bims-medebr 2023-01-22 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–01–22
twenty-two papers selected by
Regina F. Fernández, Johns Hopkins University

Cortical Thickness and Brain Glucose Metabolism in Healthy Aging.
PDZD8-deficient mice manifest behavioral abnormalities related to emotion, cognition, and adaptation due to dyslipidemia in the brain.
Cerebral metabolism of glucose and selected glucose transporters in neurodegenerative diseases
Isoform-specific Modification of Apolipoprotein E by 4-Hydroxynonenal: Protective Role of Apolipoprotein E3 Against Oxidative Species.
Butyrate Improves Neuroinflammation and Mitochondrial Impairment in Cerebral Cortex and Synaptic Fraction in an Animal Model of Diet-Induced Obesity.
Lipid Adaptations against Oxidative Challenge in the Healthy Adult Human Brain.
SIRT6 is a key regulator of mitochondrial function in the brain.
Astroglial CB1 receptors, energy metabolism, and gliotransmission: an integrated signaling system?
Construction of Glucose-6-Phosphate Dehydrogenase Overexpression Strain of Schizochytrium sp. H016 to Improve Docosahexaenoic Acid Production.
Cerebral Metabolic Rate of Glucose and Cognitive Tests in Long COVID Patients.
The Endocannabinoid System as a Target for Neuroprotection/Neuroregeneration in Perinatal Hypoxic-Ischemic Brain Injury.
Age-Related Decline in Gangliosides GM1 and GD1a in Non-CNS Tissues of Normal Mice: Implications for Peripheral Symptoms of Parkinson's Disease.
Chronic neuronal activation leads to elevated lactate dehydrogenase A through the AMP-activated protein kinase/hypoxia-inducible factor-1α hypoxia pathway.
Mitochondria-containing extracellular vesicles (EV) reduce mouse brain infarct sizes and EV/HSP27 protect ischemic brain endothelial cultures.
Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging.
Carnitine-acylcarnitine Translocase Deficiency with c.199-10T>G Mutation in Two Filipino Neonates Detected through Parental Carrier Testing.
Isolation of Mitochondrial Lipids and Mass Spectrometric Analysis.
Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.
Meta-analysis of brain samples of individuals with schizophrenia detects down-regulation of multiple ATP synthase encoding genes in both females and males.
Lactate-Mediated Signaling in the Brain-An Update.
Curcumin and N-Acetylcysteine Nanocarriers Alone or Combined with Deferoxamine Target the Mitochondria and Protect against Neurotoxicity and Oxidative Stress in a Co-Culture Model of Parkinson's Disease.
Astrocytes transplanted during early postnatal development integrate, mature, and survive long-term in mouse cortex.

J Clin Neurol. 2023 Jan 02.

Cortical Thickness and Brain Glucose Metabolism in Healthy Aging.

Kyoungwon Baik, Seun Jeon, Soh-Jeong Yang, Yeona Na, Seok Jong Chung, Han Soo Yoo, Mijin Yun, Phil Hyu Lee, Young H Sohn, Byoung Seok Ye.

BACKGROUND AND PURPOSE: We aimed to determine the effect of demographic factors on cortical thickness and brain glucose metabolism in healthy aging subjects.
METHODS: The following tests were performed on 71 subjects with normal cognition: neurological examination, 3-tesla magnetic resonance imaging, 18F-fluorodeoxyglucose positron-emission tomography, and neuropsychological tests. Cortical thickness and brain metabolism were measured using vertex- and voxelwise analyses, respectively. General linear models (GLMs) were used to determine the effects of age, sex, and education on cortical thickness and brain glucose metabolism. The effects of mean lobar cortical thickness and mean lobar metabolism on neuropsychological test scores were evaluated using GLMs after controlling for age, sex, and education. The intracranial volume (ICV) was further included as a predictor or covariate for the cortical thickness analyses.
RESULTS: Age was negatively correlated with the mean cortical thickness in all lobes (frontal and parietal lobes, p=0.001; temporal and occipital lobes, p<0.001) and with the mean temporal metabolism (p=0.005). Education was not associated with cortical thickness or brain metabolism in any lobe. Male subjects had a lower mean parietal metabolism than did female subjects (p<0.001), while their mean cortical thicknesses were comparable. ICV was positively correlated with mean cortical thickness in the frontal (p=0.016), temporal (p=0.009), and occipital (p=0.007) lobes. The mean lobar cortical thickness was not associated with cognition scores, while the mean temporal metabolism was positively correlated with verbal memory test scores.
CONCLUSIONS: Age and sex affect cortical thickness and brain glucose metabolism in different ways. Demographic factors must therefore be considered in analyses of cortical thickness and brain metabolism.

Keywords: FDG; MRI; brain glucose metabolism; cortical thickness; healthy aging
Mol Brain. 2023 Jan 19. 16(1): 11

PDZD8-deficient mice manifest behavioral abnormalities related to emotion, cognition, and adaptation due to dyslipidemia in the brain.

Yuji Kurihara, Kotone Mitsunari, Nagi Mukae, Hirotaka Shoji, Tsuyoshi Miyakawa, Michiko Shirane.

