bims-brabim 2022-01-16 papers

bims-brabim

Biomed News

on Brain bioenergetics and metabolism

Issue of 2022–01–16
27 papers selected by
João Victor Cabral-Costa, University of São Paulo

Phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer's disease.
Elevated hippocampal mGlut2 receptors in rats with metabolic syndrome-induced-memory impairment, possible protection by vitamin D.
Insulin signaling in clock neurons regulates sleep in Drosophila.
AGC1 Deficiency: Pathology and Molecular and Cellular Mechanisms of the Disease.
Neuroprotective effect of cajaninstilbene acid against cerebral ischemia and reperfusion damages by activating AMPK/Nrf2 pathway.
Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.
The Nerve Growth Factor Metabolic Pathway Dysregulation as Cause of Alzheimer's Cholinergic Atrophy.
Effects of vitamin D (VD3) supplementation on the brain mitochondrial function of male rats, in the 6-OHDA-induced model of Parkinson's disease.
The involvement of TRPM2 on the MPP+-induced oxidative neurotoxicity and apoptosis in hippocampal neurons from neonatal mice: protective role of resveratrol.
Dopamine and Methamphetamine Differentially Affect Electron Transport Chain Complexes and Parkin in Rat Striatum: New Insight into Methamphetamine Neurotoxicity.
Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis.
Aging is associated with increased brain iron through cortex-derived hepcidin expression.
Electroacupuncture Relieves Hippocampal Injury by Heme Oxygenase-1 to Improve Mitochondrial Function.
Protective effect of mesenchymal stem cell-derived exosomal treatment of hippocampal neurons against oxygen-glucose deprivation/reperfusion-induced injury.
Novel Probable Glance at Inflammatory Scenario Development in Autistic Pathology.
Covering the Role of PGC-1α in the Nervous System.
Accumulation of APP-CTF induces mitophagy dysfunction in the iNSCs model of Alzheimer's disease.
Effects of Mdivi-1 on Neural Mitochondrial Dysfunction and Mitochondria-Mediated Apoptosis in Ischemia-Reperfusion Injury After Stroke: A Systematic Review of Preclinical Studies.
Dysfunctional ER-mitochondrion coupling is associated with ER stress-induced apoptosis and neurological deficits in a rodent model of severe head injury.
Divergent Effect of Central Incretin Receptors Inhibition in a Rat Model of Sporadic Alzheimer's Disease.
Inhibition of Brain GTP Cyclohydrolase I Attenuates 3-Nitropropionic Acid-Induced Striatal Toxicity: Involvement of Mas Receptor/PI3k/Akt/CREB/ BDNF Axis.
Mitochondria-Microbiota Interaction in Neurodegeneration.
Disruption of CRTC1 and CRTC2 in Sim1 cells strongly increases high-fat diet intake in female mice but has a modest impact on male mice.
Neuroimmunometabolism: A new pathological nexus underlying neurodegenerative disorders.
Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.
Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling.
Elevated microglial oxidative phosphorylation and phagocytosis stimulate post-stroke brain remodeling and cognitive function recovery in mice.

Neural Regen Res. 2022 Aug;17(8): 1645-1651

Phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer's disease.

Angie K Torres, Bastián I Rivera, Catalina M Polanco, Claudia Jara, Cheril Tapia-Rojas.

  During normal aging, there is a decline in all physiological functions in the organism. One of the most affected organs is the brain, where neurons lose their proper synaptic function leading to cognitive impairment. Aging is one of the main risk factors for the development of neurodegenerative diseases, such as Alzheimer's disease. One of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming aggregates. The most studied brain aggregates are the senile plaques, formed by Aβ peptide; however, the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their toxicity. It is reported that neurons undergo severe mitochondrial dysfunction with age, with a decrease in adenosine 5'-triphosphate production, loss of the mitochondrial membrane potential, redox imbalance, impaired mitophagy, and loss of calcium buffer capacity. Interestingly, abnormal tau protein interacts with several mitochondrial proteins, suggesting that it could induce mitochondrial dysfunction. Nevertheless, whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown. A recent study of our laboratory shows that phosphorylated tau at Ser396/404 (known as PHF-1), an epitope commonly related to pathology, accumulates inside mitochondria during normal aging. This accumulation occurs preferentially in synaptic mitochondria, which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged individuals. Here, we review the main tau modifications promoting mitochondrial dysfunction, and the possible mechanism involved. Also, we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in aging. Finally, we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer's disease, which could be considered as an early event in the neurodegenerative process. Thus, phosphorylated tau PHF-1 inside the mitochondria could be considered such a potential therapeutic target to prevent or attenuate age-related cognitive impairment.

Keywords:  Alzheimer’s disease; PHF-1; age pathology; aging; hippocampus; memory; mitochondria; phosphorylated tau; synaptic mitochondria; tau

DOI:  https://doi.org/10.4103/1673-5374.332125
Brain Res Bull. 2022 Jan 10. pii: S0361-9230(22)00005-3. [Epub ahead of print]

Elevated hippocampal mGlut2 receptors in rats with metabolic syndrome-induced-memory impairment, possible protection by vitamin D.

Zienab Alrefaie, Soad S Ali, Enas A Hamed.

   BACKGROUND: Metabolic syndrome patients are commonly prone to major health problems as cardiovascular diseases, diabetes mellitus, chronic kidney disease, cancer and neuropsychological complications including dementia.
OBJECTIVES: This research investigates mechanisms linking metabolic syndrome to cognitive impairment and possible impact of vitamin D supplementation.
METHODS: Forty male Wistar rats were divided into 4 groups. Control, metabolic syndrome (20% fructose solution in drinking water for 12 weeks, vitamin D supplemented (500 IU/kg/day) and metabolic syndrome supplemented with vitamin D. Animals were assessed for spatial memory, hippocampal expression of SNAP 25, VAMP and mGlut2 receptor and hippocampus histological examination. Animals with metabolic syndrome showed prolonged acquisition and retention latencies in morris water maze, decreased hippocampal expression of SNAP 25 and VAMP and increased mGlut2 expression. Histologically CA1, CA3 regions and dentate nucleus revealed increase in degenerated neurons and glia cells with decreased pyramidal cell layer thickness. Vitamin D supplementation mitigated alterations induced by metabolic syndrome.
CONCLUSIONS: Metabolic syndrome decreased hippocampal synaptic proteins and altered glutamatergic transmission and increased hippocampal neuronal degeneration. Vitamin D supplementation offered neuroprotective effects.

Keywords:  Hippocampal synaptic proteins; Vitamin D; mGlut2; metabolic syndrome; spatial memory

DOI:  https://doi.org/10.1016/j.brainresbull.2022.01.002
Biochem Biophys Res Commun. 2021 Dec 28. pii: S0006-291X(21)01752-6. [Epub ahead of print]591 44-49

Insulin signaling in clock neurons regulates sleep in Drosophila.

