bims-medebr 2022-03-27 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022‒03‒27
24 papers selected by
Regina F. Fernández
Johns Hopkins University

Evidence That Substantia Nigra Pars Compacta Dopaminergic Neurons Are Selectively Vulnerable to Oxidative Stress Because They Are Highly Metabolically Active.
N-3 polyunsaturated fatty acids prevent the D-galactose-induced cognitive impairment by up-regulating the levels of 5-hydroxymethylcytosine in the mouse brain.
Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability.
Effects of Intermittent Fasting on Brain Metabolism.
Mitochondrial dynamics in the neonatal brain - a potential target following injury?
Susceptibility of Female Mice to the Dietary Omega-3/Omega-6 Fatty-Acid Ratio: Effects on Adult Hippocampal Neurogenesis and Glia.
SPG15 protein deficits are at the crossroads between lysosomal abnormalities, altered lipid metabolism and synaptic dysfunction.
Caloric Restriction Mimetic 2-Deoxyglucose Reduces Inflammatory Signaling in Human Astrocytes: Implications for Therapeutic Strategies Targeting Neurodegenerative Diseases.
Neurons Release Injured Mitochondria as "Help-Me" Signaling After Ischemic Stroke.
Hexokinase 1 cellular localization regulates the metabolic fate of glucose.
D-galactose-induced aging in rats - The effect of metformin on bioenergetics of brain, skeletal muscle and liver.
Bezafibrate Rescues Mitochondrial Encephalopathy in Mice via Induction of Daily Torpor and Hypometabolic State.
Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice.
Changes in Plasma Lipid Levels Following Cortical Spreading Depolarization in a Transgenic Mouse Model of Familial Hemiplegic Migraine.
Loss of Microglial Insulin Receptor Leads to Sex-Dependent Metabolic Disorders in Obese Mice.
Overview of (f)MRI Studies of Cognitive Aging for Non-Experts: Looking through the Lens of Neuroimaging.
The C-glucosyl flavone isoorientin pretreatment attenuates the methylglyoxal-induced mitochondrial dysfunction in the human neuroblastoma SH-SY5Y cells: role for the AMPK-PI3K/Akt/Nrf2/γ-GCL/GSH axis.
Reviewing the mitochondrial dysfunction paradigm in rodent models as platforms for neuropsychiatric disease research.
HDL Accessory Proteins in Parkinson's Disease-Focusing on Clusterin (Apolipoprotein J) in Regard to Its Involvement in Pathology and Diagnostics-A Review.
Acid Sphingomyelinase Is a Modulator of Contextual Fear.
Oleanolic acid and ursolic acid: therapeutic potential in neurodegenerative diseases, neuropsychiatric diseases and other brain disorders.
Sphingolipid control of cognitive functions in health and disease.
4-Hydroxy-3,5-di-tret-butyl cinnamic acid restores the activity of the hippocampal mitochondria in rats under permanent focal cerebral ischemia.
Brain Functional Network and Amino Acid Metabolism Association in Females with Subclinical Depression.

Front Cell Neurosci. 2022 ;16 826193

Evidence That Substantia Nigra Pars Compacta Dopaminergic Neurons Are Selectively Vulnerable to Oxidative Stress Because They Are Highly Metabolically Active.

Anjie Ni, Carl Ernst.

  There are 400-500 thousand dopaminergic cells within each side of the human substantia nigra pars compacta (SNpc) making them a minuscule portion of total brain mass. These tiny clusters of cells have an outsized impact on motor output and behavior as seen in disorders such as Parkinson's disease (PD). SNpc dopaminergic neurons are more vulnerable to oxidative stress compared to other brain cell types, but the reasons for this are not precisely known. Here we provide evidence to support the hypothesis that this selective vulnerability is because SNpc neurons sustain high metabolic rates compared to other neurons. A higher baseline requirement for ATP production may lead to a selective vulnerability to impairments in oxidative phosphorylation (OXPHOS) or genetic insults that impair Complex I of the electron transport chain. We suggest that the energy demands of the unique morphological and electrophysiological properties of SNpc neurons may be one reason these cells produce more ATP than other cells. We further provide evidence to support the hypothesis that transcription factors (TFs) required to drive induction, differentiation, and maintenance of midbrain dopaminergic neural progenitor cells which give rise to terminally differentiated SNpc neurons are uniquely involved in both developmental patterning and metabolism, a dual function unlike other TFs that program neurons in other brain regions. The use of these TFs during induction and differentiation may program ventral midbrain progenitor cells metabolically to higher ATP levels, allowing for the development of those specialized cell processes seen in terminally differentiated cells. This paper provides a cellular and developmental framework for understanding the selective vulnerability of SNpc dopaminergic cells to oxidative stress.

Keywords:  FOXA; LMX1; NR4A2; dopamine; midbrain development

DOI:  https://doi.org/10.3389/fncel.2022.826193
Food Funct. 2022 Mar 22.

N-3 polyunsaturated fatty acids prevent the D-galactose-induced cognitive impairment by up-regulating the levels of 5-hydroxymethylcytosine in the mouse brain.

Tianyu Zhang, Lei Chen, Xiaofei Guo, Shan Li, Xin He, Shengjie Pei, Duo Li.