  Although dyslipidemia in the brain has been implicated in neurodegenerative disorders, the molecular mechanisms underlying its pathogenesis have been largely unclear. PDZD8 is a lipid transfer protein and mice deficient in PDZD8 (PDZD8-KO mice) manifest abnormal accumulation of cholesteryl esters (CEs) in the brain due to impaired lipophagy, the degradation system of lipid droplets. Here we show the detailed mechanism of PDZD8-dependent lipophagy. PDZD8 transports cholesterol to lipid droplets (LDs), and eventually promotes fusion of LDs and lysosomes. In addition, PDZD8-KO mice exhibit growth retardation, hyperactivity, reduced anxiety and fear, increased sensorimotor gating, and impaired cued fear conditioned memory and working memory. These results indicate that abnormal CE accumulation in the brain caused by PDZD8 deficiency affects emotion, cognition and adaptive behavior, and that PDZD8 plays an important role in the maintenance of brain function through lipid metabolism.

Keywords:  Behavior; Cholesterol; Dyslipidemia; Knockout mouse; Lipophagy; PDZD8

DOI:  https://doi.org/10.1186/s13041-023-01002-4
Postepy Biochem. 2022 12 31. 68(4): 375-380

Cerebral metabolism of glucose and selected glucose transporters in neurodegenerative diseases

Natalia Białoń, Michał Trzęsicki, Mikołaj Górka, Krzysztof Suszyński, Dariusz Górka.

Cerebral glucose metabolism is an issue of researchers’ interest for a long time. Disturbed transport and metabolism of glucose in the brain lead to development of numerous neurological pathologies. Recently, a significant correlation between perturbed cerebral glucose metabolism and development of neurodegenerative diseases has been shown. Glucose, a monosaccharide, is the main source of energy for brain cells. Brain is the organ which is the most sensitive to changes in blood glucose level. Perturbed glucose transport leads to disorders of the central glucose metabolism. Neurodegenerative diseases are defined in the literature as progressive and irreversible degeneration of nerve tissue, causing cell death as a result of degenerative processes. The aim of this article is to discuss the physiology and the role of selected glucose transporters in the development of neurodegenerative diseases: expression of selected GLUT1 and GLUT3 transporters in Alzheimer's and Huntington's diseases. Understanding of the cerebral glucose metabolism may be a crucial factor in fight with central nervous system diseases.

DOI: https://doi.org/10.18388/pb.2021_463
FEBS J. 2023 Jan 20.

Isoform-specific Modification of Apolipoprotein E by 4-Hydroxynonenal: Protective Role of Apolipoprotein E3 Against Oxidative Species.

Muhammad I Abeer, Abbas Abdulhasan, Zahraa Haguar, Vasanthy Narayanaswami.

  High levels of 4-hydroxynonenal (HNE), arising from lipid peroxidation, and HNE-modified proteins have been identified in postmortem brains of aging and Alzheimer's disease (AD) patients. The goal of this study is to understand the effect of HNE modification on the structure and function of recombinant apolipoprotein E3 (apoE3) and apolipoprotein E4 (apoE4), which play a critical role in brain cholesterol homeostasis. The two isoforms differ in a single amino acid at position 112: Cys in apoE3 and Arg in apoE4. Immunoblot with HNE-specific antibody indicates HNE modification of apoE3 and apoE4 with a major band at ~36 kDa, while LC-MS/MS revealed Michael addition at His140 (60-70% abundance) and His299 (3-5% abundance) in apoE3 and apoE4, and Cys112-adduct in apoE3 (75% abundance). Circular dichroism spectroscopy revealed no major differences in the overall secondary structure or helical content between unmodified and HNE modified apoE. HNE modification did not affect their ability to promote cholesterol efflux from J774.1 macrophages. However, it led to a 3-fold decrease in their ability to bind lipids and 25-50% decrease in the ability of cerebral cortex endothelial cells to uptake lipoproteins bearing HNE-modified HNE-apoE3 or HNE-apoE4 as noted by fluorescence microscopy and flow cytometry. Taken together, the data indicate that HNE modification impairs lipid binding and cellular uptake of both isoforms, and that apoE3, bearing a Cys, offers a protective role by sequestering lipid peroxidation products that would otherwise cause indiscriminate damage to biomolecules. ApoE4, lacking Cys, is unable to protect against oxidative damage that is commensurate with aging.

Keywords:  4-hydroxynonenal; Alzheimer's disease; Apolipoprotein E; Oxidative stress

DOI:  https://doi.org/10.1111/febs.16729
Antioxidants (Basel). 2022 Dec 20. pii: 4. [Epub ahead of print]12(1):

Butyrate Improves Neuroinflammation and Mitochondrial Impairment in Cerebral Cortex and Synaptic Fraction in an Animal Model of Diet-Induced Obesity.

Gina Cavaliere, Angela Catapano, Giovanna Trinchese, Fabiano Cimmino, Eduardo Penna, Amelia Pizzella, Claudia Cristiano, Adriano Lama, Marianna Crispino, Maria Pina Mollica.

