bims-medebr 2022-04-17 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–04–17
thirty-six papers selected by
Regina F. Fernández, Johns Hopkins University

Brain Metabolic Alterations in Alzheimer's Disease.
Synapses: The Brain's Energy-Demanding Sites.
Dysmetabolism and Neurodegeneration: Trick or Treat?
Induction of Mitochondrial Fragmentation and Mitophagy after Neonatal Hypoxia-Ischemia.
α-Lipoic Acid Reduces Ceramide Synthesis and Neuroinflammation in the Hypothalamus of Insulin-Resistant Rats, While in the Cerebral Cortex Diminishes the β-Amyloid Accumulation.
An integrated multi-omics approach revealed the regulation of melatonin on age-dependent mitochondrial function impair and lipid dyshomeostasis in mice hippocampus.
Genetic Inhibition of Plppr5 Aggravates Hypoxic-Ischemie-Induced Cortical Damage and Excitotoxic Phenotype.
Nandrolone Supplementation Promotes AMPK Activation and Divergent 18[FDG] PET Brain Connectivity in Adult and Aged Mice.
Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease.
Age- and Sex-Associated Glucose Metabolism Decline in a Mouse Model of Alzheimer's Disease.
Emerging Role of Phospholipids and Lysophospholipids for Improving Brain Docosahexaenoic Acid as Potential Preventive and Therapeutic Strategies for Neurological Diseases.
Nutrition for Brain Development.
Metabolic Syndrome and β-Oxidation of Long-Chain Fatty Acids in the Brain, Heart, and Kidney Mitochondria.
Mitochondrial Lipids: From Membrane Organization to Apoptotic Facilitation.
Cholesterol metabolism and its implication in glioblastoma therapy.
Defects of Nutrient Signaling and Autophagy in Neurodegeneration.
The Savant Syndrome: A Gift or A Disability? A Deeper Look into Metabolic Correlates of Hidden Cognitive Capacity.
Mitochondrial function in spinal cord injury and regeneration.
Diet-Induced Metabolic Dysfunction of Hypothalamic Nutrient Sensing in Rodents.
Omega-3/Omega-6 Long-Chain Fatty Acid Imbalance in Phase I Retinopathy of Prematurity.
Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice.
Hyperglycemia and Hyperinsulinemia Effects on Anterior Cingulate Cortex Myoinositol - Relation to Brain Network Functional Connectivity in Healthy Adults.
Genetic Inactivation of Free Fatty Acid Receptor 3 Impedes Behavioral Deficits and Pathological Hallmarks in the APPswe Alzheimer's Disease Mouse Model.
Second report of SHMT2 related neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities.
Neurodevelopment, nutrition and genetics. A contemporary retrospective on neurocognitive health on the occasion of the 100th anniversary of the National Institute of Nutrition, Hyderabad, India.
Mitochondrial Dynamics in the Metabolic Memory of Diabetic Retinopathy.
DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion.
HCAR1-Mediated L-Lactate Signaling Suppresses Microglial Phagocytosis.
Glucocerebrosidase Mutations Cause Mitochondrial and Lysosomal Dysfunction in Parkinson's Disease: Pathogenesis and Therapeutic Implications.
Lysophosphatidic Acid Receptor 5 (LPA5) Knockout Ameliorates the Neuroinflammatory Response In Vivo and Modifies the Inflammatory and Metabolic Landscape of Primary Microglia In Vitro.
Mitochondrial DNA Transport in Drosophila Neurons.
Reciprocal regulation of phosphatidylcholine synthesis and H3K36 methylation programs metabolic adaptation.
Luteolin Enhances Choroid Plexus 5-MTHF Brain Transport to Promote Hippocampal Neurogenesis in LOD Rats.
Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders.
PINK1-mediated Drp1S616 phosphorylation modulates synaptic development and plasticity via promoting mitochondrial fission.
Pro-resolving lipid mediators in traumatic brain injury: emerging concepts and translational approach.

Int J Mol Sci. 2022 Mar 29. pii: 3785. [Epub ahead of print]23(7):

Brain Metabolic Alterations in Alzheimer's Disease.

Carlos G Ardanaz, María J Ramírez, Maite Solas.

  The brain is one of the most energy-consuming organs in the body. Satisfying such energy demand requires compartmentalized, cell-specific metabolic processes, known to be complementary and intimately coupled. Thus, the brain relies on thoroughly orchestrated energy-obtaining agents, processes and molecular features, such as the neurovascular unit, the astrocyte-neuron metabolic coupling, and the cellular distribution of energy substrate transporters. Importantly, early features of the aging process are determined by the progressive perturbation of certain processes responsible for adequate brain energy supply, resulting in brain hypometabolism. These age-related brain energy alterations are further worsened during the prodromal stages of neurodegenerative diseases, namely Alzheimer's disease (AD), preceding the onset of clinical symptoms, and are anatomically and functionally associated with the loss of cognitive abilities. Here, we focus on concrete neuroenergetic features such as the brain's fueling by glucose and lactate, the transporters and vascular system guaranteeing its supply, and the metabolic interactions between astrocytes and neurons, and on its neurodegenerative-related disruption. We sought to review the principles underlying the metabolic dimension of healthy and AD brains, and suggest that the integration of these concepts in the preventive, diagnostic and treatment strategies for AD is key to improving the precision of these interventions.

Keywords:  GLUTs; astrocyte; astrocyte–neuron lactate shuttle (ANLS); glucose; hypometabolism; lactate; neurodegeneration

DOI:  https://doi.org/10.3390/ijms23073785
Int J Mol Sci. 2022 Mar 26. pii: 3627. [Epub ahead of print]23(7):

Synapses: The Brain's Energy-Demanding Sites.

Andreia Faria-Pereira, Vanessa A Morais.

  The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic requirements, the brain primarily uses glucose, which can be metabolized through glycolysis and/or mitochondrial oxidative phosphorylation. The relevance of these two energy production pathways in fulfilling energy at presynaptic terminals has been the subject of recent studies. In this review, we dissect the balance of glycolysis and oxidative phosphorylation to meet synaptic energy demands in both resting and stimulation conditions. Besides ATP output needs, mitochondria at synapse are also important for calcium buffering and regulation of reactive oxygen species. These two mitochondrial-associated pathways, once hampered, impact negatively on neuronal homeostasis and synaptic activity. Therefore, as mitochondria assume a critical role in synaptic homeostasis, it is becoming evident that the synaptic mitochondria population possesses a distinct functional fingerprint compared to other brain mitochondria. Ultimately, dysregulation of synaptic bioenergetics through glycolytic and mitochondrial dysfunctions is increasingly implicated in neurodegenerative disorders, as one of the first hallmarks in several of these diseases are synaptic energy deficits, followed by synapse degeneration.

Keywords:  brain energy metabolism; glycolysis; mitochondria; synapses

DOI:  https://doi.org/10.3390/ijms23073627
Nutrients. 2022 Mar 29. pii: 1425. [Epub ahead of print]14(7):

Dysmetabolism and Neurodegeneration: Trick or Treat?

Adriana M Capucho, Ana Chegão, Fátima O Martins, Hugo Vicente Miranda, Sílvia V Conde.

  Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration. We start by providing concepts regarding the role of insulin and insulin signaling pathways as well as the pathophysiological mechanisms that are in the genesis of metabolic diseases. Then, we focus on the role of insulin in the brain, with special attention to its function in the regulation of brain glucose metabolism, feeding, and cognition. Moreover, we extensively report on the association between neurodegeneration and metabolic diseases, with a particular emphasis on the evidence observed in animal models of dysmetabolism induced by hypercaloric diets. We also debate on strategies to prevent and/or delay neurodegeneration through the normalization of whole-body glucose homeostasis, particularly via the modulation of the carotid bodies, organs known to be key in connecting the periphery with the brain.

Keywords:  hypercaloric diets; insulin signaling; metabolic disorders; neurodegeneration

DOI:  https://doi.org/10.3390/nu14071425
Cells. 2022 Apr 01. pii: 1193. [Epub ahead of print]11(7):

Induction of Mitochondrial Fragmentation and Mitophagy after Neonatal Hypoxia-Ischemia.

