bims-medebr 2023-03-05 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒03‒05
nineteen papers selected by
Regina F. Fernández
Johns Hopkins University

Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol.
Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies.
Regional brain glucose metabolism is differentially affected by ketogenic diet: a human semiquantitative positron emission tomography.
The role of polyunsaturated fatty acids in neuronal signaling in depression and cognitive processes.
White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer's disease (AD) neuropathology: A hypothesis and review.
Brain glucose metabolism and nigrostriatal degeneration in isolated rapid eye movement sleep behaviour disorder.
Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells.
Mfsd2a utilizes a flippase mechanism to mediate omega-3 fatty acid lysolipid transport.
Compartment specific mitochondrial dysfunction in Drosophila knock-in model of ALS reversed by altered gene expression of OXPHOS subunits and pro-fission factor Drp1.
A novel C19orf12 frameshift mutation in a MPAN pedigree impairs mitochondrial function and connectivity leading to neurodegeneration.
The pyruvate dehydrogenase complex: Life's essential, vulnerable and druggable energy homeostat.
Widespread fMRI BOLD signal overactivations during cognitive control in older adults are not matched by corresponding increases in fPET glucose metabolism.
Comparative survey of mitochondrial ultrastructure in IDH1-mutant astrocytoma and IDH1-wildtype glioblastoma (GBM).
ATP-mediated signalling in the central synapses.
StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival.
How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?
Inhibition of monoamine oxidase-a increases respiration in isolated mouse cortical mitochondria.
Pyruvate dehydrogenase beta subunit (Pdhb) promotes peripheral axon regeneration by regulating energy supply and gene expression.
Severity of prematurity and age impact early postnatal development of GABA and glutamate systems.

J Lipid Res. 2023 Feb 25. pii: S0022-2275(23)00023-8. [Epub ahead of print] 100350

Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol.

AnilG Cashikar, DaniraToral Rios, David Timm, Johnathan Romero, Michael Strickland, JustinM Long, Xianlin Han, DavidM Holtzman, StevenM Paul.

  Neuroinflammation, a major hallmark of Alzheimer's disease and several other neurological and psychiatric disorders, is often associated with dysregulated cholesterol metabolism. Relative to homeostatic microglia, activated microglia express higher levels of Ch25h, an enzyme that hydroxylates cholesterol to produce 25-hydroxycholesterol (25HC). 25HC is an oxysterol with interesting immune roles stemming from its ability to regulate cholesterol metabolism. Since astrocytes synthesize cholesterol in the brain and transport it to other cells via apolipoprotein E (ApoE)-containing lipoproteins, we hypothesized that secreted 25HC from microglia may influence lipid metabolism as well as extracellular ApoE derived from astrocytes. Here we show that astrocytes take up externally added 25HC and respond with altered lipid metabolism. Extracellular levels of ApoE lipoprotein particles increased after treatment of astrocytes with 25HC without an increase in Apoe mRNA expression. In mouse astrocytes expressing human ApoE3 or ApoE4, 25HC promoted extracellular ApoE3 better than ApoE4. Increased extracellular ApoE was due to elevated efflux from increased Abca1 expression via LXRs as well as decreased lipoprotein reuptake from suppressed Ldlr expression via inhibition of SREBP. 25HC also suppressed expression of Srebf2, but not Srebf1, leading to reduced cholesterol synthesis in astrocytes without affecting fatty acid levels. We further show that 25HC promoted the activity of sterol-o-acyl transferase that led to a doubling of the amount of cholesteryl esters and their concomitant storage in lipid droplets. Our results demonstrate an important role for 25HC in regulating astrocyte lipid metabolism.

Keywords:  25-hydroxycholesterol; Alzheimer disease; Neuroinflammation; apolipoprotein E; astrocyte; cholesterol metabolism; microglia; oxysterols

DOI:  https://doi.org/10.1016/j.jlr.2023.100350
Aging (Albany NY). 2023 Feb 27. 15

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies.

Ariel K Frame, J Wesley Robinson, Nader H Mahmoudzadeh, Jason M Tennessen, Anne F Simon, Robert C Cumming.

  The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of Drosophila melanogaster lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.

Keywords:  Drosophila melanogaster; astrocyte-neuron lactate shuttle (ANLS); courtship conditioning; dLdh; glia; lactate; lactate dehydrogenase; long-term memory

DOI:  https://doi.org/10.18632/aging.204565
Eur J Nucl Med Mol Imaging. 2023 Mar 03.