  Neurodegenerative diseases (NDDs) are characterized by cognitive impairment and behavioural abnormalities. The incidence of NDDs in recent years has increased globally and the pathological mechanism is not fully understood. To date, plentiful evidence has showed that metabolic alterations associated with obesity and related issues such as neuroinflammation, oxidative stress and mitochondrial dysfunction may represent an important risk factor, linking obesity and NDDs. Numerous studies have indicated a correlation between diet and brain activities. In this context, a key role is played by mitochondria located in the synaptic fraction; indeed, it has been shown that high-fat diets cause their dysfunction, affecting synaptic plasticity. In this scenario, the use of natural molecules that improve brain mitochondrial function represents an important therapeutic approach to treat NDDs. Recently, it was demonstrated that butyrate, a short-chain fatty acid is capable of counteracting obesity in an animal model, modulating mitochondrial function. The aim of this study has been to evaluate the effects of butyrate on neuroinflammatory state, oxidative stress and mitochondrial dysfunction in the brain cortex and in the synaptic fraction of a mouse model of diet-induced obesity. Our data have shown that butyrate partially reverts neuroinflammation and oxidative stress in the brain cortex and synaptic area, improving mitochondrial function and efficiency.

Keywords:  butyrate; mitochondrial function; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.3390/antiox12010004
Antioxidants (Basel). 2023 Jan 12. pii: 177. [Epub ahead of print]12(1):

Lipid Adaptations against Oxidative Challenge in the Healthy Adult Human Brain.

Mariona Jové, Natàlia Mota-Martorell, Èlia Obis, Joaquim Sol, Meritxell Martín-Garí, Isidre Ferrer, Manuel Portero-Otín, Reinald Pamplona.

  It is assumed that the human brain is especially susceptible to oxidative stress, based on specific traits such as a higher rate of mitochondrial free radical production, a high content in peroxidizable fatty acids, and a low antioxidant defense. However, it is also evident that human neurons, although they are post-mitotic cells, survive throughout an entire lifetime. Therefore, to reduce or avoid the impact of oxidative stress on neuron functionality and survival, they must have evolved several adaptive mechanisms to cope with the deleterious effects of oxidative stress. Several of these antioxidant features are derived from lipid adaptations. At least six lipid adaptations against oxidative challenge in the healthy human brain can be discerned. In this work, we explore the idea that neurons and, by extension, the human brain is endowed with an important arsenal of non-pro-oxidant and antioxidant measures to preserve neuronal function, refuting part of the initial premise.

Keywords:  antioxidants; cholesterol; docosahexaenoic acid; fatty acids; lipid peroxidation; lipidomics; oleic acid; plasmalogens

DOI:  https://doi.org/10.3390/antiox12010177
Cell Death Dis. 2023 Jan 18. 14(1): 35

SIRT6 is a key regulator of mitochondrial function in the brain.

Dmitrii Smirnov, Ekaterina Eremenko, Daniel Stein, Shai Kaluski, Weronika Jasinska, Claudia Cosentino, Barbara Martinez-Pastor, Yariv Brotman, Raul Mostoslavsky, Ekaterina Khrameeva, Debra Toiber.

The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mouse brains. Our analysis reveals that SIRT6 is a central regulator of mitochondrial activity in the brain. SIRT6 deficiency in the brain leads to mitochondrial deficiency with a global downregulation of mitochondria-related genes and pronounced changes in metabolite content. We suggest that SIRT6 affects mitochondrial functions through its interaction with the transcription factor YY1 that, together, regulate mitochondrial gene expression. Moreover, SIRT6 target genes include SIRT3 and SIRT4, which are significantly downregulated in SIRT6-deficient brains. Our results demonstrate that the lack of SIRT6 leads to decreased mitochondrial gene expression and metabolomic changes of TCA cycle byproducts, including increased ROS production, reduced mitochondrial number, and impaired membrane potential that can be partially rescued by restoring SIRT3 and SIRT4 levels. Importantly, the changes we observed in SIRT6-deficient brains are also occurring in aging human brains and particularly in patients with Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis disease. Overall, our results suggest that the reduced levels of SIRT6 in the aging brain and neurodegeneration initiate mitochondrial dysfunction by altering gene expression, ROS production, and mitochondrial decay.

DOI: https://doi.org/10.1038/s41419-022-05542-w
Essays Biochem. 2023 Jan 16. pii: EBC20220089. [Epub ahead of print]

Astroglial CB1 receptors, energy metabolism, and gliotransmission: an integrated signaling system?

Ignacio Fernández-Moncada, Giovanni Marsicano.

  Astrocytes are key players in brain homeostasis and function. During the last years, several studies have cemented this notion by showing that these cells respond to neuronal signals and, via the release of molecules that modulate and support synaptic activity (gliotransmission) participates in the functions of the so-called tripartite synapse. Thus, besides their established control of brain metabolism, astrocytes can also actively control synaptic activity and behavior. Among the signaling pathways that shape the functions of astrocyte, the cannabinoid type-1 (CB1) receptor is emerging as a critical player in the control of both gliotransmission and the metabolic cooperation between astrocytes and neurons. In the present short review, we describe known and newly discovered properties of the astroglial CB1 receptors and their role in modulating brain function and behavior. Based on this evidence, we finally discuss how the functions and mode of actions of astrocyte CB1 receptors might represent a clear example of the inextricable relationship between energy metabolism and gliotransmission. These tight interactions will need to be taken into account for future research in astrocyte functions and call for a reinforcement of the theoretical and experimental bridges between studies on metabolic and synaptic functions of astrocytes.