Syam Nair, Anna-Lena Leverin, Eridan Rocha-Ferreira, Kristina S Sobotka, Claire Thornton, Carina Mallard, Henrik Hagberg.

  Hypoxia-ischemia (HI) leads to immature brain injury mediated by mitochondrial stress. If damaged mitochondria cannot be repaired, mitochondrial permeabilization ensues, leading to cell death. Non-optimal turnover of mitochondria is critical as it affects short and long term structural and functional recovery and brain development. Therefore, disposal of deficient mitochondria via mitophagy and their replacement through biogenesis is needed. We utilized mt-Keima reporter mice to quantify mitochondrial morphology (fission, fusion) and mitophagy and their mechanisms in primary neurons after Oxygen Glucose Deprivation (OGD) and in brain sections after neonatal HI. Molecular mechanisms of PARK2-dependent and -independent pathways of mitophagy were investigated in vivo by PCR and Western blotting. Mitochondrial morphology and mitophagy were investigated using live cell microscopy. In primary neurons, we found a primary fission wave immediately after OGD with a significant increase in mitophagy followed by a secondary phase of fission at 24 h following recovery. Following HI, mitophagy was upregulated immediately after HI followed by a second wave at 7 days. Western blotting suggests that both PINK1/Parkin-dependent and -independent mechanisms, including NIX and FUNDC1, were upregulated immediately after HI, whereas a PINK1/Parkin mechanism predominated 7 days after HI. We hypothesize that excessive mitophagy in the early phase is a pathologic response which may contribute to secondary energy depletion, whereas secondary mitophagy may be involved in post-HI regeneration and repair.

Keywords:  metabolism; mitochondria; mitochondrial fission; mitophagy; neonatal brain injury; neonatal hypoxia–ischemia; reactive oxygen species

DOI:  https://doi.org/10.3390/cells11071193
J Inflamm Res. 2022 ;15 2295-2312

α-Lipoic Acid Reduces Ceramide Synthesis and Neuroinflammation in the Hypothalamus of Insulin-Resistant Rats, While in the Cerebral Cortex Diminishes the β-Amyloid Accumulation.

Mateusz Maciejczyk, Ewa Żebrowska, Miłosz Nesterowicz, Elżbieta Supruniuk, Barbara Choromańska, Adrian Chabowski, Małgorzata Żendzian-Piotrowska, Anna Zalewska.

   Background: Oxidative stress underlies metabolic diseases and cognitive impairment; thus, the use of antioxidants may improve brain function in insulin-resistant conditions. We are the first to evaluate the effects of α-lipoic acid (ALA) on redox homeostasis, sphingolipid metabolism, neuroinflammation, apoptosis, and β-amyloid accumulation in the cerebral cortex and hypothalamus of insulin-resistant rats.
Methods: The experiment was conducted on male cmdb/outbred Wistar rats fed a high-fat diet (HFD) for 10 weeks with intragastric administration of ALA (30 mg/kg body weight) for 4 weeks. Pro-oxidant and pro-inflammatory enzymes, oxidative stress, sphingolipid metabolism, neuroinflammation, apoptosis, and β-amyloid level were assessed in the hypothalamus and cerebral cortex using colorimetric, fluorimetric, ELISA, and HPLC methods. Statistical analysis was performed using three-way ANOVA followed by the Tukey HSD test.
Results: ALA normalizes body weight, food intake, glycemia, insulinemia, and systemic insulin sensitivity in HFD-fed rats. ALA treatment reduces nicotinamide adenine dinucleotide phosphate (NADPH) and xanthine oxidase activity, increases ferric-reducing antioxidant power (FRAP) and thiol levels in the hypothalamus of insulin-resistant rats. In addition, it decreases myeloperoxidase, glucuronidase, and metalloproteinase-2 activity and pro-inflammatory cytokines (IL-1β, IL-6) levels, while in the cerebral cortex ALA reduces β-amyloid accumulation. In both brain structures, ALA diminishes ceramide synthesis and caspase-3 activity. ALA improves systemic oxidative status and reduces insulin-resistant rats' serum cytokines, chemokines, and growth factors.
Conclusion: ALA normalizes lipid and carbohydrate metabolism in insulin-resistant rats. At the brain level, ALA primarily affects hypothalamic metabolism. ALA improves redox homeostasis by decreasing the activity of pro-oxidant enzymes, enhancing total antioxidant potential, and reducing protein and lipid oxidative damage in the hypothalamus of HFD-fed rats. ALA also reduces hypothalamic inflammation and metalloproteinases activity, and cortical β-amyloid accumulation. In both brain structures, ALA diminishes ceramide synthesis and neuronal apoptosis. Although further study is needed, ALA may be a potential treatment for patients with cerebral complications of insulin resistance.

Keywords:  brain; ceramide; inflammation; insulin resistance; oxidative stress; α-lipoic acid

DOI:  https://doi.org/10.2147/JIR.S358799
Pharmacol Res. 2022 Apr 07. pii: S1043-6618(22)00155-4. [Epub ahead of print] 106210

An integrated multi-omics approach revealed the regulation of melatonin on age-dependent mitochondrial function impair and lipid dyshomeostasis in mice hippocampus.

Xiaowen Jiang, Zihua Xu, Dong Yao, Xin Liu, Wenwu Liu, Nan Wang, Xiang Li, Yao Diao, Yingshi Zhang, Qingchun Zhao.

  Melatonin can improve mitochondrial dysfunction associated with the aging process by removing active oxygen, as well as inhibiting lipid peroxidation to maintain biofilm fluidity and resist free radical attack. However, there is poor understanding of the effect of melatonin on age-dependent mitochondrial function and lipid profile changes in brain. In this study, we investigated the energy metabolism of the whole body and brain of mice at 9 months, 13 months, and 25 months of continuous gastric administration of 3mg/kg/d melatonin once per day morning for two months. In addition, we performed transcriptomic, proteomic and lipidomic analysis in the hippocampus of mice at different ages. Proteomics showed that melatonin regulated mitochondrial electron transport and leucine degradation in mouse hippocampus. Lipomics suggested that the long-chain unsaturated glycerol phospholipids in mouse hippocampus increased in an age-dependent manner, while ceramide and glycerol phospholipids decreased significantly in hippocampus of mouse chronically exposed to melatonin. The combined analysis of proteome and liposome demonstrated that Mpst, Ccsap, Hdhd5, Rpl5 and Flna were the key proteins of the network which involved in the regulation of numerous lipids. Furthermore, ultrastructure observation results illustrated that melatonin could improve the damaged mitochondrial and morphologies of 25-month-old mice hippocampus. In conclusion, we describe a mechanism that age-dependent up-regulation of long-chain unsaturated lipids is a driving risk factor for mitochondrial damage and this effect could be reversed by chronic supplement of low-dose melatonin.

Keywords:  Multi-omics; aging-dependent; energy metabolism; lipid dyshomeostasis; melatonin; mitochondrial function

DOI:  https://doi.org/10.1016/j.phrs.2022.106210
Front Neurosci. 2022 ;16 751489

Genetic Inhibition of Plppr5 Aggravates Hypoxic-Ischemie-Induced Cortical Damage and Excitotoxic Phenotype.

Yuxiao Sun, Mei-Fang Jin, Lili Li, Yueying Liu, Dandan Wang, Hong Ni.

