitochondrial stroke-like event is an evolving subacute neurological syndrome linked to seizure activity and focal metabolic brain derangement in a genetically determined mitochondrial disorder. The acronym "MELAS" (mitochondrial encephalopathy associated with lactic acidosis and stroke-like lesions) identifies subjects with molecular, biochemical and/or histological evidence of mitochondrial disorder who experience stroke-like lesions. MELAS is a rare inherited mitochondrial disease linked to severe multiorgan involvement and stress-induced episodes of metabolic decompensation and lactic acidosis. Unfortunately, there are no etiopathogenetic therapies for stroke-like episodes to date, and the treatment is mainly based on anti-epileptic drugs and supportive therapies. This perspective opinion article discusses the current care standards for MELAS patients and revises current and innovative emerging therapies for mitochondrial stroke-like episodes.
    Keywords:  MELAS; MTTL1; POLG; m.3243A>G; stroke; stroke-like episodes; stroke-like lesion
    DOI:  https://doi.org/10.1016/j.phrs.2022.106228
  23. Front Mol Neurosci. 2022 ;15 841047
    LIS1 and NDEL1 Regulate Axonal Trafficking of Mitochondria in Mature Neurons.
    Jai P Pandey, Liang Shi, Remi A Brebion, Deanna S Smith.
      Defective mitochondrial dynamics in axons have been linked to both developmental and late-onset neurological disorders. Axonal trafficking is in large part governed by the microtubule motors kinesin-1 and cytoplasmic dynein 1 (dynein). Dynein is the primary retrograde transport motor in axons, and mutations in dynein and many of its regulators also cause neurological diseases. Depletion of LIS1, famous for linking dynein deregulation to lissencephaly (smooth brain), in adult mice leads to severe neurological phenotypes, demonstrating post-developmental roles. LIS1 stimulates retrograde transport of acidic organelles in cultured adult rat dorsal root ganglion (DRG) axons but findings on its role in mitochondrial trafficking have been inconsistent and have not been reported for adult axons. Here we report that there is an increased number of mitochondria in cross-sections of sciatic nerve axons from adult LIS1+/- mice. This is probably related to reduced dynein activity as axons from adult rat nerves exposed to the dynein inhibitor, ciliobrevin D also had increased numbers of mitochondria. Moreover, LIS1 overexpression (OE) in cultured adult rat DRG axons stimulated retrograde mitochondrial transport while LIS1 knockdown (KD) or expression of a LIS1 dynein-binding mutant (LIS1-K147A) inhibited retrograde transport, as did KD of dynein heavy chain (DHC). These findings are consistent with our report on acidic organelles. However, KD of NDEL1, a LIS1 and dynein binding protein, or expression of a LIS1 NDEL1-binding mutant (LIS1-R212A) also dramatically impacted retrograde mitochondrial transport, which was not the case for acidic organelles. Manipulations that disrupted retrograde mitochondrial transport also increased the average length of axonal mitochondria, suggesting a role for dynein in fusion or fission events. Our data point to cargo specificity in NDEL1 function and raise the possibility that defects in the LIS1/NDEL1 dynein regulatory pathway could contribute to mitochondrial diseases with axonal pathologies.
    Keywords:  DRG; LIS1; NDEL1; axon; dynein; mitochondria; sciatic nerve
    DOI:  https://doi.org/10.3389/fnmol.2022.841047
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