Sho T Yamaguchi, Jun Tomita, Kazuhiko Kume.

  Sleep relates to numerous biological functions, including metabolism. Both dietary conditions and genes related to metabolism are known to affect sleep behavior. Insulin signaling is well conserved across species including the fruit fly and relates to both metabolism and sleep. However, the neural mechanism of sleep regulation by insulin signaling is poorly understood. Here, we report that insulin signaling in specific neurons regulates sleep in Drosophila melanogaster. We analyzed the sleep behavior of flies with the mutation in insulin-like ligands expressed in the brain and found that three insulin-like ligands participate in sleep regulation with some redundancy. We next used 21 Gal4 drivers to express a dominant-negative form of the insulin receptor (InR DN) in various neurons including circadian clock neurons, which express the clock gene, and the pars intercerebralis (PI). Inhibition of insulin signaling in the anterior dorsal neuron group 1 (DN1a) decreased sleep. Additionally, the same manipulation in PI also decreased sleep. Pan-neuronal induced expression of InR DN also decreased sleep. These results suggested that insulin signaling in DN1a and PI regulates sleep.

Keywords:  Drosophila; Insulin; Insulin receptor; Metabolism; Sleep

DOI:  https://doi.org/10.1016/j.bbrc.2021.12.100
Int J Mol Sci. 2022 Jan 04. pii: 528. [Epub ahead of print]23(1):

AGC1 Deficiency: Pathology and Molecular and Cellular Mechanisms of the Disease.

Beatriz Pardo, Eduardo Herrada-Soler, Jorgina Satrústegui, Laura Contreras, Araceli Del Arco.

  AGC1/Aralar/Slc25a12 is the mitochondrial carrier of aspartate-glutamate, the regulatory component of the NADH malate-aspartate shuttle (MAS) that transfers cytosolic redox power to neuronal mitochondria. The deficiency in AGC1/Aralar leads to the human rare disease named "early infantile epileptic encephalopathy 39" (EIEE 39, OMIM # 612949) characterized by epilepsy, hypotonia, arrested psychomotor neurodevelopment, hypo myelination and a drastic drop in brain aspartate (Asp) and N-acetylaspartate (NAA). Current evidence suggest that neurons are the main brain cell type expressing Aralar. However, paradoxically, glial functions such as myelin and Glutamine (Gln) synthesis are markedly impaired in AGC1 deficiency. Herein, we discuss the role of the AGC1/Aralar-MAS pathway in neuronal functions such as Asp and NAA synthesis, lactate use, respiration on glucose, glutamate (Glu) oxidation and other neurometabolic aspects. The possible mechanism triggering the pathophysiological findings in AGC1 deficiency, such as epilepsy and postnatal hypomyelination observed in humans and mice, are also included. Many of these mechanisms arise from findings in the aralar-KO mice model that extensively recapitulate the human disease including the astroglial failure to synthesize Gln and the dopamine (DA) mishandling in the nigrostriatal system. Epilepsy and DA mishandling are a direct consequence of the metabolic defect in neurons due to AGC1/Aralar deficiency. However, the deficits in myelin and Gln synthesis may be a consequence of neuronal affectation or a direct effect of AGC1/Aralar deficiency in glial cells. Further research is needed to clarify this question and delineate the transcellular metabolic fluxes that control brain functions. Finally, we discuss therapeutic approaches successfully used in AGC1-deficient patients and mice.

Keywords:  AGC1/Aralar deficiency; malate-aspartate shuttle; mitochondrial aspartate-glutamate carrier; mitochondrial disorders; mitochondrial function

DOI:  https://doi.org/10.3390/ijms23010528
J Adv Res. 2021 Dec;34 199-210

Neuroprotective effect of cajaninstilbene acid against cerebral ischemia and reperfusion damages by activating AMPK/Nrf2 pathway.

Hui Xu, Jiangang Shen, Jianbo Xiao, Feng Chen, Mingfu Wang.

   Introduction: Ischemic stroke is one of the leading causes of death worldwide. Recently, neuroprotection is regarded as an important preventative and therapeutic strategy for ischemic stroke. Cajaninstilbene acid (CSA), a unique stilbenoid with a styryl group, is a potential neuroprotective agent.
Objectives: Hence, this study aimed to evaluate the neuroprotective effect and molecular mechanism of CSA against cerebral ischemia/reperfusion (I/R) damages.
Methods: Cerebral ischemia was modeled by oxygen and glucose deprivation (OGD) in SH-SY5Y cells or transient intraluminal suture middle cerebral artery occlusion (MCAO) in rats, and tert-butyl hydroperoxide (t-BHP) was used to induce oxidative stress in SH-SY5Y cells. CSA (2.5, 5 mg/kg) was intraperitoneally given upon reperfusion after 2 h of MCAO. The signaling pathways were analyzed by Western blotting and inhibitor blocking.
Results: CSA possessed significant neuroprotective activity, as evidenced by the reduced cell death in OGD/R or t-BHP injured SH-SY5Y cells, and decreased infarct volume and neurological deficits in MCAO/R rats. Further studies indicated that the protective effect was achieved via the antioxidant activity of CSA, which decreased the oxidative stress and its related mitochondrial dysfunction in SH-SY5Y cells. Notably, Nrf2 was activated in SH-SY5Y cells and MCAO/R rats by CSA, and the inhibition of Nrf2 by brusatol weakened CSA-mediated neuroprotection. Furthermore, after applying a series of kinase inhibitors, CSA-induced Nrf2 activation was markedly inhibited by BML-275 (an AMPK inhibitor), implying that AMPK was the dominant kinase to regulate the Nrf2 pathway for CSA's neuroprotective effects with enhanced AMPK phosphorylation observed both in vivo and in vitro.
Conclusion: CSA exerted neuroprotection via activating the AMPK/Nrf2 pathway to reduce I/R-induced cellular oxidative stress and mitochondrial disfunction. CSA could be a potential neuroprotective drug candidate for the treatment of ischemic stroke.

Keywords:  AMP-activated protein kinase; Cajaninstilbene acid; Ischemic stroke; Neuroprotection; Nrf2

DOI:  https://doi.org/10.1016/j.jare.2020.07.011
Brain. 2022 Jan 13. pii: awab488. [Epub ahead of print]

Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.

Zhenyu Chen, Eric Chai, Yongchao Mou, Ricardo H Roda, Craig Blackstone, Xue-Jun Li.