Keywords:  CB1 receptors; astrocytes; energy metabolism; gliotransmission

DOI:  https://doi.org/10.1042/EBC20220089
Mar Drugs. 2022 Dec 26. pii: 17. [Epub ahead of print]21(1):

Construction of Glucose-6-Phosphate Dehydrogenase Overexpression Strain of Schizochytrium sp. H016 to Improve Docosahexaenoic Acid Production.

Yumei Feng, Yuanmin Zhu, Zhendong Bao, Bohan Wang, Tingting Liu, Huihui Wang, Tianyi Yu, Ying Yang, Longjiang Yu.

  Docosahexaenoic acid (DHA) is an important omega-3 polyunsaturated fatty acid (PUFA) that plays a critical physiological role in human health. Schizochytrium sp. is considered an excellent strain for DHA production, but the synthesis of DHA is limited by the availability of nicotinamide adenine dinucleotide phosphate (NADPH). In this study, the endogenous glucose-6-phosphate dehydrogenase (G6PD) gene was overexpressed in Schizochytrium sp. H016. Results demonstrated that G6PD overexpression increased the availability of NADPH, which ultimately altered the fatty acid profile, resulting in a 1.91-fold increase in DHA yield (8.81 g/L) and increased carbon flux by shifting it from carbohydrate and protein synthesis to lipid production. Thus, G6PD played a vital role in primary metabolism. In addition, G6PD significantly increased DHA content and lipid accumulation by 31.47% and 40.29%, respectively. The fed-batch fermentation experiment results showed that DHA production reached 17.01 g/L in the overexpressing G6PD strain. These results elucidated the beneficial effects of NADPH on the synthesis of PUFA in Schizochytrium sp. H016, which may be a potential target for metabolic engineering. Furthermore, this study provides a promising regulatory strategy for the large-scale production of DHA in Schizochytrium sp.

Keywords:  NADPH; Schizochytrium sp.; docosahexaenoic acid; glucose-6-phosphate dehydrogenase; polyunsaturated fatty acid

DOI:  https://doi.org/10.3390/md21010017
Brain Sci. 2022 Dec 22. pii: 23. [Epub ahead of print]13(1):

Cerebral Metabolic Rate of Glucose and Cognitive Tests in Long COVID Patients.

Kamilla W Miskowiak, Johanne L Bech, Alexander Cuculiza Henriksen, Stine Johnsen, Daria Podlekareva, Lisbeth Marner.

   BACKGROUND: Common long-term sequelae after COVID-19 include fatigue and cognitive impairment. Although symptoms interfere with daily living, the underlying pathology is largely unknown. Previous studies report relative hypometabolism in frontal, limbic and cerebellar regions suggesting focal brain involvement. We aimed to determine whether absolute hypometabolism was present and correlated to same day standardized neurocognitive testing.
METHODS: Fourteen patients included from a long COVID clinic had cognitive testing and quantitative dynamic [18F]FDG PET of the brain on the same day to correlate cognitive function to metabolic glucose rate.
RESULTS: We found no hypometabolism in frontal, limbic and cerebellar regions in cognitively impaired relative to cognitive intact patients. In contrast, the cognitive impaired patients showed higher cerebellar metabolism (p = 0.03), which correlated with more severe deficits in working memory and executive function (p = 0.03).
CONCLUSIONS: Hypermetabolism in the cerebellum may reflect inefficient brain processing and play a role in cognitive impairments after COVID-19.

Keywords:  COVID-19; FDG; PET; brain fog; brain metabolism; cognitive impairment; positron emission tomography; quality of life; work function

DOI:  https://doi.org/10.3390/brainsci13010023
Biomedicines. 2022 Dec 22. pii: 28. [Epub ahead of print]11(1):

The Endocannabinoid System as a Target for Neuroprotection/Neuroregeneration in Perinatal Hypoxic-Ischemic Brain Injury.

Andrea Duranti, Gorane Beldarrain, Antonia Álvarez, Matilde Sbriscia, Silvia Carloni, Walter Balduini, Daniel Alonso-Alconada.

  The endocannabinoid (EC) system is a complex cell-signaling system that participates in a vast number of biological processes since the prenatal period, including the development of the nervous system, brain plasticity, and circuit repair. This neuromodulatory system is also involved in the response to endogenous and environmental insults, being of special relevance in the prevention and/or treatment of vascular disorders, such as stroke and neuroprotection after neonatal brain injury. Perinatal hypoxia-ischemia leading to neonatal encephalopathy is a devastating condition with no therapeutic approach apart from moderate hypothermia, which is effective only in some cases. This overview, therefore, gives a current description of the main components of the EC system (including cannabinoid receptors, ligands, and related enzymes), to later analyze the EC system as a target for neonatal neuroprotection with a special focus on its neurogenic potential after hypoxic-ischemic brain injury.