  Hypoxia-ischemia (HI) is the most common acute brain threat in neonates and a leading cause of neurodevelopmental impairment. Exploring the new molecular mechanism of HI brain injury has important clinical translational significance for the next clinical intervention research. Lipid phosphatase-related proteins (PLPPRs) are regulators of mitochondrial membrane integrity and energy metabolism. We recently found that Plppr5 knockout exacerbated HI impairment in some aspects and partially attenuated the neuroprotective effects of melatonin, suggesting that Plppr5 may be a novel intervention target for HI. The present study aimed to determine the long-term effects of gene knockout of Plppr5 on HI brain injury, focusing on the neuronal excitability phenotype, and to determine the effect of Plppr5 gene silencing on neuronal zinc metabolism and mitochondrial function in vitro. 10-day-old wild type (WT) mice and Plppr5-deficient (Plppr5 -/-) mice were subjected to hypoxia-ischemia. Lesion volumes and HI-induced neuroexcitotoxic phenotypes were quantified together with ZnT1 protein expression in hippocampus. In addition, HT22 (mouse hippocampal neuronal cells) cell model was established by oxygen-glucose deprivation/reoxygenation (OGD/R) treatment and was treated with medium containing LV-sh_Plppr5 or control virus. Mitochondrial oxidative stress indicator ROS, mitochondrial ZnT1 protein expression and zinc ion content were detected.
Results: Plppr5-deficient mice subjected to hypoxia-ischemia at postnatal day 10 present significantly higher cerebral infarction. Plppr5-deficient mice were endowed with a more pronounced superexcitability phenotype at 4 weeks after HI, manifested as a reduced seizure threshold. ZnT1 protein was also found reduced in Plppr5-deficient mice as well as in mice subjected to HI excitotoxicity. Plppr5 knockout in vivo exacerbates HI brain injury phenotypes, including infarct volume and seizure threshold. In addition, knockout of the Plppr5 gene reduced the MFS score to some extent. In vitro Plppr5 silencing directly interferes with neuronal zinc metabolism homeostasis and exacerbates hypoxia-induced mitochondrial oxidative stress damage. Taken together, our findings demonstrate for the first time that Plppr5-deficient mouse pups exposed to neuronal hypoxia and ischemia exhibit aggravated acute brain injury and long-term brain excitability compared with the same treated WT pups, which may be related to the disruption of zinc and mitochondria-dependent metabolic pathways in the hippocampus. These data support further investigation into novel approaches targeting Plppr5-mediated zinc and mitochondrial homeostasis in neonatal HIE.

Keywords:  excitotoxic; hypoxic-ischemia; knockout; neonatal; plppr5

DOI:  https://doi.org/10.3389/fnins.2022.751489
Neurochem Res. 2022 Apr 12.

Nandrolone Supplementation Promotes AMPK Activation and Divergent 18[FDG] PET Brain Connectivity in Adult and Aged Mice.

N R Strogulski, A Kopczynski, V G de Oliveira, R B Carteri, G Hansel, G T Venturin, S Greggio, J C DaCosta, M A De Bastiani, M S Rodolphi, L V Portela.

  Decreased anabolic androgen levels are followed by impaired brain energy support and sensing with loss of neural connectivity during physiological aging, providing a neurobiological basis for hormone supplementation. Here, we investigated whether nandrolone decanoate (ND) administration mediates hypothalamic AMPK activation and glucose metabolism, thus affecting metabolic connectivity in brain areas of adult and aged mice. Metabolic interconnected brain areas of rodents can be detected by positron emission tomography using 18FDG-mPET. Albino CF1 mice at 3 and 18 months of age were separated into 4 groups that received daily subcutaneous injections of either ND (15 mg/kg) or vehicle for 15 days. At the in vivo baseline and on the 14th day, brain 18FDG-microPET scans were performed. Hypothalamic pAMPKT172/AMPK protein levels were assessed, and basal mitochondrial respiratory states were evaluated in synaptosomes. A metabolic connectivity network between brain areas was estimated based on 18FDG uptake. We found that ND increased the pAMPKT172/AMPK ratio in both adult and aged mice but increased 18FDG uptake and mitochondrial basal respiration only in adult mice. Furthermore, ND triggered rearrangement in the metabolic connectivity of adult mice and aged mice compared to age-matched controls. Altogether, our findings suggest that ND promotes hypothalamic AMPK activation, and distinct glucose metabolism and metabolic connectivity rearrangements in the brains of adult and aged mice.

Keywords:  18FDG-PET; Aging; Anabolic-androgen steroids; Mitochondria; Nandrolone decanoate; Neural metabolic connectivity

DOI:  https://doi.org/10.1007/s11064-022-03592-2
Int J Mol Sci. 2022 Mar 26. pii: 3652. [Epub ahead of print]23(7):

Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease.

Maria Elzbieta Mycielska, Emma Naomi James, Eric Kenneth Parkinson.

  Recent mouse model experiments support an instrumental role for senescent cells in age-related diseases and senescent cells may be causal to certain age-related pathologies. A strongly supported hypothesis is that extranuclear chromatin is recognized by the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, which in turn leads to the induction of several inflammatory cytokines as part of the senescence-associated secretory phenotype. This sterile inflammation increases with chronological age and age-associated disease. More recently, several intracellular and extracellular metabolic changes have been described in senescent cells but it is not clear whether any of them have functional significance. In this review, we highlight the potential effect of dietary and age-related metabolites in the modulation of the senescent phenotype in addition to discussing how experimental conditions may influence senescent cell metabolism, especially that of energy regulation. Finally, as extracellular citrate accumulates following certain types of senescence, we focus on the recently reported role of extracellular citrate in aging and age-related pathologies. We propose that citrate may be an active component of the senescence-associated secretory phenotype and via its intake through the diet may even contribute to the cause of age-related disease.

Keywords:  ageing; cancer; citrate; energy; metabolism; senescence; telomere; transport

DOI:  https://doi.org/10.3390/ijms23073652
J Alzheimers Dis. 2022 Apr 07.

Age- and Sex-Associated Glucose Metabolism Decline in a Mouse Model of Alzheimer's Disease.

Camila Gherardelli, Pedro Cisternas, Roberto F Vera-Salazar, Carolina Mendez-Orellana, Nibaldo C Inestrosa.

   BACKGROUND: Alzheimer's disease (AD) is characterized by a high etiological and clinical heterogeneity, which has obscured the diagnostic and treatment efficacy, as well as limited the development of potential drugs. Sex differences are among the risk factors that contribute to the variability of disease manifestation. Unlike men, women are at greater risk of developing AD and suffer from higher cognitive deterioration, together with important changes in pathological features. Alterations in glucose metabolism are emerging as a key player in the pathogenesis of AD, which appear even decades before the presence of clinical symptoms.
OBJECTIVE: We aimed to study whether AD-related sex differences influence glucose metabolism.
METHODS: We used male and female APPswe/PS1dE9 (APP/PS1) transgenic mice of different ages to examine glucose metabolism effects on AD development.
RESULTS: Our analysis suggests an age-dependent decline of metabolic responses, cognitive functions, and brain energy homeostasis, together with an increase of Aβ levels in both males and females APP/PS1 mice. The administration of Andrographolide (Andro), an anti-inflammatory and anti-diabetic compound, was able to restore several metabolic disturbances, including the glycolytic and the pentose phosphate pathway fluxes, ATP levels, AMPKα activity, and Glut3 expression in 8-month-old mice, independent of the sex, while rescuing these abnormalities only in older females. Similarly, Andro also prevented Aβ accumulation and cognitive decline in all but old males.
CONCLUSION: Our study provides insight into the heterogeneity of the disease and supports the use of Andro as a potential drug to promote personalized medicine in AD.

Keywords:  Alzheimer’s disease; andrographolide; glucose metabolism; neuroprotection; sex differences

DOI:  https://doi.org/10.3233/JAD-215273
Int J Mol Sci. 2022 Apr 02. pii: 3969. [Epub ahead of print]23(7):

Emerging Role of Phospholipids and Lysophospholipids for Improving Brain Docosahexaenoic Acid as Potential Preventive and Therapeutic Strategies for Neurological Diseases.

Mayssa Hachem, Houda Nacir.

  Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 polyunsaturated fatty acid (PUFA) essential for neural development, learning, and vision. Although DHA can be provided to humans through nutrition and synthesized in vivo from its precursor alpha-linolenic acid (ALA, 18:3n-3), deficiencies in cerebral DHA level were associated with neurodegenerative diseases including Parkinson's and Alzheimer's diseases. The aim of this review was to develop a complete understanding of previous and current approaches and suggest future approaches to target the brain with DHA in different lipids' forms for potential prevention and treatment of neurodegenerative diseases. Since glycerophospholipids (GPs) play a crucial role in DHA transport to the brain, we explored their biosynthesis and remodeling pathways with a focus on cerebral PUFA remodeling. Following this, we discussed the brain content and biological properties of phospholipids (PLs) and Lyso-PLs with omega-3 PUFA focusing on DHA's beneficial effects in healthy conditions and brain disorders. We emphasized the cerebral accretion of DHA when esterified at sn-2 position of PLs and Lyso-PLs. Finally, we highlighted the importance of DHA-rich Lyso-PLs' development for pharmaceutical applications since most commercially available DHA formulations are in the form of PLs or triglycerides, which are not the preferred transporter of DHA to the brain.