  Hereditary spastic paraplegias (HSPs) are characterized by lower limb spasticity resulting from degeneration of long corticospinal axons. SPG11 is one of the most common autosomal recessive HSPs, and the SPG11 protein spatacsin forms a complex with the SPG15 protein spastizin and heterotetrameric AP5 adaptor protein complex, which includes the SPG48 protein AP5Z1. Using the integration-free episomal method, we established SPG11 patient-specific induced pluripotent stem cells (iPSCs) from patient fibroblasts. We differentiated SPG11 iPSCs, as well as SPG48 iPSCs previously established, into cortical projection neurons (PNs) and examined protective effects by targeting mitochondrial dynamics using P110, a peptide that selectively inhibits mitochondrial fission GTPase Drp1. P110 treatment mitigates mitochondrial fragmentation, improves mitochondrial motility, and restores mitochondrial health and ATP levels in SPG11 and SPG48 neurons. Neurofilament (NF) aggregations are increased in SPG11 and SPG48 axons, and these are also suppressed by P110. Similarly, P110 mitigates NF disruption in both SPG11 and SPG48 knockdown cortical PNs, confirming the contribution of HSP gene deficiency to subsequent NF and mitochondrial defects. Strikingly, NF aggregations in SPG11 and SPG48 deficient neurons double stain with ubiquitin and autophagy related proteins, resembling the pathological hallmark observed in SPG11 autopsy brain sections. To confirm the cause-effect relationship between the SPG11 mutations and disease phenotypes, we knocked-in SPG11 disease mutations to human embryonic stem cells (hESCs) and differentiated these stem cells into cortical PNs. Reduced ATP levels and accumulated NF aggregations along axons are observed, and both are mitigated by P110. Furthermore, rescue experiment with expression of wildtype SPG11 in cortical PNs derived from both SPG11 patient iPSCs and SPG11 disease mutation knock-in hESCs leads to rescue of mitochondrial dysfunction and NF aggregations in these SPG11 neurons. Finally, in SPG11 and SPG48 long-term cultures, increased release of phosphoNF-H, a biomarker for nerve degeneration, is significantly reduced by inhibiting mitochondrial fission pharmacologically using P110 and genetically using Drp1 shRNA. Taken together, our results demonstrate that impaired mitochondrial dynamics underlie both cytoskeletal disorganization and axonal degeneration in SPG11 and SPG48 neurons, highlighting the importance of targeting these pathologies therapeutically.

Keywords:  axonal degeneration; cortical projection neuron; cytoskeletal organization; hereditary spastic paraplegias; mitochondrial dynamics

DOI:  https://doi.org/10.1093/brain/awab488
Cells. 2021 Dec 22. pii: 16. [Epub ahead of print]11(1):

The Nerve Growth Factor Metabolic Pathway Dysregulation as Cause of Alzheimer's Cholinergic Atrophy.

Sonia Do Carmo, Benjamin Kannel, A Claudio Cuello.

  The cause of the loss of basal forebrain cholinergic neurons (BFCNs) and their terminal synapses in the cerebral cortex and hippocampus in Alzheimer's disease (AD) has provoked a decades-long controversy. The cholinergic phenotype of this neuronal system, involved in numerous cognitive mechanisms, is tightly dependent on the target-derived nerve growth factor (NGF). Consequently, the loss of BFCNs cholinergic phenotype in AD was initially suspected to be due to an NGF trophic failure. However, in AD there is a normal NGF synthesis and abundance of the NGF precursor (proNGF), therefore the NGF trophic failure hypothesis for the atrophy of BCNs was abandoned. In this review, we discuss the history of NGF-dependency of BFCNs and the atrophy of these neurons in Alzheimer's disease (AD). Further to it, we propose that trophic factor failure explains the BFCNs atrophy in AD. We discuss evidence of the occurrence of a brain NGF metabolic pathway, the dysregulation of which, in AD explains the severe deficiency of NGF trophic support for the maintenance of BFCNs cholinergic phenotype. Finally, we revise recent evidence that the NGF metabolic dysregulation in AD pathology starts at preclinical stages. We also propose that the alteration of NGF metabolism-related markers in body fluids might assist in the AD preclinical diagnosis.

Keywords:  Alzheimer’s disease; Down syndrome; NGF metabolic cascade; basal forebrain cholinergic nuclei; cholinergic system; nerve growth factor; trophic support

DOI:  https://doi.org/10.3390/cells11010016
Neurochem Int. 2022 Jan 10. pii: S0197-0186(22)00005-5. [Epub ahead of print] 105280

Effects of vitamin D (VD3) supplementation on the brain mitochondrial function of male rats, in the 6-OHDA-induced model of Parkinson's disease.

Ludmila Araújo de Lima, Pedro Lourenzo Oliveira Cunha, Iana Bantim Felicio Calou, Kelly Rose Tavares Neves, Heberty Tarso Facundo, Glauce Socorro de Barros Viana.

  Mitochondria dysfunction is an important factor involved in PD pathogenesis. We reported neuroprotective actions of vitamin D (VD3) on a PD model, and now we investigated the VD3 effects on the brain mitochondrial function. We focused on oxygen consumption, respiratory control ratio (RCR), ADP/O ratio, mitochondria swelling, H2O2 production, and SOD activity. Additionally, immunohistochemistry assays for the dopamine system markers (TH and DAT) and mitochondrial markers (VDAC1 and Hsp60) were also carried out in the striata. Young adult male Wistar rats (250 g, 2.5 months age) were anesthetized and subjected to stereotaxic surgery and injection of saline (SO group) or 6-OHDA, into the right striatum. Brain mitochondria were isolated from the groups: sham-operated (SO), 6-OHDA, 6-OHDA pretreated with VD3 for 7, days before the 6-OHDA lesion (6-OHDA+VD3, pre-) or treated with VD3 for 14 days, after the 6-OHDA lesion (6-OHDA+VD3, post-). VD3 prevented decreases in oxygen consumption, RCR, and ADP/O ratio observed after 6-OHDA injury. Noteworthy, a very low (oxygen consumption and RCR) or no improvement (ADP/O) were observed in the 6-OHDA+VD3 post- group. VD3 also prevented the increased mitochondria swelling and H2O2 production and a decrease in SOD activity, respectively, in the 6-OHDA injured mitochondria. Also, VD3 supplementation protected the hemiparkinsonian brain from decreases in TH and DAT expressions and decreased the upregulation of mitochondrial markers, as VDAC 1 and Hsp60. In conclusion, VD3 showed neuroprotective actions on brain mitochondria injured by 6-OHDA and should stimulate translational studies focusing on its use as a therapeutic strategy for the treatment of neurodegenerative diseases as PD.

Keywords:  6-OHDA-model of PD; Mitochondria; Oxidative stress; VD3; Vitamin D

DOI:  https://doi.org/10.1016/j.neuint.2022.105280
Neurol Res. 2022 Jan 12. 1-9

The involvement of TRPM2 on the MPP+-induced oxidative neurotoxicity and apoptosis in hippocampal neurons from neonatal mice: protective role of resveratrol.