Keywords:  FAAH inhibitors; MGL inhibitors; cannabinoid receptors; endocannabinoid system; hypoxia–ischemia; neonatal brain injury; neurogenesis; neuroprotection

DOI:  https://doi.org/10.3390/biomedicines11010028
Biomedicines. 2023 Jan 14. pii: 209. [Epub ahead of print]11(1):

Age-Related Decline in Gangliosides GM1 and GD1a in Non-CNS Tissues of Normal Mice: Implications for Peripheral Symptoms of Parkinson's Disease.

Suman Chowdhury, Gusheng Wu, Zi-Hua Lu, Ranjeet Kumar, Robert Ledeen.

  The purpose of this study was to determine whether the age-related decline in a-series gangliosides (especially GM1), shown to be a factor in the brain-related etiology of Parkinson's disease (PD), also pertains to the peripheral nervous system (PNS) and aspects of PD unrelated to the central nervous system (CNS). Following Svennerholm's demonstration of the age-dependent decline in a-series gangliosides (both GM1 and GD1a) in the human brain, we previously demonstrated a similar decline in the normal mouse brain. The present study seeks to determine whether a similar a-series decline occurs in the periphery of normal mice as a possible prelude to the non-CNS symptoms of PD. We used mice of increasing age to measure a-series gangliosides in three peripheral tissues closely associated with PD pathology. Employing high-performance thin-layer chromatography (HPTLC), we found a substantial decrease in both GM1 and GD1a in all three tissues from 191 days of age. Motor and cognitive dysfunction were also shown to worsen, as expected, in synchrony with the decrease in GM1. Based on the previously demonstrated parallel between mice and humans concerning age-related a-series ganglioside decline in the brain, we propose the present findings to suggest a similar a-series decline in human peripheral tissues as the primary contributor to non-CNS pathologies of PD. An onset of sporadic PD would thus be seen as occurring simultaneously throughout the brain and body, albeit at varying rates, in association with the decline in a-series gangliosides. This would obviate the need to postulate the transfer of aggregated α-synuclein between brain and body or to debate brain vs. body as the origin of PD.

Keywords:  GM1 ganglioside; HPTLC; Parkinson’s disease; aging; memory impairment; motor impairment; peripheral tissues

DOI:  https://doi.org/10.3390/biomedicines11010209
Brain Commun. 2023 ;5(1): fcac298

Chronic neuronal activation leads to elevated lactate dehydrogenase A through the AMP-activated protein kinase/hypoxia-inducible factor-1α hypoxia pathway.

Alexander Ksendzovsky, Muznabanu Bachani, Marcelle Altshuler, Stuart Walbridge, Armin Mortazavi, Mitchell Moyer, Chixiang Chen, Islam Fayed, Joseph Steiner, Nancy Edwards, Sara K Inati, Jahandar Jahanipour, Dragan Maric, John D Heiss, Jaideep Kapur, Kareem A Zaghloul.

  Recent studies suggest that changes in neuronal metabolism are associated with epilepsy. High rates of ATP depletion, lactate dehydrogenase A and lactate production have all been found in epilepsy patients, animal and tissue culture models. As such, it can be hypothesized that chronic seizures lead to continuing elevations in neuronal energy demand which may lead to an adapted metabolic response and elevations of lactate dehydrogenase A. In this study, we examine elevations in the lactate dehydrogenase A protein as a long-term cellular adaptation to elevated metabolic demand from chronic neuronal activation. We investigate this cellular adaptation in human tissue samples and explore the mechanisms of lactate dehydrogenase A upregulation using cultured neurones treated with low Mg2+, a manipulation that leads to NMDA-mediated neuronal activation. We demonstrate that human epileptic tissue preferentially upregulates neuronal lactate dehydrogenase A, and that in neuronal cultures chronic and repeated elevations in neural activity lead to upregulation of neuronal lactate dehydrogenase A. Similar to states of hypoxia, this metabolic change occurs through the AMP-activated protein kinase/hypoxia-inducible factor-1α pathway. Our data therefore reveal a novel long-term bioenergetic adaptation that occurs in chronically activated neurones and provide a basis for understanding the interplay between metabolism and neural activity during epilepsy.

Keywords:  HIF1α; LDHA; epilepsy; glycolysis; neuronal metabolism

DOI:  https://doi.org/10.1093/braincomms/fcac298
J Control Release. 2023 Jan 18. pii: S0168-3659(23)00026-3. [Epub ahead of print]354 368-393

Mitochondria-containing extracellular vesicles (EV) reduce mouse brain infarct sizes and EV/HSP27 protect ischemic brain endothelial cultures.

Kandarp M Dave, Donna B Stolz, Venugopal R Venna, Victoria A Quaicoe, Michael E Maniskas, Michael John Reynolds, Riyan Babidhan, Duncan X Dobbins, Maura N Farinelli, Abigail Sullivan, Tarun N Bhatia, Hannah Yankello, Rohan Reddy, Younsoo Bae, Rehana K Leak, Sruti S Shiva, Louise D McCullough, Devika S Manickam.