Decreased 5-hydroxymethylcytosine (5hmC) levels caused by mitochondrial dysfunction in the brain are closely associated with the development of neurodegenerative disease. It has been reported that n-3 polyunsaturated fatty acids (PUFAs) prevent cognitive dysfunction by improving mitochondrial function in the brain. However, whether n-3 PUFA prevents cognitive dysfunction by increasing the levels of 5hmC in the brain is undisclosed. Mice were randomly divided into six groups (n = 10), injected with D-galactose (200 mg kg-1 day-1) for the model group and given different oils [0.1 mL per 10 g body weight per day, fish oil (FO), peony seed oil (PSO), corn oil (CO) and olive oil (OO)] for the prevention groups, and injected with the same dose of saline for the normal control group (NC) for 10 weeks, respectively. Peony seed oil and fish oil have shown preventive effects on D-galactose-induced cognitive dysfunction in behavioral tests. The content of docosahexaenoic acid (C22:6n-3, DHA content) in the brain was significantly higher in FO and PSO groups than in the other groups. Brain oxidative stress and neuronal apoptosis were significantly lower in PSO and FO groups than in the other groups. RNA-seq results showed that the different genes between PSO and FO compared with the model group were involved in the DNA demethylation process and the 5-methylcytosine metabolic process. The brain levels of 5hmC and the ten-eleven translocation family of dioxygenases (TETs) were significantly higher in FO and PSO groups compared with the model group, as analyzed by dot-blot and western blot. In conclusion, peony seed oil and fish oil increased the C22:6n-3 content, which activated the TET activity, led to up-regulation of the 5hmc level, resulted in inhibition of neuronal apoptosis, and then improved the cognitive function in D-gal-induced mice.

DOI: https://doi.org/10.1039/d1fo04420f
Mol Psychiatry. 2022 Mar 25.

Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability.

Haibin Zhang, Qiuyang Zheng, Tiantian Guo, Shijun Zhang, Shuang Zheng, Ruimin Wang, Qingfang Deng, Guowei Yang, Shuo Zhang, Linxin Tang, Qiuping Qi, Lin Zhu, Xiu-Fang Zhang, Hong Luo, Xian Zhang, Hao Sun, Yue Gao, Hongfeng Zhang, Ying Zhou, Aidong Han, Chen-Song Zhang, Huaxi Xu, Xin Wang.

Astrocyte aerobic glycolysis provides vital trophic support for central nervous system neurons. However, whether and how astrocytic metabolic dysregulation contributes to neuronal dysfunction in intellectual disability (ID) remain unclear. Here, we demonstrate a causal role for an ID-associated SNX27 mutation (R198W) in cognitive deficits involving reshaping astrocytic metabolism. We generated SNX27R196W (equivalent to human R198W) knock-in mice and found that they displayed deficits in synaptic function and learning behaviors. SNX27R196W resulted in attenuated astrocytic glucose uptake via GLUT1, leading to reduced lactate production and a switch from homeostatic to reactive astrocytes. Importantly, lactate supplementation or a ketogenic diet restored neuronal oxidative phosphorylation and reversed cognitive deficits in SNX27R196W mice. In summary, we illustrate a key role for astrocytic SNX27 in maintaining glucose supply and glycolysis and reveal that altered astrocytic metabolism disrupts the astrocyte-neuron interaction, which contributes to ID. Our work also suggests a feasible strategy for treating ID by restoring astrocytic metabolic function.

DOI: https://doi.org/10.1038/s41380-022-01521-x
Nutrients. 2022 Mar 17. pii: 1275. [Epub ahead of print]14(6):

Effects of Intermittent Fasting on Brain Metabolism.

Alex Brocchi, Eleni Rebelos, Angela Dardano, Michele Mantuano, Giuseppe Daniele.

  We are facing an obesity epidemic, and obesity itself and its close companion, type 2 diabetes, are independent risk factors for neurodegeneration. While most medical treatments fail to induce a clinically meaningful improvement in neurodegenerative disorders, lifestyle interventions have emerged in the spotlight. A recently rediscovered approach is intermittent fasting (IF), which, compared to the classic caloric restriction regimens, limits only the time of eating, rather than the number of calories allowed per day. There is already a large amount of evidence from preclinical and clinical studies showing the beneficial effects of IF. In this review, we specifically focus on the effects of IF on brain metabolism. Key molecular players modified during IF and involved in its beneficial central effects (ketone bodies, BDNF, GABA, GH/IGF-1, FGF2, sirtuin-3, mTOR, and gut microbiota) are identified and discussed. Studies suggest that IF induces several molecular and cellular adaptations in neurons, which, overall, enhance cellular stress resistance, synaptic plasticity, and neurogenesis. Still, the absence of guidelines regarding the application of IF to patients hampers its broad utilization in clinical practice, and further studies are needed to improve our knowledge on the different IF protocols and long-term effects of IF on brain metabolism before it can be widely prescribed.

Keywords:  intermittent fasting; ketone bodies; neuroprotection

DOI:  https://doi.org/10.3390/nu14061275
Biosci Rep. 2022 Mar 31. pii: BSR20211696. [Epub ahead of print]42(3):

Mitochondrial dynamics in the neonatal brain - a potential target following injury?

Adam Jones, Claire Thornton.