Kenan Yildizhan, Ramazan Çinar, Mustafa Naziroğlu.

  Parkinson's disease (PD) is an age-related chronic neurodegenerative disease. Although PD is known to be a result of damage to hippocampal neurons, its molecular mechanism has yet to be completely clarified. The neurodegeneration in hippocampal neurons has been suggested to include excessive production of reactive oxygen species (ROS). Mitochondrial dysfunction and disruption of intracellular Ca2+ homeostasis play the most important role in the increase in ROS production for the cells. Remarkably, it is stated in the literature that especially the change of Ca2+ homeostasis triggers neuronal degeneration. TRPM2 is a unique calcium-permeable nonselective cation channel, and densest in the numberless neuronal population. The current study aims to elucidate the effect of antioxidant resveratrol (Resv) on TRPM2-mediated oxidative stress (OS) induced by 1-methyl-4-phenylpyridinium (MPP) exposure in the primary mouse hippocampal neurons. The neurons were divided into four groups as Control, Resv , MPP, and MPP+ Resv. In the current results, the activation of TRPM2 was observed in primary hippocampal neurons with MPP incubation. TRPM2 channel expression levels in the MPP group increased in hippocampal neurons after MPP exposure. In addition, intracellular free Ca2+ concentration and TRPM2 channel currents were highest in MPP groups, although they were decreased by the Resv treatment. In addition, mitochondrial membrane depolarization, ROS, caspase-3, caspase-9, and apoptosis values induced by MPP decreased with resveratrol treatment. In conclusion, in our study, we observed that the dysregulation of OS-induced TRPM2 channel activation in hippocampal neurons exposed to MPP caused apoptotic cell death in neurons, while the use of resveratrol had a protective effect by reducing OS resources in the environment.

Keywords:  Apoptosis; TRPM2; calcium signaling; hippocampal neurons; oxidative stress; parkinson’s disease

DOI:  https://doi.org/10.1080/01616412.2022.2027644
Int J Mol Sci. 2021 Dec 29. pii: 363. [Epub ahead of print]23(1):

Dopamine and Methamphetamine Differentially Affect Electron Transport Chain Complexes and Parkin in Rat Striatum: New Insight into Methamphetamine Neurotoxicity.

Viktoriia Bazylianska, Akhil Sharma, Heli Chauhan, Bernard Schneider, Anna Moszczynska.

  Methamphetamine (METH) is a highly abused psychostimulant that is neurotoxic to dopaminergic (DAergic) nerve terminals in the striatum and increases the risk of developing Parkinson's disease (PD). In vivo, METH-mediated DA release, followed by DA-mediated oxidative stress and mitochondrial dysfunction in pre- and postsynaptic neurons, mediates METH neurotoxicity. METH-triggered oxidative stress damages parkin, a neuroprotective protein involved in PD etiology via its involvement in the maintenance of mitochondria. It is not known whether METH itself contributes to mitochondrial dysfunction and whether parkin regulates complex I, an enzymatic complex downregulated in PD. To determine this, we separately assessed the effects of METH or DA alone on electron transport chain (ETC) complexes and the protein parkin in isolated striatal mitochondria. We show that METH decreases the levels of selected complex I, II, and III subunits (NDUFS3, SDHA, and UQCRC2, respectively), whereas DA decreases the levels only of the NDUFS3 subunit in our preparations. We also show that the selected subunits are not decreased in synaptosomal mitochondria under similar experimental conditions. Finally, we found that parkin overexpression does not influence the levels of the NDUFS3 subunit in rat striatum. The presented results indicate that METH itself is a factor promoting dysfunction of striatal mitochondria; therefore, it is a potential drug target against METH neurotoxicity. The observed decreases in ETC complex subunits suggest that DA and METH decrease activities of the ETC complexes via oxidative damage to their subunits and that synaptosomal mitochondria may be somewhat "resistant" to DA- and METH-induced disruption in mitochondrial ETC complexes than perikaryal mitochondria. The results also suggest that parkin does not regulate NDUFS3 turnover in rat striatum.

Keywords:  dopamine; electron transport chain complexes; methamphetamine; parkin

DOI:  https://doi.org/10.3390/ijms23010363
Front Nutr. 2021 ;8 783659

Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis.

Angela M Poff, Sara Moss, Maricel Soliven, Dominic P D'Agostino.

  Diverse neurological disorders are associated with a deficit in brain energy metabolism, often characterized by acute or chronic glucose hypometabolism. Ketones serve as the brain's only significant alternative fuel and can even become the primary fuel in conditions of limited glucose availability. Thus, dietary supplementation with exogenous ketones represents a promising novel therapeutic strategy to help meet the energetic needs of the brain in an energy crisis. Preliminary evidence suggests ketosis induced by exogenous ketones may attenuate damage or improve cognitive and motor performance in neurological conditions such as seizure disorders, mild cognitive impairment, Alzheimer's disease, and neurotrauma.

Keywords:  brain metabolism; energy deficit; exogenous ketone; ketogenic diet; ketone

DOI:  https://doi.org/10.3389/fnut.2021.783659
Elife. 2022 Jan 11. pii: e73456. [Epub ahead of print]11

Aging is associated with increased brain iron through cortex-derived hepcidin expression.

Tatsuya Sato, Jason Solomon Shapiro, Hsiang-Chun Chang, Richard A Miller, Hossein Ardehali.

  Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrated that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain cortex exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, ferroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.

Keywords:  Aging; Iron; medicine; mouse; oxidative stress

DOI:  https://doi.org/10.7554/eLife.73456
J Surg Res. 2022 Jan 08. pii: S0022-4804(21)00741-1. [Epub ahead of print]273 15-23

Electroacupuncture Relieves Hippocampal Injury by Heme Oxygenase-1 to Improve Mitochondrial Function.

Rui Mu, Na Li, Jian-Bo Yu, Li-Rong Gong, Shu-An Dong, Jia Shi, Yuan Zhang, Zi-Lei Xie.