Regional brain glucose metabolism is differentially affected by ketogenic diet: a human semiquantitative positron emission tomography.

Tatiana Horowitz, Emilie Doche, Mary Philip, Serge Cammilleri, Laurent Suissa, Eric Guedj.

  PURPOSE: Ketogenic diet (KD) is recommended to avoid intense [18F]FDG myocardial physiologic uptake in PET imaging. Neuroprotective and anti-seizure effects of KD have been suggested, but their mechanisms remain to be elucidated. This [18F]FDG PET study aims to evaluate the effect of KD on glucose brain metabolism.METHOD: Subjects who underwent KD prior to whole-body and brain [18F]FDG PET between January 2019 and December 2020 in our department for suspected endocarditis were retrospectively included. Myocardial glucose suppression (MGS) on whole-body PET was analyzed. Patients with brain abnormalities were excluded. Thirty-four subjects with MGS (mean age: 61.8 ± 17.2 years) were included in the KD population, and 14 subjects without MGS were considered for a partial KD group (mean age: 62.3 ± 15.1 years). Brain SUVmax was first compared between these two KD groups to determine possible global uptake difference. Semiquantitative voxel-based intergroup analyses were secondarily performed to determine possible inter-regional differences by comparing KD groups with and without MGS, separately, to 27 healthy subjects fasting for at least 6 h (mean age of 62.4 ± 10.9 years), and KD groups between them (p-voxel < 0.001, and p-cluster < 0.05, FWE-corrected).
RESULTS: A 20% lower brain SUVmax was found in subjects under KD with MGS in comparison to those without MGS (Student's t-test, p = 0.02). Whole-brain voxel-based intergroup analysis revealed that patients under KD with and without MGS had relative hypermetabolism of limbic regions including medial temporal cortices and cerebellum lobes and relative hypometabolism of bilateral posterior regions (occipital), without significant difference between them.
CONCLUSION: KD globally reduces brain glucose metabolism but with regional differences, requiring special attention to clinical interpretation. On a pathophysiological perspective, these findings could help understand underlying neurological effects of KD through possible decrease of oxidative stress in posterior regions and functional compensation in the limbic regions.

Keywords:  Brain PET; Ketogenic diet; Ketone; Metabolism; PET

DOI:  https://doi.org/10.1007/s00259-023-06156-w
Arch Biochem Biophys. 2023 Feb 25. pii: S0003-9861(23)00054-1. [Epub ahead of print]737 109555

The role of polyunsaturated fatty acids in neuronal signaling in depression and cognitive processes.

Katarzyna Stachowicz.

  This study aimed to evaluate research findings on the role of polyunsaturated fatty acids (PUFAs) in neuronal signaling. Polyunsaturated fatty acids (PUFAs) are the building blocks of the brain and are responsible for the proper functioning of neurons, synapses, and neuronal communication. The deficiency of a significant component, omega-3 (ω-3) FA, in favor of omega-6 (ω-6) FA can exacerbate the course of mental illness and be one of the triggers of the cascade of neurodegenerative changes. PUFAs play an essential role in transmitting neuronal signals, affecting brain homeostasis. Physicochemical parameters of lipid layers significantly affect their functioning; interactions between lipids and proteins in brain cells are critical for mechanical stability and maintaining adequate elasticity for vesicle budding and membrane fusion. This paper discusses the role of PUFA deficiency or inappropriate ratios in brain tissue. The deficiency is a crucial element in depressive disorders and cognitive impairment, while in Alzheimer's disease, there is some controversy.

Keywords:  Alzheimer's disease; Cognition; Depression; Neurotransmission; Omega-3; Omega-6; PUFAs; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.abb.2023.109555
Front Aging Neurosci. 2023 ;15 1096206

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer's disease (AD) neuropathology: A hypothesis and review.

Frank R Sharp, Charles S DeCarli, Lee-Way Jin, Xinhua Zhan.

  We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer's disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer's initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer's disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.

Keywords:  APOE; Abeta; Alzheimer’s disease; amyloid; cholesterol; myelin; tau; white matter

DOI:  https://doi.org/10.3389/fnagi.2023.1096206
Brain Commun. 2023 ;5(1): fcad021

Brain glucose metabolism and nigrostriatal degeneration in isolated rapid eye movement sleep behaviour disorder.