  The impact of birth asphyxia and its sequelae, hypoxic-ischaemic (HI) brain injury, is long-lasting and significant, both for the infant and for their family. Treatment options are limited to therapeutic hypothermia, which is not universally successful and is unavailable in low resource settings. The energy deficits that accompany neuronal death following interruption of blood flow to the brain implicate mitochondrial dysfunction. Such HI insults trigger mitochondrial outer membrane permeabilisation leading to release of pro-apoptotic proteins into the cytosol and cell death. More recently, key players in mitochondrial fission and fusion have been identified as targets following HI brain injury. This review aims to provide an introduction to the molecular players and pathways driving mitochondrial dynamics, the regulation of these pathways and how they are altered following HI insult. Finally, we review progress on repurposing or repositioning drugs already approved for other indications, which may target mitochondrial dynamics and provide promising avenues for intervention following brain injury. Such repurposing may provide a mechanism to fast-track, low-cost treatment options to the clinic.

Keywords:  cell death; hypoxia; ischaemia-reperfusion injury; mitochondrial dynamics; neonatal

DOI:  https://doi.org/10.1042/BSR20211696
Int J Mol Sci. 2022 Mar 21. pii: 3399. [Epub ahead of print]23(6):

Susceptibility of Female Mice to the Dietary Omega-3/Omega-6 Fatty-Acid Ratio: Effects on Adult Hippocampal Neurogenesis and Glia.

Noelia Rodríguez-Iglesias, Agnes Nadjar, Amanda Sierra, Jorge Valero.

  Maternal intake of omega-3 (n-3 PUFAs) and omega-6 (n-6 PUFAs) polyunsaturated fatty acids impacts hippocampal neurogenesis during development, an effect that may extend to adulthood by altering adult hippocampal neurogenesis (AHN). The n-3 PUFAs and n-6 PUFAs are precursors of inflammatory regulators that potentially affect AHN and glia. Additionally, n-3 PUFA dietary supplementation may present a sexually dimorphic action in the brain. Therefore, we postulated that dietary n-6/n-3 PUFA balance shapes the adult DG in a sex-dependent manner influencing AHN and glia. We test our hypothesis by feeding adult female and male mice with n-3 PUFA balanced or deficient diets. To analyze the immunomodulatory potential of the diets, we injected mice with the bacterial endotoxin lipopolysaccharide (LPS). LPS reduced neuroblast number, and its effect was exacerbated by the n-3 PUFA-deficient diet. The n-3 PUFA-deficient diet reduced the DG volume, AHN, microglia number, and surveilled volume. The diet effect on most mature neuroblasts was exclusively significant in female mice. Colocalization and multivariate analysis revealed an association between microglia and AHN, as well as the sexual dimorphic effect of diet. Our study reveals that female mice are more susceptible than males to the effect of dietary n-6/n-3 PUFA ratio on AHN and microglia.

Keywords:  LPS; adult neurogenesis; bacterial endotoxin lipopolysaccharide; dentate gyrus; diet; microglia; omega 3; polyunsaturated fatty acids; sexual dimorphism; systemic inflammation

DOI:  https://doi.org/10.3390/ijms23063399
Hum Mol Genet. 2022 Mar 21. pii: ddac063. [Epub ahead of print]

SPG15 protein deficits are at the crossroads between lysosomal abnormalities, altered lipid metabolism and synaptic dysfunction.

Lara Marrone, Paolo M Marchi, Christopher P Webster, Raffaele Marroccella, Ian Coldicott, Steven Reynolds, João Alves-Cruzeiro, Zih-Liang Yang, Adrian Higginbottom, Mukhran Khundadze, Pamela J Shaw, Christian A Hübner, Matthew R Livesey, Mimoun Azzouz.

Hereditary Spastic Paraplegia type 15 (HSP15) is a neurodegenerative condition caused by the inability to produce SPG15 protein, which leads to lysosomal swelling. However, the link between lysosomal aberrations and neuronal death is poorly explored. To uncover the functional consequences of lysosomal aberrations in disease pathogenesis, we analyze human dermal fibroblasts from HSP15 patients as well as primary cortical neurons derived from an SPG15 knockout (KO) mouse model. We find that SPG15 protein loss induces defective anterograde transport, impaired neurite outgrowth, axonal swelling and reduced autophagic flux in association with the onset of lysosomal abnormalities. Additionally, we observe lipid accumulation within the lysosomal compartment, suggesting that distortions in cellular lipid homeostasis are intertwined with lysosomal alterations. We further demonstrate that SPG15 KO neurons exhibit synaptic dysfunction, accompanied by augmented vulnerability to glutamate-induced excitotoxicity. Overall, our study establishes an intimate link between lysosomal aberrations, lipid metabolism and electrophysiological impairments, suggesting that lysosomal defects are at the core of multiple neurodegenerative disease processes in HSP15.

DOI: https://doi.org/10.1093/hmg/ddac063
Brain Sci. 2022 Feb 24. pii: 308. [Epub ahead of print]12(3):

Caloric Restriction Mimetic 2-Deoxyglucose Reduces Inflammatory Signaling in Human Astrocytes: Implications for Therapeutic Strategies Targeting Neurodegenerative Diseases.

Kaylie-Anna Juliette Vallee, Jerel Adam Fields.