   INTRODUCTION: Electroacupuncture (EA) treatment has been demonstrated to have the potential to prevent sepsis-induced hippocampal injury; however, the mechanisms underlying the protective effects of EA against such injury remain unclear. Herein, to elucidate these mechanisms, we constructed a mouse model of lipopolysaccharide (LPS)-induced hippocampal injury to investigate the protection mechanism of EA and to determine whether heme oxygenase-1 (HO-1)-mediated mitochondrial function is involved in the protective effect of EA.
MATERIALS AND METHODS: The sepsis model of hippocampal injury was induced by administering LPS. The Zusanli and Baihui acupoints were stimulated using EA for 30 min once a day, for 5 d before LPS exposure and the first day after administering LPS. Hippocampal injury was investigated by hematoxylin and eosin staining and Nissl staining. HO-1 levels were measured using Western blotting. Mitochondrial metabolism was validated by assessing adenosine triphosphate, superoxide dismutase, malondialdehyde levels, reactive oxygen species production, and mitochondrial respiratory chain activity. Mitochondrial morphology was analyzed by transmission electron microscopy.
RESULTS: EA treatment alleviated neuronal injury, impeded oxidative stress, and improved mitochondrial respiratory function, energy metabolism, and mitochondrial morphology in LPS-exposed mice. In addition, HO-1 knockout aggravated LPS-induced hippocampal injury, aggravated oxidative stress, and reduced mitochondrial respiratory function and aggravated mitochondrial swelling, crest relaxation, and vacuole degeneration. Moreover, EA was unable to reverse the hippocampal damage and mitochondrial dysfunction caused by LPS exposure after HO-1 knockout.
CONCLUSIONS: EA improves LPS-induced hippocampal injury by regulating HO-1-mediated mitochondrial function. Furthermore, HO-1 plays a critical role in maintaining mitochondrial function and resisting oxidative injury.

Keywords:  Electroacupuncture; Heme oxygenase-1; Hippocampal injury; Lipopolysaccharide; Mitochondrial function

DOI:  https://doi.org/10.1016/j.jss.2021.12.013
World J Emerg Med. 2022 ;13(1): 46-53

Protective effect of mesenchymal stem cell-derived exosomal treatment of hippocampal neurons against oxygen-glucose deprivation/reperfusion-induced injury.

Xiao-Fang Guo, Shuang-Shuang Gu, Jun Wang, Hao Sun, Yu-Juan Zhang, Peng-Fei Yu, Jin-Song Zhang, Lei Jiang.

   BACKGROUND: Individuals who survive a cardiac arrest often sustain cognitive impairments due to ischemia-reperfusion injury. Mesenchymal stem cell (MSC) transplantation is used to reduce tissue damage, but exosomes are more stable and highly conserved than MSCs. This study was conducted to investigate the therapeutic effects of MSC-derived exosomes (MSC-Exo) on cerebral ischemia-reperfusion injury in an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R), and to explore the underlying mechanisms.
METHODS: Primary hippocampal neurons obtained from 18-day Sprague-Dawley rat embryos were subjected to OGD/R treatment, with or without MSC-Exo treatment. Exosomal integration, cell viability, mitochondrial membrane potential, and generation of reactive oxygen species (ROS) were examined. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling (TUNEL) staining was performed to detect neuronal apoptosis. Moreover, mitochondrial function-associated gene expression, Nrf2 translocation, and expression of downstream antioxidant proteins were determined.
RESULTS: MSC-Exo attenuated OGD/R-induced neuronal apoptosis and decreased ROS generation (P<0.05). The exosomes reduced OGD/R-induced Nrf2 translocation into the nucleus (2.14±0.65 vs. 5.48±1.09, P<0.01) and increased the intracellular expression of antioxidative proteins, including superoxide dismutase and glutathione peroxidase (17.18±0.97 vs. 14.40±0.62, and 20.65±2.23 vs. 16.44±2.05, respectively; P<0.05 for both). OGD/R significantly impaired the mitochondrial membrane potential and modulated the expression of mitochondrial function-associated genes, such as PINK, DJ1, LRRK2, Mfn-1, Mfn-2, and OPA1. The abovementioned changes were partially reversed by exosomal treatment of the hippocampal neurons.
CONCLUSIONS: MSC-Exo treatment can alleviate OGD/R-induced oxidative stress and dysregulation of mitochondrial function-associated genes in hippocampal neurons. Therefore, MSC-Exo might be a potential therapeutic strategy to prevent OGD/R-induced neuronal injury.

Keywords:  Exosomes; Mesenchymal stem cells; Mitochondria; Oxygen-glucose deprivation/reperfusion; Reactive oxygen species

DOI:  https://doi.org/10.5847/wjem.j.1920-8642.2022.015
Front Psychiatry. 2021 ;12 788779

Novel Probable Glance at Inflammatory Scenario Development in Autistic Pathology.

Aida A Harutyunyan, Hayk A Harutyunyan, Konstantin B Yenkoyan.

  Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and restricted-repetitive patterns of behavior, interests, or activities. ASD is generally associated with chronic inflammatory states, which are linked to immune system dysfunction and/or hyperactivation. The latter might be considered as one of the factors damaging neuronal cells. Several cell types trigger and sustain such neuroinflammation. In this study, we traced different markers of immune system activation on both cellular (immune cell phenotypes) and mediatory levels (production of cytokines) alongside adverse hematology and biochemistry screening in a group of autistic children. In addition, we analyzed the main metabolic pathways potentially involved in ASD development: energy (citric acid cycle components), porphyrin, and neurotransmitter metabolism. Several ASD etiological factors, like heavy metal intoxication, and risk factors-genetic polymorphisms of the relevant neurotransmitters and vitamin D receptors-were also analyzed. Finally, broad linear regression analysis allowed us to elucidate the possible scenario that led to the development of chronic inflammation in ASD patients. Obtained data showed elevated levels of urinary cis-aconitate, isocitrate, alfa-ketoglutarate, and HMG. There were no changes in levels of metabolites of monoamine neurotransmitters, however, the liver-specific tryptophan kinurenine pathway metabolites showed increased levels of quinolinate (QUIN) and picolinate, whereas the level of kynurenate remained unchanged. Abovementioned data demonstrate the infringement in energy metabolism. We found elevated levels of lead in red blood cells, as well as altered porphyrin metabolism, which support the etiological role of heavy metal intoxication in ASD. Lead intoxication, the effect of which is intensified by a mutation of the VDR-Taq and MAO-A, leads to quinolinic acid increase, resulting in energy metabolism depletion and mitochondrial dysfunction. Moreover, our data backing the CD4+CD3+ T-cell dependence of mitochondrial dysfunction development in ASD patients reported in our previous study leads us to the conclusion that redox-immune cross-talk is considered a main functional cell damaging factor in ASD patients.

Keywords:  MAO-A; TNF-alfa; VDR Taq; autism spectrum disorders; energy metabolism; lead; mitochondria; monocytes

DOI:  https://doi.org/10.3389/fpsyt.2021.788779
Cells. 2021 Dec 30. pii: 111. [Epub ahead of print]11(1):

Covering the Role of PGC-1α in the Nervous System.

Zuzanna Kuczynska, Erkan Metin, Michal Liput, Leonora Buzanska.