Patricia Diaz-Galvan, Toji Miyagawa, Scott A Przybelski, Timothy G Lesnick, Matthew L Senjem, Clifford R Jack, Leah K Forsberg, Hoon-Ki Min, Erik K St Louis, Rodolfo Savica, Julie A Fields, Eduardo E Benarroch, Val Lowe, Ronald C Petersen, Bradley F Boeve, Kejal Kantarci.

  Alterations of cerebral glucose metabolism can be detected in patients with isolated rapid eye movement sleep behaviour disorder, a prodromal feature of neurodegenerative diseases with α-synuclein pathology. However, metabolic characteristics that determine clinical progression in isolated rapid eye movement sleep behaviour disorder and their association with other biomarkers need to be elucidated. We investigated the pattern of cerebral glucose metabolism on 18F-fluorodeoxyglucose PET in patients with isolated rapid eye movement sleep behaviour disorder, differentiating between those who clinically progressed and those who remained stable over time. Second, we studied the association between 18F-fluorodeoxyglucose PET and lower dopamine transporter availability in the putamen, another hallmark of synucleinopathies. Patients with isolated rapid eye movement sleep behaviour disorder from the Mayo Clinic Alzheimer's Disease Research Center and Center for Sleep Medicine (n = 22) and age-and sex-matched clinically unimpaired controls (clinically unimpaired; n = 44) from the Mayo Clinic Study of Aging were included. All participants underwent 18F-fluorodeoxyglucose PET and dopamine transporter imaging with iodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane on single-photon emission computerized tomography. A subset of patients with isolated rapid eye movement sleep behaviour disorder with follow-up evaluations (n = 17) was classified as isolated rapid eye movement sleep behaviour disorder progressors (n = 7) if they developed mild cognitive impairment or Parkinson's disease; or isolated rapid eye movement sleep behaviour disorder stables (n = 10) if they remained with a diagnosis of isolated rapid eye movement sleep behaviour disorder with no cognitive impairment. Glucose metabolic abnormalities in isolated rapid eye movement sleep behaviour disorder were determined by comparing atlas-based regional 18F-fluorodeoxyglucose PET uptake between isolated rapid eye movement sleep behaviour disorder and clinically unimpaired. Associations between 18F-fluorodeoxyglucose PET and dopamine transporter availability in the putamen were analyzed with Pearson's correlation within the nigrostriatal pathway structures and with voxel-based analysis in the cortex. Patients with isolated rapid eye movement sleep behaviour disorder had lower glucose metabolism in the substantia nigra, retrosplenial cortex, angular cortex, and thalamus, and higher metabolism in the amygdala and entorhinal cortex compared with clinically unimpaired. Patients with isolated rapid eye movement sleep behaviour disorder who clinically progressed over time were characterized by higher glucose metabolism in the amygdala and entorhinal cortex, and lower glucose metabolism in the cerebellum compared with clinically unimpaired. Lower dopamine transporter availability in the putamen was associated with higher glucose metabolism in the pallidum within the nigrostriatal pathway; and with higher 18F-fluorodeoxyglucose uptake in the amygdala, insula, and temporal pole on a voxel-based analysis, although these associations did not survive after correcting for multiple comparisons. Our findings suggest that cerebral glucose metabolism in isolated rapid eye movement sleep behaviour disorder is characterized by hypometabolism in regions frequently affected during the prodromal stage of synucleinopathies, potentially reflecting synaptic dysfunction. Hypermetabolism is also seen in isolated rapid eye movement sleep behaviour disorder, suggesting that synaptic metabolic disruptions may be leading to a lack of inhibition, compensatory mechanisms, or microglial activation, especially in regions associated with nigrostriatal degeneration.

Keywords:  FDG; Lewy bodies disease; PET; SPECT; isolated REM sleep behaviour disorder

DOI:  https://doi.org/10.1093/braincomms/fcad021
Sci Adv. 2023 Mar;9(9): eadd5220

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells.

Francesco Petrelli, Valentina Scandella, Sylvie Montessuit, Nicola Zamboni, Jean-Claude Martinou, Marlen Knobloch.

Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic Mpc1 ablation in vitro and in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.

DOI: https://doi.org/10.1126/sciadv.add5220
Proc Natl Acad Sci U S A. 2023 Mar 07. 120(10): e2215290120

Mfsd2a utilizes a flippase mechanism to mediate omega-3 fatty acid lysolipid transport.