  Ischemic stroke causes brain endothelial cell (BEC) death and damages tight junction integrity of the blood-brain barrier (BBB). We harnessed the innate mitochondrial load of BEC-derived extracellular vesicles (EVs) and utilized mixtures of EV/exogenous 27 kDa heat shock protein (HSP27) as a one-two punch strategy to increase BEC survival (via EV mitochondria) and preserve their tight junction integrity (via HSP27 effects). We demonstrated that the medium-to-large (m/lEV) but not small EVs (sEV) transferred their mitochondrial load, that subsequently colocalized with the mitochondrial network of the recipient primary human BECs. Recipient BECs treated with m/lEVs showed increased relative ATP levels and mitochondrial function. To determine if the m/lEV-meditated increase in recipient BEC ATP levels was associated with m/lEV mitochondria, we isolated m/lEVs from donor BECs pre-treated with oligomycin A (OGM, mitochondria electron transport complex V inhibitor), referred to as OGM-m/lEVs. BECs treated with naïve m/lEVs showed a significant increase in ATP levels compared to untreated OGD cells, OGM-m/lEVs treated BECs showed a loss of ATP levels suggesting that the m/lEV-mediated increase in ATP levels is likely a function of their innate mitochondrial load. In contrast, sEV-mediated ATP increases were not affected by inhibition of mitochondrial function in the donor BECs. Intravenously administered m/lEVs showed a reduction in brain infarct sizes compared to vehicle-injected mice in a mouse middle cerebral artery occlusion model of ischemic stroke. We formulated binary mixtures of human recombinant HSP27 protein with EVs: EV/HSP27 and ternary mixtures of HSP27 and EVs with a cationic polymer, poly (ethylene glycol)-b-poly (diethyltriamine): (PEG-DET/HSP27)/EV. (PEG-DET/HSP27)/EV and EV/HSP27 mixtures decreased the paracellular permeability of small and large molecular mass fluorescent tracers in oxygen glucose-deprived primary human BECs. This one-two punch approach to increase BEC metabolic function and tight junction integrity may be a promising strategy for BBB protection and prevention of long-term neurological dysfunction post-ischemic stroke.

Keywords:  BBB protection; Extracellular vesicles; Heat shock protein; Ischemic stroke; Mitochondria; Paracellular permeability

DOI:  https://doi.org/10.1016/j.jconrel.2023.01.025
J Transl Med. 2023 Jan 20. 21(1): 36

Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging.

Wei Wan, Lieliang Zhang, Yue Lin, Xiuqing Rao, Xifeng Wang, Fuzhou Hua, Jun Ying.

  MOTS-c is a peptide encoded by the short open reading frame of the mitochondrial 12S rRNA gene. It is significantly expressed in response to stress or exercise and translocated to the nucleus, where it regulates the expression of stress adaptation-related genes with antioxidant response elements (ARE). MOTS-c mainly acts through the Folate-AICAR-AMPK pathway, thereby influencing energy metabolism, insulin resistance, inflammatory response, exercise, aging and aging-related pathologies. Because of the potential role of MOTS-c in maintaining energy and stress homeostasis to promote healthy aging, especially in view of the increasing aging of the global population, it is highly pertinent to summarize the relevant studies. This review summarizes the retrograde signaling of MOTS-c toward the nucleus, the regulation of energy metabolism, stress homeostasis, and aging-related pathological processes, as well as the underlying molecular mechanisms.

Keywords:  Aging; Inflammation; MOTS-c; Mitochondrial gene; Stress response

DOI:  https://doi.org/10.1186/s12967-023-03885-2
Int J Neonatal Screen. 2023 Jan 11. pii: 4. [Epub ahead of print]9(1):

Carnitine-acylcarnitine Translocase Deficiency with c.199-10T>G Mutation in Two Filipino Neonates Detected through Parental Carrier Testing.

Suzanne Marie G Carmona, Mary Ann R Abacan, Maria Melanie Liberty B Alcausin.

  Carnitine-acylcarnitine translocase deficiency (CACTD), a fatty acid oxidation defect (FAOD), can present in the neonatal period with non-specific findings and hypoglycemia. A high index of suspicion is needed to recognize the disorder. The case is of a 24-year-old G2P2(2000) mother who sought consultation for recurrent neonatal deaths. The neonates, born two years apart, were apparently well at birth but had a fair cry and no spontaneous eye opening within the first 24 h of life and died before the 72nd hour of life. Newborn screening of both babies revealed elevated long chain acylcarnitines and hypocarnitinemia suggestive of a FAOD. However, due to their early demise, no confirmatory tests were done. Parental carrier testing was performed, revealing both parents to be heterozygous carriers of a pathogenic variant, c.199 10T>G (intronic), in the SLC25A20 gene associated with autosomal recessive CACTD. This is the first reported case of CACTD in the Filipino population.

Keywords:  SLC25A20; c.199 10T>G mutation; carnitine acylcarnitine translocase deficiency (CACTD); fatty acid oxidation defect

DOI:  https://doi.org/10.3390/ijns9010004
Methods Mol Biol. 2023 ;2625 1-6

Isolation of Mitochondrial Lipids and Mass Spectrometric Analysis.