  The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a well-known transcriptional coactivator involved in mitochondrial biogenesis. PGC-1α is implicated in the pathophysiology of many neurodegenerative disorders; therefore, a deep understanding of its functioning in the nervous system may lead to the development of new therapeutic strategies. The central nervous system (CNS)-specific isoforms of PGC-1α have been recently identified, and many functions of PGC-1α are assigned to the particular cell types of the central nervous system. In the mice CNS, deficiency of PGC-1α disturbed viability and functioning of interneurons and dopaminergic neurons, followed by alterations in inhibitory signaling and behavioral dysfunction. Furthermore, in the ALS rodent model, PGC-1α protects upper motoneurons from neurodegeneration. PGC-1α is engaged in the generation of neuromuscular junctions by lower motoneurons, protection of photoreceptors, and reduction in oxidative stress in sensory neurons. Furthermore, in the glial cells, PGC-1α is essential for the maturation and proliferation of astrocytes, myelination by oligodendrocytes, and mitophagy and autophagy of microglia. PGC-1α is also necessary for synaptogenesis in the developing brain and the generation and maintenance of synapses in postnatal life. This review provides an outlook of recent studies on the role of PGC-1α in various cells in the central nervous system.

Keywords:  PGC-1α; central nervous system; mitochondrial biogenesis

DOI:  https://doi.org/10.3390/cells11010111
Cell Death Discov. 2022 Jan 10. 8(1): 1

Accumulation of APP-CTF induces mitophagy dysfunction in the iNSCs model of Alzheimer's disease.

Seung-Eun Lee, Daekee Kwon, Nari Shin, Dasom Kong, Nam Gyo Kim, Hee-Yeong Kim, Min-Ji Kim, Soon Won Choi, Kyung-Sun Kang.

Mitochondrial dysfunction is associated with familial Alzheimer's disease (fAD), and the accumulation of damaged mitochondria has been reported as an initial symptom that further contributes to disease progression. In the amyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by β-secretase to generate a C-terminal fragment, which is then cleaved by γ-secretase to produce amyloid-beta (Aβ). The accumulation of Aβ and its detrimental effect on mitochondrial function are well known, yet the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) contributing to this pathology have rarely been reported. We demonstrated the effects of APP-CTFs-related pathology using induced neural stem cells (iNSCs) from AD patient-derived fibroblasts. APP-CTFs accumulation was demonstrated to mainly occur within mitochondrial domains and to be both a cause and a consequence of mitochondrial dysfunction. APP-CTFs accumulation also resulted in mitophagy failure, as validated by increased LC3-II and p62 and inconsistent PTEN-induced kinase 1 (PINK1)/E3 ubiquitin ligase (Parkin) recruitment to mitochondria and failed fusion of mitochondria and lysosomes. The accumulation of APP-CTFs and the causality of impaired mitophagy function were also verified in AD patient-iNSCs. Furthermore, we confirmed this pathological loop in presenilin knockout iNSCs (PSEN KO-iNSCs) because APP-CTFs accumulation is due to γ-secretase blockage and similarly occurs in presenilin-deficient cells. In the present work, we report that the contribution of APP-CTFs accumulation is associated with mitochondrial dysfunction and mitophagy failure in AD patient-iNSCs as well as PSEN KO-iNSCs.

DOI: https://doi.org/10.1038/s41420-021-00796-3
Front Mol Neurosci. 2021 ;14 778569

Effects of Mdivi-1 on Neural Mitochondrial Dysfunction and Mitochondria-Mediated Apoptosis in Ischemia-Reperfusion Injury After Stroke: A Systematic Review of Preclinical Studies.

Nguyen Thanh Nhu, Qing Li, Yijie Liu, Jian Xu, Shu-Yun Xiao, Shin-Da Lee.

  This systematic review sought to determine the effects of Mitochondrial division inhibitor-1 (Mdivi-1) on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in ischemia/reperfusion (I/R) injury after ischemic stroke. Pubmed, Web of Science, and EMBASE databases were searched through July 2021. The studies published in English language that mentioned the effects of Mdivi-1 on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in I/R-induced brain injury were included. The CAMARADES checklist (for in vivo studies) and the TOXRTOOL checklist (for in vitro studies) were used for study quality evaluation. Twelve studies were included (median CAMARADES score = 6; TOXRTOOL scores ranging from 16 to 18). All studies investigated neural mitochondrial functions, providing that Mdivi-1 attenuated the mitochondrial membrane potential dissipation, ATP depletion, and complexes I-V abnormalities; enhanced mitochondrial biogenesis, as well as inactivated mitochondrial fission and mitophagy in I/R-induced brain injury. Ten studies analyzed neural mitochondria-mediated apoptosis, showing that Mdivi-1 decreased the levels of mitochondria-mediated proapoptotic factors (AIF, Bax, cytochrome c, caspase-9, and caspase-3) and enhanced the level of antiapoptotic factor (Bcl-2) against I/R-induced brain injury. The findings suggest that Mdivi-1 can protect neural mitochondrial functions, thereby attenuating neural mitochondria-mediated apoptosis in I/R-induced brain injury. Our review supports Mdivi-1 as a potential therapeutic compound to reduce brain damage in ischemic stroke (PROSPERO protocol registration ID: CRD42020205808). Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42020205808].

Keywords:  Mdivi-1; apoptosis; ischemia-reperfusion injury; mitochondrial function; stroke

DOI:  https://doi.org/10.3389/fnmol.2021.778569
J Neurotrauma. 2022 Jan 12.

Dysfunctional ER-mitochondrion coupling is associated with ER stress-induced apoptosis and neurological deficits in a rodent model of severe head injury.

Xin Chen, Liang Mi, Gang Gu, Xiangliang Gao, Mingming Shi, Yan Chai, Fanglian Chen, Weidong Yang, Jian-Ning Zhang.

  Cellular homeostasis requires critical communications between the endoplasmic reticulum (ER) and mitochondria to maintain the viability of cells. This communication is mediated and maintained by the mitochondria-associated membranes (MAMs) and may be disrupted during acute traumatic brain injury (TBI), leading to structural and functional damages of neurons and supporting cells. To test this hypothesis, we subjected male C57BL/6 mice to severe TBI (sTBI) using a controlled cortical impact (CCI) device. We analyzed the physical ER-mitochondrion contacts in the perilesional cortex using transmission electron microscopy, western blot, and immunofluorescence. We specifically measured changes in the production of reactive oxygen species (ROS) in mitochondria, the unfolded protein response (UPR), the neuroinflammatory response, and ER stress-mediated apoptosis in the traumatic injured cerebral tissue. A modified neurological severity score (mNSS) was used to evaluate neurological function in the sTBI mice. We found that sTBI induced significant reorganizations of MEMs in the cerebral cortex within the first 24 hr post-injury. This ER-mitochondrion coupling was enhanced, reaching its peak level at 6 hrs post-sTBI. This enhanced coupling correlated closely with increases in the expression of the Ca2+ regulatory proteins (IP3R1, VDAC1, GRP75, Sigma-1R), production of ROS, degree of ER stress, levels of UPR, and release of proinflammatory cytokines. Furthermore, the neurological function of sTBI mice was significantly improved by silencing the gene for the ER-mitochondrion tethering factor PACS2, restoring the IP3R1-GRP75-VDAC1 axis of Ca2+ regulation, alleviating mitochondria-derived oxidative stress, suppressing inflammatory response through the PERK/eIF2α/ATF4/CHOP pathway, and inhibiting ER stress and associated apoptosis. These results indicate that dysfunctional ER-mitochondrion coupling might be primarily involved in the neuronal apoptosis and neurological deficits, and modulating the ER-mitochondrion crosstalk might be a novel therapeutic strategy for sTBI.