  Therapeutic interventions are greatly needed for age-related neurodegenerative diseases. Astrocytes regulate many aspects of neuronal function including bioenergetics and synaptic transmission. Reactive astrocytes are implicated in neurodegenerative diseases due to their pro-inflammatory phenotype close association with damaged neurons. Thus, strategies to reduce astrocyte reactivity may support brain health. Caloric restriction and a ketogenic diet limit energy production via glycolysis and promote oxidative phosphorylation, which has gained traction as a strategy to improve brain health. However, it is unknown how caloric restriction affects astrocyte reactivity in the context of neuroinflammation. We investigated how a caloric restriction mimetic and glycolysis inhibitor, 2-deoxyglucose (2-DG), affects interleukin 1β-induced inflammatory gene expression in human astrocytes. Human astrocyte cultures were exposed to 2-DG or vehicle for 24 h and then to recombinant IL-1β for 6 or 24 h to analyze mRNA and protein expression, respectively. Gene expression levels of proinflammatory genes (complement component 3, IL-1β, IL6, and TNFα) were analyzed by real-time PCR, immunoblot, and immunohistochemistry. As expected, IL-1β induced elevated levels of proinflammatory genes. 2-DG reversed this effect at the mRNA and protein levels without inducing cytotoxicity. Collectively, these data suggest that inhibiting glycolysis in human astrocytes reduces IL-1β-induced reactivity. This finding may lead to novel therapeutic strategies to limit inflammation and enhance bioenergetics toward the goal of preventing and treating neurodegenerative diseases.

Keywords:  2-deoxyglucose; astrogliosis; caloric restriction; glycolysis; immunometabolism; inflammation; neurodegenerative disease

DOI:  https://doi.org/10.3390/brainsci12030308
Front Aging Neurosci. 2022 ;14 785761

Neurons Release Injured Mitochondria as "Help-Me" Signaling After Ischemic Stroke.

Li Gao, Fan Liu, Pin-Pin Hou, Anatol Manaenko, Zhi-Peng Xiao, Fei Wang, Tian-Le Xu, Qin Hu.

  Mitochondrial dysfunction has been regarded as one of the major contributors of ischemic neuronal death after stroke. Recently, intercellular mitochondrial transfer between different cell types has been widely studied and suggested as a potential therapeutic approach. However, whether mitochondria are involved in the neuron-glia cross-talk following ischemic stroke and the underlying mechanisms have not been explored yet. In this study, we demonstrated that under physiological condition, neurons release few mitochondria into the extracellular space, and the mitochondrial release increased when subjected to the challenges of acidosis, hydrogen peroxide (H2O2), N-methyl-D-aspartate (NMDA), or glutamate. Acidosis reduced the mitochondrial basal respiration and lowered the membrane potential in primary-cultured mouse cortical neurons. These defective mitochondria were prone to be expelled to the extracellular space by the injured neurons, and were engulfed by adjacent astrocytes, leading to increased astrocytic expressions of mitochondrial Rho GTPase 1 (Miro 1) and mitochondrial transcription factor A (TFAM) at mRNA level. In mice subjected to transient focal cerebral ischemia, the number of defective mitochondria in the cerebrospinal fluid increased. Our results suggested that the neuron-derived mitochondria may serve as a "help-me" signaling and mediate the neuron-astrocyte cross-talk following ischemic stroke. Promoting the intercellular mitochondrial transfer by accelerating the neuronal releasing or astrocytic engulfing might be a potential and attractive therapeutic strategy for the treatment of ischemic stroke in the future.

Keywords:  ischemic stroke; metabolic stress; mitochondrial biogenesis; mitochondrial release; neuron-glial crosstalk

DOI:  https://doi.org/10.3389/fnagi.2022.785761
Mol Cell. 2022 Mar 14. pii: S1097-2765(22)00166-6. [Epub ahead of print]

Hexokinase 1 cellular localization regulates the metabolic fate of glucose.

Adam De Jesus, Farnaz Keyhani-Nejad, Carolina M Pusec, Lauren Goodman, Justin A Geier, Joshua S Stoolman, Paulina J Stanczyk, Tivoli Nguyen, Kai Xu, Krishna V Suresh, Yihan Chen, Arianne E Rodriguez, Jason S Shapiro, Hsiang-Chun Chang, Chunlei Chen, Kriti P Shah, Issam Ben-Sahra, Brian T Layden, Navdeep S Chandel, Samuel E Weinberg, Hossein Ardehali.

  The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1). These mice produced a hyper-inflammatory response when challenged with lipopolysaccharide. Additionally, there was decreased glucose flux below the level of GAPDH and increased upstream flux through the PPP. The glycolytic block below GAPDH is mediated by the binding of cytosolic HK1 with S100A8/A9, resulting in GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed increased cytosolic HK1 and reduced GAPDH activity. Our data indicate that HK1 mitochondrial binding alters glucose metabolism through regulation of GAPDH.

Keywords:  GAPDH; S-nitrosylation; hexokinase; inflammation; innate immunity; macrophage; metabolism; mitochondria; pentose phosphate pathway; subcellular localization

DOI:  https://doi.org/10.1016/j.molcel.2022.02.028
Exp Gerontol. 2022 Mar 18. pii: S0531-5565(22)00078-X. [Epub ahead of print] 111770

D-galactose-induced aging in rats - The effect of metformin on bioenergetics of brain, skeletal muscle and liver.

Zuzana Sumbalová, Oľga Uličná, Jarmila Kucharská, Zuzana Rausová, Oľga Vančová, Lubomír Melicherčík, Tomáš Tvrdík, Marek Nemec, Svatava Kašparová.