Geok-Lin Chua, Bryan C Tan, Randy Y J Loke, Menglan He, Cheen-Fei Chin, Bernice H Wong, Alvin C Y Kuk, Mei Ding, Markus R Wenk, Lan Guan, Federico Torta, David L Silver.

  Major Facilitator Superfamily Domain containing 2a (Mfsd2a) is a sodium-dependent lysophosphatidylcholine (LPC) transporter expressed at the blood-brain barrier that constitutes the main pathway by which the brain obtains omega-3 fatty acids, such as docosahexanoic acid. Mfsd2a deficiency in humans results in severe microcephaly, underscoring the importance of LPC transport by Mfsd2a for brain development. Biochemical studies and recent cryo-electron microscopy (cryo-EM) structures of Mfsd2a bound to LPC suggest that Mfsd2a transports LPC via an alternating access mechanism between outward-facing and inward-facing conformational states in which the LPC inverts during transport between the outer and inner leaflet of a membrane. However, direct biochemical evidence of flippase activity by Mfsd2a has not been demonstrated and it is not understood how Mfsd2a could invert LPC between the outer and inner leaflet of the membrane in a sodium-dependent manner. Here, we established a unique in vitro assay using recombinant Mfsd2a reconstituted in liposomes that exploits the ability of Mfsd2a to transport lysophosphatidylserine (LPS) coupled with a small molecule LPS binding fluorophore that allowed for monitoring of directional flipping of the LPS headgroup from the outer to the inner liposome membrane. Using this assay, we demonstrate that Mfsd2a flips LPS from the outer to the inner leaflet of a membrane bilayer in a sodium-dependent manner. Furthermore, using cryo-EM structures as guides together with mutagenesis and a cell-based transport assay, we identify amino acid residues important for Mfsd2a activity that likely constitute substrate interaction domains. These studies provide direct biochemical evidence that Mfsd2a functions as a lysolipid flippase.

Keywords:  Mfsd2a; blood–brain barrier; flippase; membrane; transporter

DOI:  https://doi.org/10.1073/pnas.2215290120
Mol Cell Neurosci. 2023 Mar 01. pii: S1044-7431(23)00028-3. [Epub ahead of print] 103834

Compartment specific mitochondrial dysfunction in Drosophila knock-in model of ALS reversed by altered gene expression of OXPHOS subunits and pro-fission factor Drp1.

Y Nemtsova, B L Steinert, K A Wharton.

  Amyotrophic Lateral Sclerosis (ALS) is a fatal multisystem neurodegenerative disease, characterized by a loss in motor function. ALS is genetically diverse, with mutations in genes ranging from those regulating RNA metabolism, like TAR DNA-binding protein (TDP-43) and Fused in sarcoma (FUS), to those that act to maintain cellular redox homeostasis, like superoxide dismutase 1 (SOD1). Although varied in genetic origin, pathogenic and clinical commonalities are clearly evident between cases of ALS. Defects in mitochondria is one such common pathology, thought to occur prior to, rather than as a consequence of symptom onset, making these organelles a promising therapeutic target for ALS, as well as other neurodegenerative diseases. Depending on the homeostatic needs of neurons throughout life, mitochondria are normally shuttled to different subcellular compartments to regulate metabolite and energy production, lipid metabolism, and buffer calcium. While originally considered a motor neuron disease due to the dramatic loss in motor function accompanied by motor neuron cell death in ALS patients, many studies have now implicated non-motor neurons and glial cells alike. Defects in non-motor neuron cell types often preceed motor neuron death suggesting their dysfunction may initiate and/or facilitate the decline in motor neuron health. Here, we investigate mitochondria in a Drosophila Sod1 knock-in model of ALS. In depth, in vivo, examination reveals mitochondrial dysfunction evident prior to onset of motor neuron degeneration. Genetically encoded redox biosensors identify a general disruption in the electron transport chain (ETC). Compartment specific abnormalities in mitochondrial morphology is observed in diseased sensory neurons, accompanied by no apparent defects in the axonal transport machinery, but instead an increase in mitophagy in synaptic regions. The decrease in networked mitochondria at the synapse is reversed upon downregulation of the pro-fission factor Drp1. Furthermore, altered expression of specific OXPHOS subunits reverses ALS-associated defects in mitochondrial morphology and function.