Keywords:  cerebral accretion; docosahexaenoic acid; lysophospholipids; neurodegenerative diseases; phospholipids

DOI:  https://doi.org/10.3390/ijms23073969
Nutrients. 2022 Mar 29. pii: 1419. [Epub ahead of print]14(7):

Nutrition for Brain Development.

M Hasan Mohajeri.

This Special Issue focuses on the fundamental role of nutrition in brain development [...].

DOI: https://doi.org/10.3390/nu14071419
Int J Mol Sci. 2022 Apr 06. pii: 4047. [Epub ahead of print]23(7):

Metabolic Syndrome and β-Oxidation of Long-Chain Fatty Acids in the Brain, Heart, and Kidney Mitochondria.

Alexander Panov, Vladimir I Mayorov, Sergey Dikalov.

  We present evidence that metabolic syndrome (MetS) represents the postreproductive stage of the human postembryonic ontogenesis. Accordingly, the genes governing this stage experience relatively weak evolutionary selection pressure, thus representing the metabolic phenotype of distant ancestors with β-oxidation of long-chain fatty acids (FAs) as the primary energy source. Mitochondria oxidize at high-rate FAs only when succinate, glutamate, or pyruvate are present. The heart and brain mitochondria work at a wide range of functional loads and possess an intrinsic inhibition of complex II to prevent oxidative stress at periods of low functional activity. Kidney mitochondria constantly work at a high rate and lack inhibition of complex II. We suggest that in people with MetS, oxidative stress is the central mechanism of the heart and brain pathologies. Oxidative stress is a secondary pathogenetic mechanism in the kidney, while the primary mechanisms are kidney hypoxia caused by persistent hyperglycemia and hypertension. Current evidence suggests that most of the nongenetic pathologies associated with MetS originate from the inconsistencies between the metabolic phenotype acquired after the transition to the postreproductive stage and excessive consumption of food rich in carbohydrates and a sedentary lifestyle.

Keywords:  brain mitochondria; heart; human postembryonic ontogenesis; kidney; long-chain fatty acids; metabolic syndrome; oxidative stress; β-oxidation

DOI:  https://doi.org/10.3390/ijms23074047
Int J Mol Sci. 2022 Mar 29. pii: 3738. [Epub ahead of print]23(7):

Mitochondrial Lipids: From Membrane Organization to Apoptotic Facilitation.

Aikaterini Poulaki, Stavroula Giannouli.

  Mitochondria are the most complex intracellular organelles, their function combining energy production for survival and apoptosis facilitation for death. Such a multivariate physiology is structurally and functionally reflected upon their membrane configuration and lipid composition. Mitochondrial double membrane lipids, with cardiolipin as the protagonist, show an impressive level of complexity that is mandatory for maintenance of mitochondrial health and protection from apoptosis. Given that lipidomics is an emerging field in cancer research and that mitochondria are the organelles with the most important role in malignant maintenance knowledge of the mitochondrial membrane, lipid physiology in health is mandatory. In this review, we will thus describe the delicate nature of the healthy mitochondrial double membrane and its role in apoptosis. Emphasis will be given on mitochondrial membrane lipids and the changes that they undergo during apoptosis induction and progression.

Keywords:  apoptosis; cardiolipin; ceramide; cytochrome C; double membrane; mitochondria; mitochondrial lipids

DOI:  https://doi.org/10.3390/ijms23073738
J Cancer. 2022 ;13(6): 1745-1757

Cholesterol metabolism and its implication in glioblastoma therapy.

Xuyang Guo, Shaolong Zhou, Zhuo Yang, Zi-An Li, Weihua Hu, Lirui Dai, Wulong Liang, Xinjun Wang.

Glioblastoma (GBM) is the most lethal malignant tumor in the central nervous system, with a median survival of only 14 months. Cholesterol, which is the main component of cell membrane and the precursor of many hormones, is one of the most important lipid components in human body. Since reprogramming of the cholesterol metabolic profile has been discovered in many cancers including GBM, cholesterol metabolism becomes a promising potential target for therapy. Since GBM cells rely on external cholesterol to survive and accumulate lipid droplets to meet their rapid growth needs, targeting the metabolism of cholesterol by different strategies including inhibition of cholesterol uptake and promotion of cholesterol efflux by activating LXRs and disruption of cellular cholesterol trafficking, inhibition of SREBP signaling, inhibition of cholesterol esterification, could potentially oppose the growth of glial tumors. In this review, we discussed the above findings and describe cholesterol synthesis and homeostatic feedback pathways in normal brain tissues and brain tumors, statin use in GBM and the role of lipid rafts and cholesterol precursors and oxysterols in the treatment and pathogenesis of GBM are also summarized.

DOI: https://doi.org/10.7150/jca.63609
Front Cell Dev Biol. 2022 ;10 836196

Defects of Nutrient Signaling and Autophagy in Neurodegeneration.

Jon Ondaro, Haizea Hernandez-Eguiazu, Maddi Garciandia-Arcelus, Raúl Loera-Valencia, Laura Rodriguez-Gómez, Andrés Jiménez-Zúñiga, Julen Goikolea, Patricia Rodriguez-Rodriguez, Javier Ruiz-Martinez, Fermín Moreno, Adolfo Lopez de Munain, Ian James Holt, Francisco Javier Gil-Bea, Gorka Gereñu.

  Neurons are post-mitotic cells that allocate huge amounts of energy to the synthesis of new organelles and molecules, neurotransmission and to the maintenance of redox homeostasis. In neurons, autophagy is not only crucial to ensure organelle renewal but it is also essential to balance nutritional needs through the mobilization of internal energy stores. A delicate crosstalk between the pathways that sense nutritional status of the cell and the autophagic processes to recycle organelles and macronutrients is fundamental to guarantee the proper functioning of the neuron in times of energy scarcity. This review provides a detailed overview of the pathways and processes involved in the balance of cellular energy mediated by autophagy, which when defective, precipitate the neurodegenerative cascade of Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis or Alzheimer's disease.

Keywords:  AMPK; autophagy; glucose metabolism; lipid metabolism; mTORC1 (mechanistic target of rapamycin complex 1); mitochondrial metabolism; neurodegenerative diseases; nutrient sensing pathways

DOI:  https://doi.org/10.3389/fcell.2022.836196
Endocr Metab Immune Disord Drug Targets. 2022 Apr 08.

The Savant Syndrome: A Gift or A Disability? A Deeper Look into Metabolic Correlates of Hidden Cognitive Capacity.

Irem Onin, Lütfü Hanoglu, Burak Yulug.

  Savant syndrome is a rare unusual skill that occurs in the presence of severe developmental disabilities, disorders and injuries. The syndrome can appear either congenital as from birth through childhood or acquired as brain injury or central nervous system damage There are several findings which indicate that savant syndrome usually occurs with significant brain metabolism alterations resulting with critical brain network changes. These types of changes in the brain, usually explained by "tyranny of the left hemisphere" theory which indicates the inhibition of the left hemisphere allows the right hemisphere to develop the savant abilities. Another way to temporarily simulate these types of changes in the brain may obtain by different neuromodulation techniques such as transcranial magnetic stimulation and transcranial direct current stimulation. Such neuromodulation techniques might help us to discover the "hidden talent" potential through modulating the brain network metabolism. We herein discussed the types of savant syndrome along with relation to specific neurometabolic network alterations. Furthermore, we provide a perspective on how newly developed neuromodulation and cognitive rehabilitation techniques can help to simulate savant syndrome in healthy individuals through modulating the brain network activity.

Keywords:  Acquired Savant; Autism Spectrum Disorder; Congenital Savant; Epilepsy; Savant syndrome; Traumatic Brain Injury

DOI:  https://doi.org/10.2174/1871530322666220408134359
Cell Mol Life Sci. 2022 Apr 13. 79(5): 239

Mitochondrial function in spinal cord injury and regeneration.

Paula G Slater, Miguel E Domínguez-Romero, Maximiliano Villarreal, Verónica Eisner, Juan Larraín.