  Chronic D-galactose administration induces accelerated aging in rodents. The aim of the study was to find by in vivo31P MRS suitable markers of early stages of brain degeneration on this metabolic model in rats. Additionally, we studied the therapeutic effect of antidiabetic drug metformin. The study has been extended by in vitro determination of mitochondrial function in brain, skeletal muscle and liver mitochondria, oxidative stress parameter thiobarbituric acid reactive substances (TBARS), and lipophilic antioxidants levels. In vivo31P MRS revealed lower intracellular pH (pHi) and lower inorganic phosphate to ATP ratio (Pi/ATP), with higher index of oxidative phosphorylation - phosphocreatine (PCr) to Pi ratio - in brain of rats chronically administered with D-galactose. The function of brain mitochondria was not affected. Administration of metformin diminished changes in brain pHi and plasma TBARS. The function of skeletal muscle mitochondria and their coenzyme Q (CoQ) content were considerably reduced after D-galactose administration. Metformin administered simultaneously with D-galactose did not prevent these changes. The results of in vivo31P MRS revealed evidence of early stage of neurodegeneration that may indicate pre-inflammation. Our data show different susceptibility of brain, skeletal muscle, and liver to the chronic exposure to D-galactose and metformin. The D-galactose model presented in the literature as a model for "age-related dementia" had much more devastating effects on skeletal muscle than on the brain.

Keywords:  (31)P MRS; Aging; Coenzyme Q; D-galactose model; Metformin; Mitochondria respiration

DOI:  https://doi.org/10.1016/j.exger.2022.111770
Neurotherapeutics. 2022 Mar 25.

Bezafibrate Rescues Mitochondrial Encephalopathy in Mice via Induction of Daily Torpor and Hypometabolic State.

Jingwei Lyu, Yuying Zhao, Na Zhang, Xuebi Xu, Rui Zheng, Wenfei Yu, Wang Xin, Chuanzhu Yan, Kunqian Ji.

  Leigh syndrome (LS) is one of the most common mitochondrial encephalopathy diseases in infants. To date, there is still an absence of effective therapy. Bezafibrate (BEZ), a pan-peroxisome proliferator-activated receptor (PPAR) agonist, ameliorates the phenotype of the mouse model of mitochondrial disease via an unclear mechanism. Here, we applied it to Ndufs4 knockout (KO) mice, a widely used LS animal model, to observe the therapeutic effects and metabolic changes associated with BEZ treatment to explore the therapeutic strategies for mitochondrial diseases. Administration of BEZ significantly enhances survival and attenuates disease progression in Ndufs4 KO mice. Decreased oxidative stress and stunted growth were also observed. As a PPAR agonist, we did not find mitochondrial biogenesis or enhanced metabolism upon BEZ treatment. On the contrary, mice with dietary BEZ showed daily torpor bouts and lower metabolic rates. We speculate that activating energy-saving metabolism in mice may be associated with the therapeutic effects of BEZ, but the exact mechanism of action requires further study.

Keywords:  Bezafibrate; Leigh syndrome; Ndufs4 knockout mice; Torpor

DOI:  https://doi.org/10.1007/s13311-022-01216-9
Sci Rep. 2022 Mar 25. 12(1): 5196

Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice.

Gregory S McElroy, Ram P Chakrabarty, Karis B D'Alessandro, Karthik Vasan, Jerica Tan, Joshua S Stoolman, Samuel E Weinberg, Elizabeth M Steinert, Paul A Reyfman, Benjamin D Singer, Warren C Ladiges, Lin Gao, José Lopéz-Barneo, G R Scott Budinger, Navdeep S Chandel.

Aging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson's disease are in part due to modest decrease in expression of mitochondrial complex I subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results indicate that Ndufs2 hemizygous mice (Ndufs2+/-) show no overt impairment in aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a C57BL6/J background. Despite a significant reduction of Ndufs2 mRNA, the mice do not demonstrate a significant decrease in complex I function. However, there are detectable transcriptomic changes in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a 50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither beneficial nor detrimental to healthspan.

DOI: https://doi.org/10.1038/s41598-022-09074-3
Metabolites. 2022 Mar 01. pii: 220. [Epub ahead of print]12(3):

Changes in Plasma Lipid Levels Following Cortical Spreading Depolarization in a Transgenic Mouse Model of Familial Hemiplegic Migraine.

Inge C M Loonen, Isabelle Kohler, Mohan Ghorasaini, Martin Giera, Arn M J M van den Maagdenberg, Oleg A Mayboroda, Else A Tolner.

  Metabolite levels in peripheral body fluids can correlate with attack features in migraine patients, which underscores the potential of plasma metabolites as possible disease biomarkers. Migraine headache can be preceded by an aura that is caused by cortical spreading depolarization (CSD), a transient wave of neuroglial depolarization. We previously identified plasma amino acid changes after CSD in familial hemiplegic migraine type 1 (FHM1) mutant mice that exhibit increased neuronal excitability and various migraine-related features. Here, we aimed to uncover lipid metabolic pathways affected by CSD, guided by findings on the involvement of lipids in hemiplegic migraine pathophysiology. Using targeted lipidomic analysis, we studied plasma lipid metabolite levels at different time points after CSD in wild-type and FHM1 mutant mice. Following CSD, the most prominent plasma lipid change concerned a transient increase in PGD2, which lasted longer in mutant mice. In wild-type mice only, levels of anti-inflammatory lipid mediators DPAn-3, EPA, ALA, and DHA were elevated 24 h following CSD compared to Sham-treated animals. Given the role of PGs and neuroinflammation in migraine pathophysiology, our findings underscore the potential of monitoring peripheral changes in lipids to gain insight in central brain mechanisms.