Keywords:  ALS; Drosophila; Mitochondrial dysfunction; Neurodegeneration; Sensory neurons

DOI:  https://doi.org/10.1016/j.mcn.2023.103834
Parkinsonism Relat Disord. 2023 Feb 27. pii: S1353-8020(23)00076-7. [Epub ahead of print]109 105353

A novel C19orf12 frameshift mutation in a MPAN pedigree impairs mitochondrial function and connectivity leading to neurodegeneration.

Huan-Yun Chen, Han-I Lin, Chia-Lang Hsu, Pei-Lung Chen, Cheng-Yen Huang, Shu-Chun Teng, Chin-Hsien Lin.

BACKGROUND: Mitochondrial membrane protein‒associated neurodegeneration (MPAN) is a rare genetic disease characterized by progressive neurodegeneration with brain iron accumulations combined with neuronal α-synuclein and tau aggregations. Mutations in C19orf12 have been associated with both autosomal recessive and autosomal dominant inheritance patterns of MPAN.METHODS: We present clinical features and functional evidence from a Taiwanese family with autosomal dominant MPAN caused by a novel heterozygous frameshift and nonsense mutation in C19orf12, c273_274 insA (p.P92Tfs*9). To verify the pathogenicity of the identified variant, we examined the mitochondrial function, morphology, protein aggregation, neuronal apoptosis, and RNA interactome in p.P92Tfs*9 mutant knock-in SH-SY5Y cells created with CRISPR-Cas9 technology.
RESULTS: Clinically, the patients with the C19orf12 p.P92Tfs*9 mutation presented with generalized dystonia, retrocollis, cerebellar ataxia, and cognitive decline, starting in their mid-20s. The identified novel frameshift mutation is located in the evolutionarily conserved region of the last exon of C19orf12. In vitro studies revealed that the p.P92Tfs*9 variant is associated with impaired mitochondrial function, reduced ATP production, aberrant mitochondria interconnectivity and ultrastructure. Increased neuronal α-synuclein and tau aggregations, and apoptosis were observed under conditions of mitochondrial stress. Transcriptomic analysis revealed that the expression of genes in clusters related to mitochondrial fission, lipid metabolism, and iron homeostasis pathways was altered in the C19orf12 p.P92Tfs*9 mutant cells compared to control cells.
CONCLUSION: Our findings provide clinical, genetic, and mechanistic insight revealing a novel heterozygous C19orf12 frameshift mutation to be a cause of autosomal dominant MPAN, further strengthening the importance of mitochondrial dysfunction in the pathogenesis of MPAN.

DOI: https://doi.org/10.1016/j.parkreldis.2023.105353
Mitochondrion. 2023 Feb 28. pii: S1567-7249(23)00016-8. [Epub ahead of print]

The pyruvate dehydrogenase complex: Life's essential, vulnerable and druggable energy homeostat.

Peter W Stacpoole, Charles E McCall.

  Found in all organisms, pyruvate dehydrogenase complexes (PDC) are the keystones of prokaryotic and eukaryotic energy metabolism. In eukaryotic organisms these multi-component megacomplexes provide a crucial mechanistic link between cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. As a consequence, PDCs also influence the metabolism of branched chain amino acids, lipids and, ultimately, oxidative phosphorylation (OXPHOS). PDC activity is an essential determinant of the metabolic and bioenergetic flexibility of metazoan organisms in adapting to changes in development, nutrient availability and various stresses that challenge maintenance of homeostasis. This canonical role of the PDC has been extensively probed over the past decades by multidisciplinary investigations into its causal association with diverse physiological and pathological conditions, the latter making the PDC an increasingly viable therapeutic target. Here we review the biology of the remarkable PDC and its emerging importance in the pathobiology and treatment of diverse congenital and acquired disorders of metabolic integration.

Keywords:  Aerobic glycolysis; Aging; Cancer; Diabetes; Embryogenesis; Inflammation; Neurodegeneration; Oxidative phosphorylation; Pyruvate dehydrogenase complex; Sepsis

DOI:  https://doi.org/10.1016/j.mito.2023.02.007
J Neurosci. 2023 Mar 02. pii: JN-RM-1331-22. [Epub ahead of print]

Widespread fMRI BOLD signal overactivations during cognitive control in older adults are not matched by corresponding increases in fPET glucose metabolism.

Lars Stiernman, Filip Grill, Charlotte McNulty, Philip Bahrd, Vania Panes Lundmark, Jan Axelsson, Alireza Salami, Anna Rieckmann.