  Many people around the world suffer from some form of paralysis caused by spinal cord injury (SCI), which has an impact on quality and life expectancy. The spinal cord is part of the central nervous system (CNS), which in mammals is unable to regenerate, and to date, there is a lack of full functional recovery therapies for SCI. These injuries start with a rapid and mechanical insult, followed by a secondary phase leading progressively to greater damage. This secondary phase can be potentially modifiable through targeted therapies. The growing literature, derived from mammalian and regenerative model studies, supports a leading role for mitochondria in every cellular response after SCI: mitochondrial dysfunction is the common event of different triggers leading to cell death, cellular metabolism regulates the immune response, mitochondrial number and localization correlate with axon regenerative capacity, while mitochondrial abundance and substrate utilization regulate neural stem progenitor cells self-renewal and differentiation. Herein, we present a comprehensive review of the cellular responses during the secondary phase of SCI, the mitochondrial contribution to each of them, as well as evidence of mitochondrial involvement in spinal cord regeneration, suggesting that a more in-depth study of mitochondrial function and regulation is needed to identify potential targets for SCI therapeutic intervention.

Keywords:  Axon regeneration; Cell death; Cell metabolism; Immune response; Mitochondria; Neurogenesis; Spinal cord

DOI:  https://doi.org/10.1007/s00018-022-04261-x
Int J Mol Sci. 2022 Apr 02. pii: 3958. [Epub ahead of print]23(7):

Diet-Induced Metabolic Dysfunction of Hypothalamic Nutrient Sensing in Rodents.

Isabel Arrieta-Cruz, Blanca Samara Torres-Ávila, Hilda Martínez-Coria, Héctor Eduardo López-Valdés, Roger Gutiérrez-Juárez.

  A sedentary lifestyle and excessive nutrient intake resulting from the consumption of high-fat and calorie-rich diets are environmental factors contributing to the rapid growth of the current pandemic of type 2 diabetes mellitus (DM2). Fasting hyperglycemia, an established hallmark of DM2, is caused by excessive production of glucose by the liver, resulting in the inability of insulin to suppress endogenous glucose production. To prevent inappropriate elevations of circulating glucose resulting from changes in nutrient availability, mammals rely on complex mechanisms for continuously detecting these changes and to respond to them with metabolic adaptations designed to modulate glucose output. The mediobasal hypothalamus (MBH) is the key center where nutritional cues are detected and appropriate modulatory responses are integrated. However, certain environmental factors may have a negative impact on these adaptive responses. For example, consumption of a diet enriched in saturated fat in rodents resulted in the development of a metabolic defect that attenuated these nutrient sensing mechanisms, rendering the animals prone to developing hyperglycemia. Thus, high-fat feeding leads to a state of "metabolic disability" in which animals' glucoregulatory responses fail. We postulate that the chronic faltering of the hypothalamic glucoregulatory mechanisms contributes to the development of metabolic disease.

Keywords:  amino acids; diabetes; glycemia; high-fat diet; liver; mediobasal hypothalamus; nutrients

DOI:  https://doi.org/10.3390/ijms23073958
Nutrients. 2022 Mar 23. pii: 1333. [Epub ahead of print]14(7):

Omega-3/Omega-6 Long-Chain Fatty Acid Imbalance in Phase I Retinopathy of Prematurity.

Zhongjie Fu, Wenjun Yan, Chuck T Chen, Anders K Nilsson, Edward Bull, William Allen, Jay Yang, Minji Ko, John Paul SanGiovanni, James D Akula, Saswata Talukdar, Ann Hellström, Lois E H Smith.

  There is a gap in understanding the effect of the essential ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFA) on Phase I retinopathy of prematurity (ROP), which precipitates proliferative ROP. Postnatal hyperglycemia contributes to Phase I ROP by delaying retinal vascularization. In mouse neonates with hyperglycemia-associated Phase I retinopathy, dietary ω-3 (vs. ω-6 LCPUFA) supplementation promoted retinal vessel development. However, ω-6 (vs. ω-3 LCPUFA) was also developmentally essential, promoting neuronal growth and metabolism as suggested by a strong metabolic shift in almost all types of retinal neuronal and glial cells identified with single-cell transcriptomics. Loss of adiponectin (APN) in mice (mimicking the low APN levels in Phase I ROP) decreased LCPUFA levels (including ω-3 and ω-6) in retinas under normoglycemic and hyperglycemic conditions. ω-3 (vs. ω-6) LCPUFA activated the APN pathway by increasing the circulating APN levels and inducing expression of the retinal APN receptor. Our findings suggested that both ω-3 and ω-6 LCPUFA are crucial in protecting against retinal neurovascular dysfunction in a Phase I ROP model; adequate ω-6 LCPUFA levels must be maintained in addition to ω-3 supplementation to prevent retinopathy. Activation of the APN pathway may further enhance the ω-3 and ω-6 LCPUFA's protection against ROP.

Keywords:  LCPUFA; adiponectin; hyperglycemia; retinal neuron; retinal vessel; retinopathy of prematurity

DOI:  https://doi.org/10.3390/nu14071333
Mol Psychiatry. 2022 Apr 13.

Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice.

Andreas Giannisis, Kalicharan Patra, Anna K Edlund, Lur Agirrezabala Nieto, Joan Benedicto-Gras, Simon Moussaud, Andrés de la Rosa, Daniel Twohig, Tore Bengtsson, Yuan Fu, Guojun Bu, Greg Bial, Lander Foquet, Christina Hammarstedt, Stephen Strom, Kristina Kannisto, Jacob Raber, Ewa Ellis, Henrietta M Nielsen.

Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer's disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes neurodegeneration is unknown. Here we investigated the brains of Fah-/-, Rag2-/-, Il2rg-/- mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk of neurodegenerative disease.

DOI: https://doi.org/10.1038/s41380-022-01548-0
J Neurophysiol. 2022 Apr 13.

Hyperglycemia and Hyperinsulinemia Effects on Anterior Cingulate Cortex Myoinositol - Relation to Brain Network Functional Connectivity in Healthy Adults.

Nicolas R Bolo, Alan M Jacobson, Gail Musen, Donald C Simonson.

  Brain mechanisms underlying the association of diabetes metabolic disorders - hyperglycemia and insulin resistance - with cognitive impairment are unknown. Myoinositol is a brain metabolite involved in cell osmotic balance, membrane phospholipid turnover and second messenger neurotransmission, which affect brain function. Increased brain myoinositol and altered functional-connectivity have been found in diabetes, mild cognitive impairment and Alzheimer's disease, but the independent effects of plasma glucose and insulin on brain myoinositol and function are not characterized. We measured myoinositol concentrations in the pregenual anterior cingulate cortex (ACC), a region involved in self-reflective awareness and decision-making, using proton magnetic resonance spectroscopy, and whole brain resting state functional-connectivity using fMRI, during acute hyperglycemia (with attendant hyperinsulinemia) and euglycemic-hyperinsulinemia compared to basal fasting-euglycemia (EU) in 11 healthy non-diabetic participants (5women/6men, mean±SD, age: 27±7yrs, fasting-glucose: 5.2±0.4mmol/L, fasting-insulin: 4.9±4.4μU/ml). Brain MR data were acquired during two separate visits: 1) EU followed by a 60-minute hyperglycemic-clamp (glucose: 10.7±0.2mmol/L, insulin: 33±6μU/mL); 2) EU followed by a hyperinsulinemic-euglycemic-clamp (glucose: 5.3±0.1mmol/L, insulin: 27±5μU/mL) designed to match individual insulin levels achieved during the visit-1 hyperglycemic-clamp. Myoinositol decreased by 14% during the hyperglycemic-clamp (from 7.7±1.5mmol/kg to 6.6±0.8mmol/kg, p=0.031), and by 9% during the hyperinsulinemic-euglycemic-clamp (from 7.1±0.7mmol/kg to 6.5±0.7mmol/kg, p=0.014), with no significant difference between the two clamps. Lower myoinositol was associated with higher functional connectivity of the thalamus and precentral cortex with insula-ACC-related networks, suggesting myoinositol is involved in insulin-modulation of cognitive/emotional network function in healthy adults. Regional brain myoinositol levels may be useful biomarkers for monitoring cognitive and mood-enhancing treatment responses.