Keywords:  Apoptosis; MITOCHONDRIA; OXIDATIVE STRESS; TRAUMATIC BRAIN INJURY

DOI:  https://doi.org/10.1089/neu.2021.0347
Int J Mol Sci. 2022 Jan 04. pii: 548. [Epub ahead of print]23(1):

Divergent Effect of Central Incretin Receptors Inhibition in a Rat Model of Sporadic Alzheimer's Disease.

Jelena Osmanovic Barilar, Ana Knezovic, Jan Homolak, Ana Babic Perhoc, Melita Salkovic-Petrisic.

  The incretin system is an emerging new field that might provide valuable contributions to the research of both the pathophysiology and therapeutic strategies in the treatment of diabetes, obesity, and neurodegenerative disorders. This study aimed to explore the roles of central glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) on cell metabolism and energy in the brain, as well as on the levels of these incretins, insulin, and glucose via inhibition of the central incretin receptors following intracerebroventricular administration of the respective antagonists in healthy rats and a streptozotocin-induced rat model of sporadic Alzheimer's disease (sAD). Chemical ablation of the central GIP receptor (GIPR) or GLP-1 receptor (GLP-1R) in healthy and diseased animals indicated a region-dependent role of incretins in brain cell energy and metabolism and central incretin-dependent modulation of peripheral hormone secretion, markedly after GIPR inhibition, as well as a dysregulation of the GLP-1 system in experimental sAD.

Keywords:  Alzheimer’s disease; gastric inhibitory polypeptide; glucagon-like peptide-1; hippocampus; hypothalamus

DOI:  https://doi.org/10.3390/ijms23010548
Front Pharmacol. 2021 ;12 740966

Inhibition of Brain GTP Cyclohydrolase I Attenuates 3-Nitropropionic Acid-Induced Striatal Toxicity: Involvement of Mas Receptor/PI3k/Akt/CREB/ BDNF Axis.

Aya M Mustafa, Mostafa A Rabie, Hala F Zaki, Aya M Shaheen.

  GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis; the latter is an essential factor for iNOS activation that contributes neuronal loss in Huntington's disease (HD). The aim of the study was to investigate the neuroprotective effect of 2,4-diamino-6-hydroxypyrimidine (DAHP), GTPCH I enzyme inhibitor, against neuronal loss in 3-nitropropinic acid (3-NP)-induced HD in rats and to reveal the possible involved mechanisms mediated through PI3K/Akt axis and its correlation to Mas receptor (MasR). Rats received 3-NP (10 mg/kg/day; i.p.) with or without administration of DAHP (0.5 g/kg/day; i.p.) or wortmannin (WM), a PI3K inhibitor, (15 μg/kg/day; i.v.) for 14 days. DAHP improved cognitive, memory, and motor abnormalities induced by 3-NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. Moreover, DAHP treatment inhibited GTPCH I activity, resulting in decreased BH4 levels and iNOS activation. Also, DAHP upregulated the protein expression of survival protein; p85/p55 (pY458/199)-PI3K and pS473-Akt that, in turn, boosted the activation of striatal neurotrophic factors and receptor, pS133-CREB, BDNF and pY515-TrKB, which positively affect MasR protein expression and improve mitochondrial dysfunction, as indicated by enhancing both SDH and PGC-1α levels. Indeed, DAHP attenuates oxidative stress by increasing SOD activity and Nrf2 expression in addition to reducing neuro-inflammatory status by inhibiting NF-κB p65 and TNF-α expression. Interestingly, all the previous effects were blocked by co-administration of WM with DAHP. In conclusion, DAHP exerts neuroprotective effect against neuronal loss induced by 3-NP administration via inhibition of GTPCH I and iNOS activity and activation of MasR/PI3K/Akt/CREB/BDNF/TrKB axis besides its antioxidant and anti-inflammatory effect.

Keywords:  3-nitropropionic acid; DAHP 3; PI3K/AKT signaling; mas receptor; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fphar.2021.740966
Front Aging Neurosci. 2021 ;13 776936

Mitochondria-Microbiota Interaction in Neurodegeneration.

Peter Kramer.

  Alzheimer's and Parkinson's are the two best-known neurodegenerative diseases. Each is associated with the excessive aggregation in the brain and elsewhere of its own characteristic amyloid proteins. Yet the two afflictions have much in common and often the same amyloids play a role in both. These amyloids need not be toxic and can help regulate bile secretion, synaptic plasticity, and immune defense. Moreover, when they do form toxic aggregates, amyloids typically harm not just patients but their pathogens too. A major port of entry for pathogens is the gut. Keeping the gut's microbe community (microbiota) healthy and under control requires that our cells' main energy producers (mitochondria) support the gut-blood barrier and immune system. As we age, these mitochondria eventually succumb to the corrosive byproducts they themselves release, our defenses break down, pathogens or their toxins break through, and the side effects of inflammation and amyloid aggregation become problematic. Although it gets most of the attention, local amyloid aggregation in the brain merely points to a bigger problem: the systemic breakdown of the entire human superorganism, exemplified by an interaction turning bad between mitochondria and microbiota.

Keywords:  Alzheimer’s disease; Parkinson’s disease; butyrate; gut-blood barrier; hydrogen sulfide; methionine; microbiota; mitochondria

DOI:  https://doi.org/10.3389/fnagi.2021.776936
PLoS One. 2022 ;17(1): e0262577

Disruption of CRTC1 and CRTC2 in Sim1 cells strongly increases high-fat diet intake in female mice but has a modest impact on male mice.