A common observation in functional magnetic resonance imaging (fMRI) studies using the blood-oxygenation level-dependent (BOLD) signal is that older adults, compared to young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37y) and 34 older (65-86y) healthy human adults of both sexes with hybrid positron emission tomography (PET)/MRI. The radioligand [18F]fluoro-deoxyglucose (FDG) was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks, one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations when compared to the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.SIGNIFICANCE STATEMENT:Findings of increased functional magnetic resonance imaging (fMRI) activations in older as compared to younger adults have been suggested to reflect increased use of neuronal resources to cope with reduced brain function. The physiological underpinnings of such compensatory processes are poorly understood however, and rest on the assumption that vascular signals accurately reflect neuronal activity. Comparing fMRI and simultaneously acquired functional positron emission tomography (fPET) as an alternative index of synaptic activity we show that age-related overactivations do not appear to be neuronal in origin. This result is important because mechanisms underlying compensatory processes in aging are potential targets for interventions aiming to prevent age-related cognitive decline.

DOI: https://doi.org/10.1523/JNEUROSCI.1331-22.2023
Ultrastruct Pathol. 2023 Feb 25. 1-6

Comparative survey of mitochondrial ultrastructure in IDH1-mutant astrocytoma and IDH1-wildtype glioblastoma (GBM).

Haitham H Maraqah, Mones S Abu-Asab, Han Sung Lee, Orwa Aboud.

  Gliomas are the most common malignant brain tumors with poor prognosis. The WHO's classification recognizes isocitrate dehydrogenase 1 (IDH1) mutant astrocytoma and IDH1-wildtype glioblastoma (GBM). The IDH1 mutation confers a survival advantage over the wildtype. There are several explanations for the metabolic advantage of the IDH1 mutation, some involve mitochondrial implications. Since an ultrastructural comparison of both tumor genotypes is still lacking, we surveyed the ultrastructural effects of the IDH1 mutation on the mitochondria of the IDH1-mutant astrocytoma (n = 15) and IDH1-wildtype glioblastoma (n = 15) tumors. Our results show that both IDH1 genotypes have degenerate and uncoupled mitochondria; this has not been reported before. The presence of ample lipid inclusions and lipid droplets in the cytoplasm of both genotypes support our conclusion of dysfunctional uncoupled mitochondria. Thus, the IDH1 mutation may have no ultrastructural consequences on the mitochondria, and the aberrant mitochondria in both genotypes may be the result of other unknown mutations. The status of the mitochondria in these genotypes portends a clinical challenge since tumor cells with uncoupled mitochondria are more primitive, aggressive, and considerably treatment resistant.

Keywords:  Glioblastoma; TCA cycle; beta-oxidation; isocitrate dehydrogenase; mitochondria

DOI:  https://doi.org/10.1080/01913123.2023.2175942
Neuropharmacology. 2023 Feb 24. pii: S0028-3908(23)00067-9. [Epub ahead of print]229 109477

ATP-mediated signalling in the central synapses.

Ulyana Lalo, Yuriy Pankratov.

ATP released from the synaptic terminals and astrocytes can activate neuronal P2 receptors at a variety of locations across the CNS. Although the postsynaptic ATP-mediated signalling does not bring a major contribution into the excitatory transmission, it is instrumental for slow and diffuse modulation of synaptic dynamics and neuronal firing in many CNS areas. Neuronal P2X and P2Y receptors can be activated by ATP released from the synaptic terminals, astrocytes and microglia and thereby can participate in the regulation of synaptic homeostasis and plasticity. There is growing evidence of importance of purinergic regulation of synaptic transmission in different physiological and pathological contexts. Here, we review the main mechanisms underlying the complexity and diversity of purinergic signalling and purinergic modulation in central neurons.

DOI: https://doi.org/10.1016/j.neuropharm.2023.109477
J Cell Sci. 2023 Mar 01. pii: jcs260662. [Epub ahead of print]136(5):

StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival.

Felicity R Sterling, Jon D'Amico, Alexandria M Brumfield, Kara L Huegel, Patricia S Vaughan, Kathryn Morris, Shelby Schwarz, Michelle V Joyce, Bill Boggess, Matthew M Champion, Kevin Maciuba, Philip Allen, Eric Marasco, Grant Koch, Peter Gonzalez, Shannon Hodges, Shannon Leahy, Erica Gerstbauer, Edward H Hinchcliffe, Kevin T Vaughan.