Keywords:  cortical spreading depolarization; familial hemiplegic migraine; lipid mediators; metabolomics

DOI:  https://doi.org/10.3390/metabo12030220
Int J Mol Sci. 2022 Mar 08. pii: 2933. [Epub ahead of print]23(6):

Loss of Microglial Insulin Receptor Leads to Sex-Dependent Metabolic Disorders in Obese Mice.

Irina V Milanova, Nikita L Korpel, Felipe Correa-da-Silva, Eline Berends, Samar Osman, Susanne E la Fleur, Eric Fliers, Andries Kalsbeek, Chun-Xia Yi.

  Obesity and type 2 diabetes mellitus (T2DM) are highly prevalent disorders, associated with insulin resistance and chronic inflammation. The brain is key for energy homeostasis and contains many insulin receptors. Microglia, the resident brain immune cells, are known to express insulin receptors (InsR) and to be activated by a hypercaloric environment. The aim of this study was to evaluate whether microglial insulin signaling is involved in the control of systemic energy homeostasis and whether this function is sex-dependent. We generated a microglia-specific knockout of the InsR gene in male and female mice and exposed them to control or obesogenic dietary conditions. Following 10 weeks of diet exposure, we evaluated insulin tolerance, energy metabolism, microglial morphology and phagocytic function, and neuronal populations. Lack of microglial InsR resulted in increased plasma insulin levels and insulin resistance in obese female mice. In the brain, loss of microglial InsR led to a decrease in microglial primary projections in both male and female mice, irrespective of the diet. In addition, in obese male mice lacking microglial InsR the number of proopiomelanocortin neurons was decreased, compared to control diet, while no differences were observed in female mice. Our results demonstrate a sex-dependent effect of microglial InsR-signaling in physiology and obesity, and stress the importance of a heterogeneous approach in the study of diseases such as obesity and T2DM.

Keywords:  diabetes; immunometabolism; microglia; obesity; sex difference

DOI:  https://doi.org/10.3390/ijms23062933
Life (Basel). 2022 Mar 12. pii: 416. [Epub ahead of print]12(3):

Overview of (f)MRI Studies of Cognitive Aging for Non-Experts: Looking through the Lens of Neuroimaging.

Toshikazu Kawagoe.

  This special issue concerning Brain Functional and Structural Connectivity and Cognition aims to expand our understanding of brain connectivity. Herein, I review related topics including the principle and concepts of functional MRI, brain activation, and functional/structural connectivity in aging for uninitiated readers. Visuospatial attention, one of the well-studied functions in aging, is discussed from the perspective of neuroimaging.

Keywords:  aging; brain; functional connectivity; structural connectivity; visuospatial attention

DOI:  https://doi.org/10.3390/life12030416
Metab Brain Dis. 2022 Mar 22.

The C-glucosyl flavone isoorientin pretreatment attenuates the methylglyoxal-induced mitochondrial dysfunction in the human neuroblastoma SH-SY5Y cells: role for the AMPK-PI3K/Akt/Nrf2/γ-GCL/GSH axis.

Flávia Bittencourt Brasil, Fhelipe Jolner Souza de Almeida, Matheus Dargesso Luckachaki, Evandro Luiz Dall'Oglio, Marcos Roberto de Oliveira.

  The reactive dicarbonyl methylglyoxal (MG) behaves as a pro-oxidant agent, causing redox dysfunction and cell death by different mechanisms in mammalian cells. MG is also a mitochondrial toxicant, impairing the oxidative phosphorylation (OXPHOS) system and leading to bioenergetics and redox collapses. MG induces glycation and exerts an important role in neurodegenerative and cardiovascular diseases. Isoorientin (ISO), a C-glucosyl flavone found in Aspalathus linearis, Fagopyrum esculentum, and Passiflora edulis, among others, is an antioxidant and anti-inflammatory molecule. ISO is a potent inducer of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), the master modulator of the redox environment in mammals. We investigated here whether ISO would prevent the mitochondria-related redox and bioenergetics impairments induced by MG in the human neuroblastoma SH-SY5Y cells. The cells were administrated with ISO at 20 μM for 18 h prior to the exposure to MG at 500 μM for further 24 h. It was observed that ISO efficiently prevented the mitochondrial impairments caused by MG. ISO upregulated the activity of the enzyme γ-glutamate-cysteine ligase (γ-GCL), consequently stimulating the synthesis of glutathione (GSH). The inhibition of γ-GCL, adenosine monophosphate-activated protein kinase (AMPK), and phosphoinositide 3-kinase/Akt (PI3K/Akt) suppressed the beneficial effects induced by ISO on the MG-challenged cells. Moreover, silencing of Nrf2 blocked the ISO-dependent γ-GCL and GSH upregulation and the effects on the mitochondria of the MG-challenged cells. Then, ISO caused mitochondrial protection by an AMPK-PI3K/Akt/Nrf2/γ-GCL/GSH-dependent manner in MG-administrated SH-SY5Y cells.

Keywords:  Nrf2; glutathione; isoorientin; methylglyoxal; mitochondria; γ-glutamate-cyteine ligase

DOI:  https://doi.org/10.1007/s11011-022-00966-x
Mitochondrion. 2022 Mar 17. pii: S1567-7249(22)00021-6. [Epub ahead of print]

Reviewing the mitochondrial dysfunction paradigm in rodent models as platforms for neuropsychiatric disease research.