Jin Tanaka, Fuka Ishikawa, Tomoki Jinno, Motoki Miyakita, Haruka Miyamori, Tsutomu Sasaki, Takumi Yokokawa, Tsuyoshi Goto, Kazuo Inoue, Shigenobu Matsumura.

cAMP responsive element binding protein (CREB)-regulated transcription coactivators (CRTCs) regulate gene transcription in response to an increase in intracellular cAMP or Ca2+ levels. To date, three isoforms of CRTC have been identified in mammals. All CRTCs are widely expressed in various regions of the brain. Numerous studies have shown the importance of CREB and CRTC in energy homeostasis. In the brain, the paraventricular nucleus of the hypothalamus (PVH) plays a critical role in energy metabolism, and CRTC1 and CRTC2 are highly expressed in PVH neuronal cells. The single-minded homolog 1 gene (Sim1) is densely expressed in PVH neurons and in some areas of the amygdala neurons. To determine the role of CRTCs in PVH on energy metabolism, we generated mice that lacked CRTC1 and CRTC2 in Sim1 cells using Sim-1 cre mice. We found that Sim1 cell-specific CRTC1 and CRTC2 double-knockout mice were sensitive to high-fat diet (HFD)-induced obesity. Sim1 cell-specific CRTC1 and CRTC2 double knockout mice showed hyperphagia specifically for the HFD, but not for the normal chow diet, increased fat mass, and no change in energy expenditure. Interestingly, these phenotypes were stronger in female mice than in male mice, and a weak phenotype was observed in the normal chow diet. The lack of CRTC1 and CRTC2 in Sim1 cells changed the mRNA levels of some neuropeptides that regulate energy metabolism in female mice fed an HFD. Taken together, our findings suggest that CRTCs in Sim1 cells regulate gene expression and suppress excessive fat intake, especially in female mice.

DOI: https://doi.org/10.1371/journal.pone.0262577
J Neurosci. 2022 Jan 13. pii: JN-RV-0998-21. [Epub ahead of print]

Neuroimmunometabolism: A new pathological nexus underlying neurodegenerative disorders.

Swarup Mitra, Avijit Banik, Sumit Saurabh, Malabika Maulik, Shailesh N Khatri.

Neuroimmunometabolism is an emerging field that examines the intersection of immunological and metabolic cascades in the brain. Neuroinflammatory conditions often involve differential metabolic reprogramming in neuronal and glial cells through their immunometabolic sensors. The impact of such bioenergetic adaptation on general brain function is poorly understood, but this cross-talk becomes increasingly important in neurodegenerative disorders that exhibit reshaping of neuroimmunometabolic pathways. Here we summarize the intrinsic balance of neuroimmunometabolic substrates and sensors in the healthy brain and how their dysregulation can contribute to the pathophysiology of various neurodegenerative disorders. This review also proposes possible avenues for disease management through neuroimmunometabolic profiling and therapeutics to bridge translational gaps and guide future treatment strategies.SIGNIFICANCE STATEMENTNeuroimmunometabolism intersects with neuroinflammation and immunometabolic regulation of neurons and glial cells in the CNS. There is emerging evidence that neuroimmunometabolism plays an essential role in the manifestation of CNS degeneration. This review highlights how neuroimmunometabolic homeostasis is disrupted in various neurodegenerative conditions and could be a target for new therapeutic strategies.

DOI: https://doi.org/10.1523/JNEUROSCI.0998-21.2022
Front Cell Dev Biol. 2021 ;9 767407

Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.

Martine Uittenbogaard, Kuntal Sen, Matthew Whitehead, Christine A Brantner, Yue Wang, Lee-Jun Wong, Andrea Gropman, Anne Chiaramello.

  In this study, we aimed to establish the mitochondrial etiology of the proband's progressive neurodegenerative disease suggestive of an atypical Leigh syndrome, by determining the proband's pathogenic variants. Brain MRI showed a constellation of multifocal temporally disparate lesions in the cerebral deep gray nuclei, brainstem, cerebellum, spinal cord along with rhombencephalic atrophy, and optic nerve atrophy. Single voxel 1H MRS performed concurrently over the left cerebral deep gray nuclei showed a small lactate peak, increased glutamate and citrate elevation, elevating suspicion of a mitochondrial etiology. Whole exome sequencing revealed three heterozygous nuclear variants mapping in three distinct genes known to cause Leigh syndrome. Our mitochondrial bioenergetic investigations revealed an impaired mitochondrial energy metabolism. The proband's overall ATP deficit is further intensified by an ineffective metabolic reprogramming between oxidative phosphorylation and glycolysis. The deficient metabolic adaptability and global energy deficit correlate with the proband's neurological symptoms congruent with an atypical Leigh syndrome. In conclusion, our study provides much needed insights to support the development of molecular diagnostic and therapeutic strategies for atypical Leigh syndrome.

Keywords:  combined oxidative phosphorylation deficiency; leigh syndrome; metabolic adaptability; mitochondrial energy metabolism; nuclear variants; whole exome sequencing

DOI:  https://doi.org/10.3389/fcell.2021.767407
J Cereb Blood Flow Metab. 2022 Jan 13. 271678X211069006

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling.

Charles E Seaks, Erica M Weekman, Tiffany L Sudduth, Kevin Xie, Brandi Wasek, David W Fardo, Lance A Johnson, Teodoro Bottiglieri, Donna M Wilcock.

  Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer's disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

Keywords:  APOE; SERPIN; VCID; inflammation; metabolism

DOI:  https://doi.org/10.1177/0271678X211069006
Commun Biol. 2022 Jan 11. 5(1): 35

Elevated microglial oxidative phosphorylation and phagocytosis stimulate post-stroke brain remodeling and cognitive function recovery in mice.

Shanshan Song, Lauren Yu, Md Nabiul Hasan, Satya S Paruchuri, Steven J Mullett, Mara L G Sullivan, Victoria M Fiesler, Cullen B Young, Donna B Stolz, Stacy G Wendell, Dandan Sun.

New research shows that disease-associated microglia in neurodegenerative brains present features of elevated phagocytosis, lysosomal functions, and lipid metabolism, which benefit brain repair. The underlying mechanisms remain poorly understood. Intracellular pH (pHi) is important for regulating aerobic glycolysis in microglia, where Na/H exchanger (NHE1) is a key pH regulator by extruding H+ in exchange of Na+ influx. We report here that post-stroke Cx3cr1-CreER+/-;Nhe1flox/flox (Nhe1 cKO) brains displayed stimulation of microglial transcriptomes of rate-limiting enzyme genes for glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. The other upregulated genes included genes for phagocytosis and LXR/RXR pathway activation as well as the disease-associated microglia hallmark genes (Apoe, Trem2, Spp1). The cKO microglia exhibited increased oxidative phosphorylation capacity, and higher phagocytic activity, which likely played a role in enhanced synaptic stripping and remodeling, oligodendrogenesis, and remyelination. This study reveals that genetic blockade of microglial NHE1 stimulated oxidative phosphorylation immunometabolism, and boosted phagocytosis function which is associated with tissue remodeling and post-stroke cognitive function recovery.

DOI: https://doi.org/10.1038/s42003-021-02984-4