Keywords:  Brain Metabolism and Function; Cognition; Diabetes; Magnetic Resonance Spectroscopy; Mood

DOI:  https://doi.org/10.1152/jn.00408.2021
Int J Mol Sci. 2022 Mar 24. pii: 3533. [Epub ahead of print]23(7):

Genetic Inactivation of Free Fatty Acid Receptor 3 Impedes Behavioral Deficits and Pathological Hallmarks in the APPswe Alzheimer's Disease Mouse Model.

Marta Zamarbide, Eva Martinez-Pinilla, Francisco Gil-Bea, Masashi Yanagisawa, Rafael Franco, Alberto Perez-Mediavilla.

  The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism, but its function in the brain is unknown. We aimed, first, to investigate the expression of the receptor in the hippocampus of Alzheimer disease (AD) patients at different stages of the disease and, second, to assess whether genetic inactivation of the Ffar3 gene could affect the phenotypic features of the APPswe mouse model. The expression of transcripts for FFA receptors in postmortem human hippocampal samples and in the hippocampus of wild-type and transgenic mice was analyzed by RT-qPCR. We generated a double transgenic mouse, FFA3R-/-/APPswe, to perform cognition studies and to assess, by immunoblotting Aβ and tau pathologies and the differential expression of synaptic plasticity-related proteins. For the first time, the occurrence of the FFA3R in the human hippocampus and its overexpression, even in the first stages of AD, was demonstrated. Remarkably, FFA3R-/-/APPswe mice do not have the characteristic memory impairment of 12-month-old APPswe mice. Additionally, this newly generated transgenic line does not develop the most important Alzheimer's disease (AD)-related features, such as amyloid beta (Aβ) brain accumulations and tau hyperphosphorylation. These findings are accompanied by increased levels of the insulin-degrading enzyme (IDE) and lower activity of the tau kinases GSK3β and Cdk5. We conclude that the brain FFA3R is involved in cognitive processes and that its inactivation prevents AD-like cognitive decline and pathological hallmarks.

Keywords:  Alzheimer’s disease; amyloid; learning and memory; neuroprotection; synaptic plasticity; therapy

DOI:  https://doi.org/10.3390/ijms23073533
Eur J Med Genet. 2022 Apr 06. pii: S1769-7212(22)00062-3. [Epub ahead of print]65(6): 104481

Second report of SHMT2 related neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities.

Purvi Majethia, Vivekananda Bhat, B L Yatheesha, Shahyan Siddiqui, Anju Shukla.

  Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB; MIM# 619121) is a recently described metabolic disorder with characteristic features of mild dysmorphism, intellectual disability, spasticity, peripheral neuropathy, cardiomyopathy, and thin corpus callosum. Biallelic variants in SHMT2 (MIM 138450), encoding mitochondrial serine hydroxymethyltransferase enzyme, have been recently linked to this disorder. Till now, a total of seven variants including six missense and one deletion-insertion has been reported in SHMT2. We hereby report an additional individual with novel homozygous missense variant c.1133A > G in SHMT2 (NM_005412.6) identified by exome sequencing and review the phenotype and genotype of the previously reported individuals with NEDCASB.

Keywords:  Cardiomyopathy; Mitochondria; SHMT2

DOI:  https://doi.org/10.1016/j.ejmg.2022.104481
Prostaglandins Leukot Essent Fatty Acids. 2022 Apr 06. pii: S0952-3278(22)00039-4. [Epub ahead of print]180 102427

Neurodevelopment, nutrition and genetics. A contemporary retrospective on neurocognitive health on the occasion of the 100th anniversary of the National Institute of Nutrition, Hyderabad, India.

Michael A Crawford, Yiqun Wang, David E Marsh, Mark R Johnson, Enitan Ogundipe, Ahamed Ibrahim, Hemalatha Rajkumar, S Kowsalya, Kumar S D Kothapalli, J T Brenna.

  In celebration of the centenary of the National Institute of Nutrition (NIN), Hyderabad, India (1918-2018), a symposium highlighted the progress in nutrition knowledge made over the century, as well as major gaps in implementation of that knowledge. Brain famine caused by a shortage of nutrients required for perinatal brain development has unfortunately become a global reality, even as protein-calorie famine was largely averted by the development of high yield crops. While malnutrition remains widespread, the neglect of global food policies that support brain development and maintenance are most alarming. Brain disorders now top the list of the global burden of disease, even with obesity rising throughout the world. Neurocognitive health, remarkably, is seldom listed among the non-communicable diseases (NCDs) and is therefore seldom considered as a component of food policy. Most notably, the health of mothers before conception and through pregnancy as mediated by proper nutrition has been neglected by the current focus on early death in non-neurocognitive NCDs, thereby compromising intellectual development of the ensuing generations. Foods with balanced essential fatty acids and ample absorbable micronutrients are plentiful for populations with access to shore-based foods, but deficient only a few kilometres away from the sea. Sustained access to brain supportive foods is a priority for India and throughout the world to enable each child to develop to their intellectual potential, and support a prosperous, just, and peaceful world. Nutrition education and food policy should place the nutritional requirements for the brain on top of the list of priorities.

Keywords:  Brain; Dietary fats; Docosahexaenoic acid (DHA); Essential fats; Mental ill health; Nutrition

DOI:  https://doi.org/10.1016/j.plefa.2022.102427
J Diabetes Res. 2022 ;2022 3555889

Mitochondrial Dynamics in the Metabolic Memory of Diabetic Retinopathy.

Ghulam Mohammad, Renu A Kowluru.

Mitochondria play a central role in the development of diabetic retinopathy and in the metabolic memory associated with its continued progression. Mitochondria have a regulated fusion fission process, which is essential for their homeostasis. One of the major fission proteins, dynamin-related protein 1 (Drp1), is recruited to the mitochondria by fission protein 1 (Fis1) to initiate fragmentation. Our aim is to investigate the role of Drp1 in the altered mitochondrial dynamics in the continued progression of diabetic retinopathy. Methods. Drp1 activation, mitochondrial transport, and Drp1-Fis1 interactions were analyzed in retinal endothelial cells incubated in 20 mM glucose (HG), followed by 5 mM glucose (NG), for four days each (HG-NG group). The results were confirmed in retinal microvessels from streptozotocin-induced diabetic rats with poor glycemia (>350 mg/dl blood glucose, PC group), followed by normal glycemia (~100 mg/dl), for four months each (PC-GC group). Results. GTPase activity of Drp1, Fis1-Drp1 interactions, mitochondrial levels of Drp1, and fragmentation of the mitochondria were elevated in HG group. Mitochondrial Division Inhibitor 1 (Mdiv) or Drp1-siRNA attenuated Drp1 activation, mitochondrial fragmentation, and DNA damage. In HG-NG group, NG failed to ameliorate Drp1 activation and Drp1-Fis1 interactions, and the mitochondria remained fragmented. However, Mdiv supplementation in normal glucose, which had followed four days of high glucose (HG-NG/Mdiv group), inhibited Drp1 activation, mitochondrial fragmentation, and increase in ROS and prevented mitochondrial damage. Retinal microvessels from the rats in PC and PC-GC groups had similar Drp1 activation. Conclusion. Thus, Drp1 plays a major role in mitochondrial homeostasis in diabetic retinopathy and in the metabolic memory phenomenon associated with its continued progression. Supplementation of normal glycemia with a Drp1 inhibitor could retard development and further progression of diabetic retinopathy.

DOI: https://doi.org/10.1155/2022/3555889
EMBO J. 2022 Apr 12. e109390

DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion.

Maeve Long, Alvaro Sanchez-Martinez, Marianna Longo, Fumi Suomi, Hans Stenlund, Annika I Johansson, Homa Ehsan, Veijo T Salo, Lambert Montava-Garriga, Seyedehshima Naddafi, Elina Ikonen, Ian G Ganley, Alexander J Whitworth, Thomas G McWilliams.

  Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether mitophagy is a cause or consequence of such state changes. The signalling pathways that integrate with mitophagy to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated with deferiprone, a therapeutic iron chelator that stimulates PINK1/PARKIN-independent mitophagy. Iron depletion profoundly rewired the metabolome, hallmarked by remodelling of lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurred several hours before mitochondrial clearance, with lipid droplets bordering mitochondria upon iron chelation. We demonstrate that DGAT1 inhibition restricts mitophagy in vitro, with impaired lysosomal homeostasis and cell viability. Importantly, genetic depletion of DGAT1 in vivo significantly impaired neuronal mitophagy and locomotor function in Drosophila. Our data define iron depletion as a potent signal that rapidly reshapes metabolism and establishes an unexpected synergy between lipid homeostasis and mitophagy that safeguards cell and tissue integrity.

Keywords:  DGAT1; iron; lipid droplet; metabolism; mitophagy

DOI:  https://doi.org/10.15252/embj.2021109390
Neuromolecular Med. 2022 Apr 11.

HCAR1-Mediated L-Lactate Signaling Suppresses Microglial Phagocytosis.

Raneen Nicola, Ravit Madar, Eitan Okun.

  Microglia, the primary brain-resident immune cells, protect the brain from various harmful pathogens, insulting and maintaining its homeostasis by phagocytosing extracellular particles. How microglia are metabolically regulated by their microenvironment remains largely elusive. Here, we investigated how extracellular lactate, which is abundant in the brain and dynamically changes in pathological states, affects microglial phagocytotic ability. We show that L-lactate reduces microglia phagocytic capacity in a Hydroxycarboxylic Acid Receptor 1 but not Monocarboxylate transporter 1-dependent manner. Our findings point to a potential role for extracellular lactate in suppressing the phagocytic activity of microglial cells in homeostasis and inflammatory conditions.

Keywords:  Amyloid-beta; HCAR1; Lactate; Microglia; Phagocytosis

DOI:  https://doi.org/10.1007/s12017-022-08710-5
Front Aging Neurosci. 2022 ;14 851135

Glucocerebrosidase Mutations Cause Mitochondrial and Lysosomal Dysfunction in Parkinson's Disease: Pathogenesis and Therapeutic Implications.

Wei Zheng, Dongsheng Fan.

  Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by multiple motor and non-motor symptoms. Mutations in the glucocerebrosidase (GBA) gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), which hydrolyzes glucosylceramide (GlcCer) to glucose and ceramide, are the most important and common genetic PD risk factors discovered to date. Homozygous GBA mutations result in the most common lysosomal storage disorder, Gaucher's disease (GD), which is classified according to the presence (neuronopathic types, type 2 and 3 GD) or absence (non-neuronopathic type, type 1 GD) of neurological symptoms. The clinical manifestations of PD in patients with GBA mutations are indistinguishable from those of sporadic PD at the individual level. However, accumulating data have indicated that GBA-associated PD patients exhibit a younger age of onset and a greater risk for cognitive impairment and psychiatric symptoms. The mechanisms underlying the increased risk of developing PD in GBA mutant carriers are currently unclear. Contributors to GBA-PD pathogenesis may include mitochondrial dysfunction, autophagy-lysosomal dysfunction, altered lipid homeostasis and enhanced α-synuclein aggregation. Therapeutic strategies for PD and GD targeting mutant GCase mainly include enzyme replacement, substrate reduction, gene and pharmacological small-molecule chaperones. Emerging clinical, genetic and pathogenic studies on GBA mutations and PD are making significant contributions to our understanding of PD-associated pathogenetic pathways, and further elucidating the interactions between GCase activity and neurodegeneration may improve therapeutic approaches for slowing PD progression.

Keywords:  Gaucher’s disease (GD); Parkinson’s disease (PD); glucocerebrosidase (GBA); lysosomal; mitochondrial

DOI:  https://doi.org/10.3389/fnagi.2022.851135
Cells. 2022 Mar 22. pii: 1071. [Epub ahead of print]11(7):

Lysophosphatidic Acid Receptor 5 (LPA5) Knockout Ameliorates the Neuroinflammatory Response In Vivo and Modifies the Inflammatory and Metabolic Landscape of Primary Microglia In Vitro.

Lisha Joshi, Ioanna Plastira, Eva Bernhart, Helga Reicher, Zhanat Koshenov, Wolfgang F Graier, Nemanja Vujic, Dagmar Kratky, Richard Rivera, Jerold Chun, Wolfgang Sattler.

  Systemic inflammation induces alterations in the finely tuned micromilieu of the brain that is continuously monitored by microglia. In the CNS, these changes include increased synthesis of the bioactive lipid lysophosphatidic acid (LPA), a ligand for the six members of the LPA receptor family (LPA1-6). In mouse and human microglia, LPA5 belongs to a set of receptors that cooperatively detect danger signals in the brain. Engagement of LPA5 by LPA polarizes microglia toward a pro-inflammatory phenotype. Therefore, we studied the consequences of global LPA5 knockout (-/-) on neuroinflammatory parameters in a mouse endotoxemia model and in primary microglia exposed to LPA in vitro. A single endotoxin injection (5 mg/kg body weight) resulted in lower circulating concentrations of TNFα and IL-1β and significantly reduced gene expression of IL-6 and CXCL2 in the brain of LPS-injected LPA5-/- mice. LPA5 deficiency improved sickness behavior and energy deficits produced by low-dose (1.4 mg LPS/kg body weight) chronic LPS treatment. LPA5-/- microglia secreted lower concentrations of pro-inflammatory cyto-/chemokines in response to LPA and showed higher maximal mitochondrial respiration under basal and LPA-activated conditions, further accompanied by lower lactate release, decreased NADPH and GSH synthesis, and inhibited NO production. Collectively, our data suggest that LPA5 promotes neuroinflammation by transmiting pro-inflammatory signals during endotoxemia through microglial activation induced by LPA.

Keywords:  chemokines; cytokines; endotoxin; immunometabolism; lysophospholipids; nitric oxide

DOI:  https://doi.org/10.3390/cells11071071
Methods Mol Biol. 2022 ;2431 409-416

Mitochondrial DNA Transport in Drosophila Neurons.

Joseph M Bateman.

  Mitochondria are essential organelles that generate energy and play vital roles in cellular metabolism. The small circular mitochondrial genome encodes key components of the mitochondrial respiratory apparatus. Depletion of, or mutations in mitochondrial DNA (mtDNA) cause mitochondrial dysfunction and disease. mtDNA is packaged into nucleoids, which are transported throughout the cell within mitochondria. Efficient transport of nucleoids is essential in neurons, where mitochondrial function is required locally at synapses. Here I describe methods for visualization of nucleoids in Drosophila neurons using a GFP fusion of the mitochondrial transcription factor TFAM. TFAM-GFP, together with mCherry-labeled mitochondria, was used to visualize nucleoids in fixed larval segmental nerves. I also describe how these tools can be used for live imaging of nucleoid dynamics. Using Drosophila as a model system, these methods will enable further characterization and analysis of nucleoid dynamics in neurons.

Keywords:  Drosophila; Live imaging; Mitochondrial DNA; Nucleoid; TFAM

DOI:  https://doi.org/10.1007/978-1-0716-1990-2_21
Cell Rep. 2022 Apr 12. pii: S2211-1247(22)00424-7. [Epub ahead of print]39(2): 110672

Reciprocal regulation of phosphatidylcholine synthesis and H3K36 methylation programs metabolic adaptation.

Wen Fang, Yibing Zhu, Sen Yang, Xiaomeng Tong, Cunqi Ye.

  Phospholipid biosynthesis plays a role in mediating membrane-to-histone communication that influences metabolic decisions. Upon nutrient deprivation, phospholipid methylation generates a starvation signal in the form of S-adenosylmethionine (SAM) depletion, leading to dynamic changes in histone methylation. Here we show that the SAM-responsive methylation of H3K36 is critical for metabolic adaptation to nutrient starvation in the budding yeast Saccharomyces cerevisiae. We find that mutants deficient in H3K36 methylation exhibit defects in membrane integrity and pyrimidine metabolism and lose viability quickly under starvation. Adjusting the synthesis of phospholipids potently rewires metabolic pathways for nucleotide synthesis and boosts the production of antioxidants, ameliorating the defects resulting from the loss of H3K36 methylation. We further demonstrate that H3K36 methylation reciprocally regulates phospholipid synthesis by influencing redox balance. Our study illustrates an adaptive mechanism whereby phospholipid synthesis entails a histone modification to reprogram metabolism for adaptation in a eukaryotic model organism.