Alexa M Jauregui, Zoé M Cubero Cortés, Sean D Meehan, Sanjoy K Bhattacharya.

  Mitochondria participate in many important metabolic processes in the body. The lipid profile of mitochondria is especially important in membrane regulation and pathway signaling. The isolation and study of these lipids can provide unparalleled information about the mechanisms behind these cellular processes. In this chapter, we describe a protocol to isolate mitochondrial lipids from homogenized murine optic nerves. The lipid extraction was performed using butanol-methanol (BUME) and subsequently analyzed using liquid chromatography-mass spectrometry. Further analysis of the raw data was conducted using LipidSearch™ and MetaboAnalyst 4.0.

Keywords:  Lipidomics; Liquid chromatography; Mitochondrial lipids; Neurodegeneration; mass spectrometry

DOI:  https://doi.org/10.1007/978-1-0716-2966-6_1
Sci Transl Med. 2023 Jan 18. 15(679): eabq6288

Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.

Katharina M Eyme, Alessandro Sammarco, Roshani Jha, Hayk Mnatsakanyan, Caline Pechdimaljian, Litia Carvalho, Rudolph Neustadt, Charlotte Moses, Ahmad Alnasser, Daniel F Tardiff, Baolong Su, Kevin J Williams, Steven J Bensinger, Chee Yeun Chung, Christian E Badr.

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies.

DOI: https://doi.org/10.1126/scitranslmed.abq6288
J Psychiatr Res. 2023 Jan 04. pii: S0022-3956(23)00005-5. [Epub ahead of print]158 350-359

Meta-analysis of brain samples of individuals with schizophrenia detects down-regulation of multiple ATP synthase encoding genes in both females and males.

Noa Katz Shroitman, Assif Yitzhaky, Dorit Ben Shachar, David Gurwitz, Libi Hertzberg.

  Schizophrenia is a chronic and debilitating mental disorder, with unknown pathophysiology. Converging lines of evidence suggest that mitochondrial functioning may be compromised in schizophrenia. Postmortem brain samples of individuals with schizophrenia showed dysregulated expression levels of genes encoding enzyme complexes comprising the mitochondrial electron transport chain (ETC), including ATP synthase, the fifth ETC complex. However, there are inconsistencies regarding the direction of change, i.e., up- or down-regulation, and differences between female and male patients were hardly examined. We have performed a systematic meta-analysis of the expression of 16 ATP synthase encoding genes in postmortem brain samples of individuals with schizophrenia vs. healthy controls of three regions: Brodmann Area 10 (BA10), BA22/Superior Temporal Gyrus (STG) and the cerebellum. Eight independent datasets were integrated (overall 294brain samples, 145 of individuals with schizophrenia and 149 controls). The meta-analysis was applied to all individuals with schizophrenia vs. the controls, and also to female and male patients vs. age-matched controls, separately. A significant down-regulation of two ATP synthase encoding genes was detected in schizophrenia, ATP5A1 and ATP5H, and a trend towards down-regulation of five further ATP synthase genes. The down-regulation tendency was shown for both females and males with schizophrenia. Our findings support the hypothesis that schizophrenia is associated with reduced ATP synthesis via the oxidative phosphorylation system, which is caused by reduced cellular demand of ATP. Abnormal cellular energy metabolism can lead to alterations in neural function and brain circuitry, and thereby to the cognitive and behavioral aberrations characteristic of schizophrenia.

Keywords:  ATP synthase; Gene expression; Male and female differences; Postmortem brain samples; Schizophrenia

DOI:  https://doi.org/10.1016/j.jpsychires.2023.01.005
Brain Sci. 2022 Dec 27. pii: 49. [Epub ahead of print]13(1):

Lactate-Mediated Signaling in the Brain-An Update.

Barbara Vaccari-Cardoso, Maria Antipina, Anja G Teschemacher, Sergey Kasparov.

  Lactate is a universal metabolite produced and released by all cells in the body. Traditionally it was viewed as energy currency that is generated from pyruvate at the end of the glycolytic pathway and sent into the extracellular space for other cells to take up and consume. In the brain, such a mechanism was postulated to operate between astrocytes and neurons many years ago. Later, the discovery of lactate receptors opened yet another chapter in the quest to understand lactate actions. Other ideas, such as modulation of NMDA receptors were also proposed. Up to this day, we still do not have a consensus view on the relevance of any of these mechanisms to brain functions or their contribution to human or animal physiology. While the field develops new ideas, in this brief review we analyze some recently published studies in order to focus on some unresolved controversies and highlight the limitations that need to be addressed in future work. Clearly, only by using similar and overlapping methods, cross-referencing experiments, and perhaps collaborative efforts, we can finally understand what the role of lactate in the brain is and why this ubiquitous molecule is so important.

Keywords:  astrocyte; lactate; metabolism; receptor; signaling

DOI:  https://doi.org/10.3390/brainsci13010049
Antioxidants (Basel). 2023 Jan 05. pii: 130. [Epub ahead of print]12(1):

Curcumin and N-Acetylcysteine Nanocarriers Alone or Combined with Deferoxamine Target the Mitochondria and Protect against Neurotoxicity and Oxidative Stress in a Co-Culture Model of Parkinson's Disease.