Daniël van Rensburg, Zander Lindeque, Brian H Harvey, Stephan F Steyn.

  Neuropsychiatric disorders have complex pathophysiological constructs, requiring translational models to improve our understanding thereof. Mitochondrial dysfunction, generally associated with neurodegenerative disorders, is gaining interest as a key factor in the etiology of psychiatric conditions because of the often comorbid psychiatric symptoms observed. Although translational models of psychiatric disorders, supports mitochondrial involvement, these models do not have a dysfunctional bio-energetic system as primary construct. Here, we consider the construct, face, and predictive validity of mitochondrial models from a neuropsychiatric perspective, to identify novel animal models that can improve our understanding of the underlying bio-energetic mechanisms of these conditions and treatments.

Keywords:  Bipolar disorder; Depression; Neurotransmission; Oxidative stress; Schizophrenia; Validity

DOI:  https://doi.org/10.1016/j.mito.2022.03.002
Antioxidants (Basel). 2022 Mar 09. pii: 524. [Epub ahead of print]11(3):

HDL Accessory Proteins in Parkinson's Disease-Focusing on Clusterin (Apolipoprotein J) in Regard to Its Involvement in Pathology and Diagnostics-A Review.

Izabela Berdowska, Małgorzata Matusiewicz, Małgorzata Krzystek-Korpacka.

  Parkinson's disease (PD)-a neurodegenerative disorder (NDD) characterized by progressive destruction of dopaminergic neurons within the substantia nigra of the brain-is associated with the formation of Lewy bodies containing mainly α-synuclein. HDL-related proteins such as paraoxonase 1 and apolipoproteins A1, E, D, and J are implicated in NDDs, including PD. Apolipoprotein J (ApoJ, clusterin) is a ubiquitous, multifunctional protein; besides its engagement in lipid transport, it modulates a variety of other processes such as immune system functionality and cellular death signaling. Furthermore, being an extracellular chaperone, ApoJ interacts with proteins associated with NDD pathogenesis (amyloid β, tau, and α-synuclein), thus modulating their properties. In this review, the association of clusterin with PD is delineated, with respect to its putative involvement in the pathological mechanism and its application in PD prognosis/diagnosis.

Keywords:  ApoA1; ApoD; ApoE; ApoJ; PON1; Parkinson’s disease; apolipoprotein J; clusterin; neurodegenerative disorders; paraoxonase

DOI:  https://doi.org/10.3390/antiox11030524
Int J Mol Sci. 2022 Mar 21. pii: 3398. [Epub ahead of print]23(6):

Acid Sphingomyelinase Is a Modulator of Contextual Fear.

Iulia Zoicas, Johannes Kornhuber.

  Acid sphingomyelinase (ASM) regulates a variety of physiological processes and plays an important role in emotional behavior. The role of ASM in fear-related behavior has not been investigated so far. Using transgenic mice overexpressing ASM (ASMtg) and ASM deficient mice, we studied whether ASM regulates fear learning and expression of cued and contextual fear in a classical fear conditioning paradigm, a model used to investigate specific attributes of post-traumatic stress disorder (PTSD). We show that ASM does not affect fear learning as both ASMtg and ASM deficient mice display unaltered fear conditioning when compared to wild-type littermates. However, ASM regulates the expression of contextual fear in a sex-specific manner. While ASM overexpression enhances the expression of contextual fear in both male and female mice, ASM deficiency reduces the expression of contextual fear specifically in male mice. The expression of cued fear, however, is not regulated by ASM as ASMtg and ASM deficient mice display similar tone-elicited freezing levels. This study shows that ASM modulates the expression of contextual fear but not of cued fear in a sex-specific manner and adds a novel piece of information regarding the involvement of ASM in hippocampal-dependent aversive memory.

Keywords:  ASM; PTSD; contextual fear; cued fear; fear conditioning; fear extinction; fear learning; knock-out mice; transgenic mice

DOI:  https://doi.org/10.3390/ijms23063398
Nutr Neurosci. 2022 Mar 21. 1-15

Oleanolic acid and ursolic acid: therapeutic potential in neurodegenerative diseases, neuropsychiatric diseases and other brain disorders.

Chen Chen, Qidi Ai, Axi Shi, Nan Wang, Lina Wang, Yuhui Wei.

  Brain disorders such as neurodegenerative diseases and neuropsychiatric diseases have become serious threatens to human health and quality of life. Oleanolic acid (OA) and ursolic acid (UA) are pentacyclic triterpenoid isomers widely distributed in various plant foods and Chinese herbal medicines. Accumulating evidence indicates that OA and UA exhibit neuroprotective effects on multiple brain disorders. Therefore, this paper reviews researches of OA and UA on neurodegenerative diseases, neuropsychiatric diseases and other brain disorders including ischemic stroke, epilepsy, etc, as well as the potential underlying molecular mechanisms.

Keywords:  Oleanolic acid; Ursolic acid; brain disorder; natural product; neurodegenerative disease; neurological disease; neuropsychiatric disease; phytochemical

DOI:  https://doi.org/10.1080/1028415X.2022.2051957
Prog Lipid Res. 2022 Mar 19. pii: S0163-7827(22)00017-0. [Epub ahead of print] 101162

Sphingolipid control of cognitive functions in health and disease.

Liubov S Kalinichenko, Erich Gulbins, Johannes Kornhuber, Christian P Müller.