Keywords:  CP: Metabolism; CP: Molecular biology; H3K36 methylation; S-adenosylmethionine; cellular metabolism; environmental adaptation; phosphatidylcholine; phosphatidylethanolamine; phospholipid; pyrimidine

DOI:  https://doi.org/10.1016/j.celrep.2022.110672
Front Pharmacol. 2022 ;13 826568

Luteolin Enhances Choroid Plexus 5-MTHF Brain Transport to Promote Hippocampal Neurogenesis in LOD Rats.

Hui-Zhen Li, Kai-Ge Liu, Ning-Xi Zeng, Xiao-Feng Wu, Wen-Jun Lu, Han-Fang Xu, Can Yan, Li-Li Wu.

  Folates, provided by food, are commonly used antidepressant synergists in late-onset depression (LOD). However, increased intake of folic acid in the elderly population might lead to the accumulation of unmetabolized folic acid in the systemic circulation, leading to enhanced deterioration of the central nervous system function. In addition, folates cannot access the brain directly because of the blood-brain barrier. Choroid plexus (CP) 5-methyltetrahydrofolate (5-MTHF) brain transport plays a critical role in regulating the cerebrospinal fluid (CSF) 5-MTHF content. Luteolin is a natural flavonoid that has antidepressant effects and is involved in the anti-folate resistance pathway. It remains unclear whether the antidepressant effects of luteolin are associated with the CP 5-MTHF brain transport. In this study, 20-21-month-old Wistar rats were exposed to the chronic unpredictable mild stress (CUMS) protocol for 6 consecutive weeks to explore the long-term effects of luteolin on behavior, 5-MTHF levels, hippocampal neurogenesis, and folate brain transport of the CP. In vitro primary hippocampal neural stem cells (NSCs) cultured in media containing 10% CSF from each group of rats and choroid plexus epithelial cells (CPECs) cultured in media containing 20 μM luteolin were treated with 100 μM corticosterone and 40 mg/ml D-galactose. We found that aged rats exposed to CUMS showed a significantly reduced sucrose preference, decreased locomotion activity in the open field test and accuracy of the Morris water maze test, increased immobility time in the forced swimming test, accelerated dysfunctional neurogenesis and neuronal loss in the dentate gyrus of LOD rats, as well as decreased CSF and hippocampus 5-MTHF levels, and zona occludens protein 1 (ZO-1), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC) protein levels. In vitro assays showed media containing 10% aged CSF or LOD+ Luteolin-CSF significantly increased the viability of CORT + D-gal-injured NSCs and alleviated dysfunctional neurogenesis and neuronal loss compared with the CORT + D-gal medium. However, media containing 10% LOD-CSF had no such effect. In the meantime, induction of CORT + D-gal significantly decreased the ZO-1, PCFT, RFC, and folate receptor alpha (FR-α) protein levels and transepithelial electrical resistance in rat CPECs. As expected, luteolin treatment was effective in improving these abnormal changes. These findings suggested that luteolin could ameliorate CUMS-induced LOD-like behaviors by enhancing the folate brain transport.

Keywords:  5-methyltetrahydrofolate; choroid plexus folate transporters; hippocampal neural stem cells; late-onset depression; luteolin

DOI:  https://doi.org/10.3389/fphar.2022.826568
Front Cell Neurosci. 2022 ;16 812887

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders.

Charles N S Allen, Sterling P Arjona, Maryline Santerre, Claudio De Lucia, Walter J Koch, Bassel E Sawaya.

  A significant number of patients infected with HIV-1 suffer from HIV-associated neurocognitive disorders (HAND) such as spatial memory impairments and learning disabilities (SMI-LD). SMI-LD is also observed in patients using combination antiretroviral therapy (cART). Our lab has demonstrated that the HIV-1 protein, gp120, promotes SMI-LD by altering mitochondrial functions and energy production. We have investigated cellular processes upstream of the mitochondrial functions and discovered that gp120 causes metabolic reprogramming. Effectively, the addition of gp120 protein to neuronal cells disrupted the glycolysis pathway at the pyruvate level. Looking for the players involved, we found that gp120 promotes increased expression of polypyrimidine tract binding protein 1 (PTBP1), causing the splicing of pyruvate kinase M (PKM) into PKM1 and PKM2. We have also shown that these events lead to the accumulation of advanced glycation end products (AGEs) and prevent the cleavage of pro-brain-derived neurotrophic factor (pro-BDNF) protein into mature brain-derived neurotrophic factor (BDNF). The accumulation of proBDNF results in signaling that increases the expression of the inducible cAMP early repressor (ICER) protein which then occupies the cAMP response element (CRE)-binding sites within the BDNF promoters II and IV, thus altering normal synaptic plasticity. We reversed these events by adding Tepp-46, which stabilizes the tetrameric form of PKM2. Therefore, we concluded that gp120 reprograms cellular metabolism, causing changes linked to disrupted memory in HIV-infected patients and that preventing the disruption of the metabolism presents a potential cure against HAND progression.

Keywords:  HIV gp120; advanced glycation end-product; glycolysis; memory; metabolic reprogramming; neurons

DOI:  https://doi.org/10.3389/fncel.2022.812887
Signal Transduct Target Ther. 2022 Apr 15. 7(1): 103

PINK1-mediated Drp1S616 phosphorylation modulates synaptic development and plasticity via promoting mitochondrial fission.

Qingtao Gao, Runyi Tian, Hailong Han, Jesse Slone, Caifang Wang, Xiao Ke, Tongmei Zhang, Xiangyu Li, Yuhong He, Panlin Liao, Fang Wang, Ye Chen, Shiqing Fu, Kexuan Zhang, Fangfang Zeng, Yingxuan Yang, Zhuo Li, Jieqiong Tan, Jiada Li, Youming Lu, Taosheng Huang, Zhonghua Hu, Zhuohua Zhang.

Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy. However, the underlying mechanism remains elusive. We show here that Pink1 knockout (KO) mice display defective dendritic spine maturation, reduced axonal synaptic vesicles, abnormal synaptic connection, and attenuated long-term synaptic potentiation (LTP). Drp1 activation via S616 phosphorylation rescues deficits of spine maturation in Pink1 KO neurons. Notably, mice harboring a knockin (KI) phosphor-null Drp1S616A recapitulate spine immaturity and synaptic abnormality identified in Pink1 KO mice. Chemical LTP (cLTP) induces Drp1S616 phosphorylation in a PINK1-dependent manner. Moreover, phosphor-mimetic Drp1S616D restores reduced dendritic spine localization of mitochondria in Pink1 KO neurons. Together, this study provides the first in vivo evidence of functional regulation of Drp1 by phosphorylation and suggests that PINK1-Drp1S616 phosphorylation coupling is essential for convergence between mitochondrial dynamics and neural circuitry formation and refinement.

DOI: https://doi.org/10.1038/s41392-022-00933-z
Am J Transl Res. 2022 ;14(3): 1482-1494

Pro-resolving lipid mediators in traumatic brain injury: emerging concepts and translational approach.

Roy A Poblete, Marcela Arenas, Nerses Sanossian, Young-Kwon Hong, William D Freeman, Patrick D Lyden, Stan G Louie.

Despite the high mortality and disability associated with traumatic brain injury (TBI), effective pharmacologic treatments are lacking. Of emerging interest, bioactive lipids, including specialized pro-resolving lipid mediators of inflammation (SPMs), act to attenuate inflammation after injury resolution. The SPM lipidome may serve as a biomarker of disease and predictor of clinical outcomes, and the use of exogenous SPM administration represents a novel therapeutic strategy for TBI. This review article provides a comprehensive discussion of the current pre-clinical and clinical literature supporting the importance of bioactive lipids, including SPMs, in TBI recovery. We additionally propose a translational approach to answer important clinical and scientific questions to advance the study of bioactive lipids and SPMs towards clinical research. Given the morbidity and mortality associated with TBI with limited treatment options, novel approaches are needed.

Keywords: SPMs; TBI; edema; inflammation; lipids; pharmacologic treatment