  The pathological accumulation of cholesterol is a signature feature of Niemann-Pick type C (NPC) disease, in which excessive lipid levels induce Purkinje cell death in the cerebellum. NPC1 encodes a lysosomal cholesterol-binding protein, and mutations in NPC1 drive cholesterol accumulation in late endosomes and lysosomes (LE/Ls). However, the fundamental role of NPC proteins in LE/L cholesterol transport remains unclear. Here, we demonstrate that NPC1 mutations impair the projection of cholesterol-containing membrane tubules from the surface of LE/Ls. A proteomic survey of purified LE/Ls identified StARD9 as a novel lysosomal kinesin responsible for LE/L tubulation. StARD9 contains an N-terminal kinesin domain, a C-terminal StART domain, and a dileucine signal shared with other lysosome-associated membrane proteins. Depletion of StARD9 disrupts LE/L tubulation, paralyzes bidirectional LE/L motility and induces accumulation of cholesterol in LE/Ls. Finally, a novel StARD9 knock-out mouse recapitulates the progressive loss of Purkinje cells in the cerebellum. Together, these studies identify StARD9 as a microtubule motor protein responsible for LE/L tubulation and provide support for a novel model of LE/L cholesterol transport that becomes impaired in NPC disease.

Keywords:  Cholesterol; Kinesin; Lysosome; Membrane tubulation; Niemann–Pick type C disease

DOI:  https://doi.org/10.1242/jcs.260662
Pediatr Res. 2023 Mar 01.

How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?

Yvonne W Wu, Sarah E Monsell, Hannah C Glass, Jessica L Wisnowski, Amit M Mathur, Robert C McKinstry, Stefan Bluml, Fernando F Gonzalez, Bryan A Comstock, Patrick J Heagerty, Sandra E Juul.

BACKGROUND: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear.METHODS: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years.
RESULTS: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury.
CONCLUSION: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes.
IMPACT: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

DOI: https://doi.org/10.1038/s41390-023-02510-8
Exp Neurol. 2023 Feb 24. pii: S0014-4886(23)00040-7. [Epub ahead of print]363 114356

Inhibition of monoamine oxidase-a increases respiration in isolated mouse cortical mitochondria.

Olivia J Kalimon, Hemendra J Vekaria, Greg A Gerhardt, Patrick G Sullivan.

  Monoamine oxidase (MAO) is an enzyme located on the outer mitochondrial membrane that metabolizes amine substrates like serotonin, norepinephrine and dopamine. MAO inhibitors (MAOIs) are frequently utilized to treat disorders such as major depression or Parkinson's disease (PD), though their effects on brain mitochondrial bioenergetics are unclear. These studies measured bioenergetic activity in mitochondria isolated from the mouse cortex in the presence of inhibitors of either MAO-A, MAO-B, or both isoforms. We found that only 10 μM clorgyline, the selective inhibitor of MAO-A and not MAO-B, increased mitochondrial oxygen consumption rate in State V(CI) respiration compared to vehicle treatment. We then assessed mitochondrial bioenergetics, reactive oxygen species (ROS) production, and Electron Transport Chain (ETC) complex function in the presence of 0, 5, 10, 20, 40, or 80 μM of clorgyline to determine if this change was dose-dependent. The results showed increased oxygen consumption rates across the majority of respiration states in mitochondria treated with 5, 10, or 20 μM with significant bioenergetic inhibition at 80 μM clorgyline. Next, we assessed mitochondrial ROS production in the presence of the same concentrations of clorgyline in two different states: high mitochondrial membrane potential (ΔΨm) induced by oligomycin and low ΔΨm induced by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP). There were no changes in ROS production in the presence of 5, 10, 20, or 40 μM clorgyline compared to vehicle after the addition of oligomycin or FCCP. There was a significant increase in mitochondrial ROS in the presence of 80 μM clorgyline after FCCP addition, as well as reduced Complex I and Complex II activities, which are consistent with inhibition of bioenergetics seen at this dose. There were no changes in Complex I, II, or IV activities in mitochondria treated with low doses of clorgyline. These studies shed light on the direct effect of MAO-A inhibition on brain mitochondrial bioenergetic function, which may be a beneficial outcome for those taking these medications.