Cognitive processes, particularly learning and memory, are crucial brain mechanisms mediating the successful adaptation of individuals to constantly changing environmental conditions. Impairments in memory performance during neurodegenerative disorders or dementias affect life quality of patients as well as their relatives and careers, and thus have a severe socio-economic impact. The last decades have viewed learning and memory as predominantly protein-mediated process at the synapses of brain neurons. However, recent developments propose a principally new, lipid-based mechanism that regulates cognition. Thereby, crucial members of cell membranes, the sphingolipids, emerged to play an outstanding role in learning and memory. The most abundant brain sphingolipids, ceramides and gangliosides, dynamically shape the composition of protein carrying cellular membranes. This, in turn, regulates protein signaling through the membranes and overall neuronal plasticity. An imbalance in sphingolipid composition and disrupted dynamics significantly affect normal functioning of cells and results in the development of multiple psychiatric and neurological disorders with cognitive impairments. Ceramides and gangliosides interact with a plethora of molecular pathways determining de novo learning and memory, as well as pathogenic pathways of neurodegenerative disorders and dementias of various origins. Considering sphingolipids as a trigger mechanism for learning and memory under physiological and pathological conditions, a principally new class of lipid-based preventive and therapeutic approaches to target cognitive impairments and dementias is emerging.

DOI: https://doi.org/10.1016/j.plipres.2022.101162
Iran J Basic Med Sci. 2021 Nov;24(11): 1590-1601

4-Hydroxy-3,5-di-tret-butyl cinnamic acid restores the activity of the hippocampal mitochondria in rats under permanent focal cerebral ischemia.

Dmitry I Pozdnyakov.

  Objectives: Ischemic stroke is a disease with complex pathogenesis that requires timely and rational pharmacological intervention. One possible treatment for this condition may be to improve mitochondrial function as part of neuroprotective therapy.Materials and Methods: Cerebral ischemic damage was reproduced by middle cerebral artery permanent occlusion in Wistar male rats. 4-hydroxy-3,5-di-tretbutyl cinnamic acid was injected intraperitoneally in dose range of 25 mg/kg, 50 mg/kg, and 100 mg/kg. The time of administration was 3 days from the ischemia modeling. Further, changes in the rats' cognitive functions in the Morris water maze test were evaluated, and the state of mitochondrial function in the hippocampal tissue was studied.
Results: The study showed that the use of the studied compound dose-dependently improved mitochondrial function in the rat hippocampus. At doses of 20 mg/kg and 50 mg/kg, administration of the test substance increased citrate synthase activity by 55.1% (P<0.05) and 43.4% (P<0.05), respectively and ATP content by 25.7% (P<0.05) and 23.9% (P<0.05). Also, the intensity of oxidative stress (activity of antioxidant enzymes increase whereas the concentration of TBARS reduces) and apoptosis (calcium content, concentration of apoptosis-inducing factor, and caspase-3 activity decrease; latent time of mitochondrial transition permeability pore opening increase) decreased against the background of administration of the test compound. At a dose of 100 mg/kg, the studied compound showed less effectiveness.
Conclusion: Administration of 25 mg/kg and 50 mg/kg 4-hydroxy-3,5-di-tretbutyl cinnamic acid demonstrated neuroprotection action on hippocampal cells under the conditions of irreversible brain ischemia.

Keywords:  Apoptosis; Cerebral ischemia; Cinnamic acid derivatives; Mitochondrial dysfunction; Neuroprotection; Oxidative stress

DOI:  https://doi.org/10.22038/IJBMS.2021.58435.12979
Int J Environ Res Public Health. 2022 Mar 11. pii: 3321. [Epub ahead of print]19(6):

Brain Functional Network and Amino Acid Metabolism Association in Females with Subclinical Depression.

Shanguang Zhao, Selina Khoo, Siew-Cheok Ng, Aiping Chi.

  This study aimed to investigate the association between complex brain functional networks and the metabolites in urine in subclinical depression. Electroencephalography (EEG) signals were recorded from 78 female college students, including 40 with subclinical depression (ScD) and 38 healthy controls (HC). The phase delay index was utilized to construct functional connectivity networks and quantify the topological properties of brain networks using graph theory. Meanwhile, the urine of all participants was collected for non-targeted LC-MS metabolic analysis to screen differential metabolites. The global efficiency was significantly increased in the α-2, β-1, and β-2 bands, while the characteristic path length of β-1 and β-2 and the clustering coefficient of β-2 were decreased in the ScD group. The severity of depression was negatively correlated with the level of cortisone (p = 0.016, r = -0.40). The metabolic pathways, including phenylalanine metabolism, phenylalanine tyrosine tryptophan biosynthesis, and nitrogen metabolism, were disturbed in the ScD group. The three metabolic pathways were negatively correlated (p = 0.014, r = -0.493) with the global efficiency of the brain network of the β-2 band, whereas they were positively correlated (p = 0.014, r = 0.493) with the characteristic path length of the β-2 band. They were mainly associated with low levels of L-phenylalanine, and the highest correlation sparsity was 0.11. The disturbance of phenylalanine metabolism and the phenylalanine, tryptophan, tyrosine biosynthesis pathways cause depressive symptoms and changes in functional brain networks. The decrease in the L-phenylalanine level may be related to the randomization trend of the β-1 frequency brain functional network.

Keywords:  brain–gut axis; complex brain network; phase lag index; subclinical depression

DOI:  https://doi.org/10.3390/ijerph19063321