Leah Mursaleen, Stefanie Ho Yi Chan, Brendon Noble, Satyanarayana Somavarapu, Mohammed Gulrez Zariwala.

  As the blood-brain barrier (BBB) prevents most compounds from entering the brain, nanocarrier delivery systems are frequently being explored to potentially enhance the passage of drugs due to their nanometer sizes and functional characteristics. This study aims to investigate whether Pluronic® F68 (P68) and dequalinium (DQA) nanocarriers can improve the ability of curcumin, n-acetylcysteine (NAC) and/or deferoxamine (DFO), to access the brain, specifically target mitochondria and protect against rotenone by evaluating their effects in a combined Transwell® hCMEC/D3 BBB and SH-SY5Y based cellular Parkinson's disease (PD) model. P68 + DQA nanoformulations enhanced the mean passage across the BBB model of curcumin, NAC and DFO by 49%, 28% and 49%, respectively (p < 0.01, n = 6). Live cell mitochondrial staining analysis showed consistent co-location of the nanocarriers within the mitochondria. P68 + DQA nanocarriers also increased the ability of curcumin and NAC, alone or combined with DFO, to protect against rotenone induced cytotoxicity and oxidative stress by up to 19% and 14% (p < 0.01, n = 6), as measured by the MTT and mitochondrial hydroxyl radical assays respectively. These results indicate that the P68 + DQA nanocarriers were successful at enhancing the protective effects of curcumin, NAC and/or DFO by increasing the brain penetrance and targeted delivery of the associated bioactives to the mitochondria in this model. This study thus emphasises the potential effectiveness of this nanocarrier strategy in fully utilising the therapeutic benefit of these antioxidants and lays the foundation for further studies in more advanced models of PD.

Keywords:  Parkinson’s disease; SH-SY5Y cells; Transwell® model; blood-brain barrier; curcumin; deferoxamine; hCMEC/D3; iron; n-acetylcysteine; neurodegeneration; oxidative stress

DOI:  https://doi.org/10.3390/antiox12010130
J Neurosci. 2023 Jan 19. pii: JN-RM-0544-22. [Epub ahead of print]

Astrocytes transplanted during early postnatal development integrate, mature, and survive long-term in mouse cortex.

Sabrina Chierzi, J Benjamin Kacerovsky, Albert Hk Fok, Sylvie Lahaie, Arielle Shibi-Rosen, W Todd Farmer, Keith K Murai.

Astrocytes have complex structural, molecular, and physiological properties and form specialized microenvironments that support circuit-specific functions in the central nervous system. To better understand how astrocytes acquire their unique features, we transplanted immature mouse cortical astrocytes into the developing cortex of male and female mice and assessed their integration, maturation, and survival. Within days, transplanted astrocytes developed morphologies and acquired territories and tiling behavior typical of cortical astrocytes. At 35-47 days post transplantation, astrocytes appeared morphologically mature and expressed levels of EAAT2/GLT-1 similar to non-transplanted astrocytes. Transplanted astrocytes also supported excitatory/inhibitory pre-synaptic terminals within their territories, and displayed normal Ca2+ events. Transplanted astrocytes showed initially reduced expression of aquaporin 4 (AQP4) at endfeet and elevated expression of EAAT1/GLAST, with both proteins showing normalized expression by 110 days and 1 year post transplantation, respectively. To understand how specific brain regions support astrocytic integration and maturation, we transplanted cortical astrocytes into the developing cerebellum. Cortical astrocytes interlaced with Bergmann glia in the cerebellar molecular layer to establish discrete territories. However, transplanted astrocytes retained many cortical astrocytic features including higher levels of EAAT2/GLT-1, lower levels of EAAT1/GLAST, and the absence of expression of the AMPAR subunit GluA1. Collectively, our findings demonstrate that immature cortical astrocytes integrate, mature, and survive (>1 year) following transplantation and retain cortical astrocytic properties. Astrocytic transplantation can be useful for investigating cell-autonomous (intrinsic) and non-cell autonomous (environmental) mechanisms contributing to astrocytic development/diversity, and for determining the optimal timing for transplanting astrocytes for cellular delivery or replacement in regenerative medicine.SIGNIFICANCE STATEMENT:The mechanisms that enable astrocytes to acquire diverse molecular and structural properties remain to be better understood. In this study, we systematically analyzed the properties of cortical astrocytes following their transplantation to the early postnatal brain. We found that immature cortical astrocytes transplanted into cerebral cortex during early postnatal mouse development integrate and establish normal astrocytic properties, and show long-term survival in vivo (>1 year). In contrast, transplanted cortical astrocytes display reduced or altered ability to integrate into the more mature cerebral cortex or developing cerebellum, respectively. This study demonstrates the developmental potential of transplanted cortical astrocytes and provides an approach to tease apart cell-autonomous (intrinsic) and non-cell autonomous (environmental) mechanisms that determine the structural, molecular, and physiological phenotype of astrocytes.

DOI: https://doi.org/10.1523/JNEUROSCI.0544-22.2023