Keywords:  Bioenergetics; Clorgyline; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.expneurol.2023.114356
Exp Neurol. 2023 Feb 28. pii: S0014-4886(23)00052-3. [Epub ahead of print] 114368

Pyruvate dehydrogenase beta subunit (Pdhb) promotes peripheral axon regeneration by regulating energy supply and gene expression.

Chunyi Jiang, Yan Lu, Ran Zhu, Ying Zong, Yuchen Huang, Dong Wang, Zhanyun Da, Bin Yu, Longxiang Shen, Qianqian Cao.

  Key metabolic enzymes not only regulate Glucose, lipid, amino acid metabolism to serve the cellular energy needs, but also modulate noncanonical or nonmetabolic signaling pathway such as gene expression, cell-cycle progression, DNA repair, apoptosis and cell proliferation in regulating the pathologic progression of disease. However, the role of glycometabolism in peripheral nerve axon regeneration is little known. In this study, we investigated the expression of Pyruvate dehydrogenase E1(PDH), a key enzyme linking glycolysis and the tricarboxylic acid (TCA) cycle, with qRT-PCR and found that pyruvate dehydrogenase beta subunit (Pdhb) is up-regulated at the early stage during peripheral nerve injury. The knockdown of Pdhb inhibits neurite outgrowth of primary DRG neurons in vitro and restrains axon regeneration of sciatic nerve after crush injury. Pdhb overexpression promoting axonal regeneration is reversed by knockdown of Monocarboxylate transporter 2(Mct2), a transporter involved in the transport and metabolism of lactate, indicating Pdhb promoting axon regeneration depends on lactate for energy supply. Given the nucleus-localization of Pdhb, further analysis revealed that Pdhb enhances the acetylation of H3K9 and affecting the expression of genes involved in arachidonic acid metabolism and Ras signaling pathway, such as Rsa-14-44 and Pla2g4a, thereby promoting axon regeneration. Collectively, our data indicates that Pdhb is a positive dual modulator of energy generation and gene expression in regulating peripheral axon regeneration.

Keywords:  Axon regeneration; Gene expression; Glycometabolism; Pdhb; Peripheral nerve injury

DOI:  https://doi.org/10.1016/j.expneurol.2023.114368
Cereb Cortex. 2023 Feb 24. pii: bhad046. [Epub ahead of print]

Severity of prematurity and age impact early postnatal development of GABA and glutamate systems.

Sudeepta K Basu, Subechhya Pradhan, Yushuf M Sharker, Kushal J Kapse, Jonathan Murnick, Taeun Chang, Catherine A Lopez, Nickie Andescavage, Adre J duPlessis, Catherine Limperopoulos.

  Gamma-aminobutyric acid (GABA) and glutamatergic system perturbations following premature birth may explain neurodevelopmental deficits in the absence of structural brain injury. Using GABA-edited spectroscopy (MEscher-GArwood Point Resolved Spectroscopy [MEGA-PRESS] on 3 T MRI), we have described in-vivo brain GABA+ (+macromolecules) and Glx (glutamate + glutamine) concentrations in term-born infants. We report previously unavailable comparative data on in-vivo GABA+ and Glx concentrations in the cerebellum, the right basal ganglia, and the right frontal lobe of preterm-born infants without structural brain injury. Seventy-five preterm-born (gestational age 27.8 ± 2.9 weeks) and 48 term-born (39.6 ± 0.9 weeks) infants yielded reliable MEGA-PRESS spectra acquired at post-menstrual age (PMA) of 40.2 ± 2.3 and 43.0 ± 2 weeks, respectively. GABA+ (median 2.44 institutional units [i.u.]) concentrations were highest in the cerebellum and Glx higher in the cerebellum (5.73 i.u.) and basal ganglia (5.16 i.u.), with lowest concentrations in the frontal lobe. Metabolite concentrations correlated positively with advancing PMA and postnatal age at MRI (Spearman's rho 0.2-0.6). Basal ganglia Glx and NAA, and frontal GABA+ and NAA concentrations were lower in preterm compared with term infants. Moderate preterm infants had lower metabolite concentrations than term and extreme preterm infants. Our findings emphasize the impact of premature extra-uterine stimuli on GABA-glutamate system development and may serve as early biomarkers of neurodevelopmental deficits.

Keywords:  GABA; MEGA-PRESS; MR spectroscopy; glutamate; premature brain

DOI:  https://doi.org/10.1093/cercor/bhad046