l
-Carnitine functions to transport long chain fatty acyl-CoAs into the mitochondria for degradation by β-oxidation. Treatment with
l
-carnitine can ameliorate metabolic imbalances in many inborn ...errors of metabolism. In recent years there has been considerable interest in the therapeutic potential of
l
-carnitine and its acetylated derivative acetyl-
l
-carnitine (ALCAR) for neuroprotection in a number of disorders including hypoxia-ischemia, traumatic brain injury, Alzheimer’s disease and in conditions leading to central or peripheral nervous system injury. There is compelling evidence from preclinical studies that
l
-carnitine and ALCAR can improve energy status, decrease oxidative stress and prevent subsequent cell death in models of adult, neonatal and pediatric brain injury. ALCAR can provide an acetyl moiety that can be oxidized for energy, used as a precursor for acetylcholine, or incorporated into glutamate, glutamine and GABA, or into lipids for myelination and cell growth. Administration of ALCAR after brain injury in rat pups improved long-term functional outcomes, including memory. Additional studies are needed to better explore the potential of
l
-carnitine and ALCAR for protection of developing brain as there is an urgent need for therapies that can improve outcome after neonatal and pediatric brain injury.
This is a tribute to John Edmond, professor emeritus of biological chemistry in the David Geffen School of Medicine at UCLA, a renowned neurochemist who had a leadership role in founding the ICBEM ...meeting series in 1993. John was known for his very warm and engaging personality and his innovative approaches to studying the developing brain and auditory system. He was a brilliant scientist and a fun and delightful person. Without John Edmond's enthusiasm and contributions, we would not have the biennial ICBEM meetings which as noted by Dienel et al. “have had a high impact on conceptual and experimental advances” … “in the energetics and metabolism underlying neural functions”… and “on promoting collaborative interactions among neuroscientists.” Sadly, John Edmond passed away on February 18, 2022, following a cerebral hemorrhage. He will be greatly missed by his colleagues and friends.
This is a tribute to John Edmond, professor emeritus of biological chemistry in the David Geffen School of Medicine at UCLA, a renowned neurochemist who had a leadership role in founding the ICBEM meeting series in 1993. Sadly, John Edmond passed away on February 18, 2022 following a cerebral hemorrhage. The photo shows John Edmond with his beloved wife Lorna at the American Society for Neurochemistry meeting in Charleston, SC in 2009.
In vitro and in vivo studies have shown that glutamate can be oxidized for energy by brain astrocytes. The ability to harvest the energy from glutamate provides astrocytes with a mechanism to offset ...the high ATP cost of the uptake of glutamate from the synaptic cleft. This brief review focuses on oxidative metabolism of glutamate by astrocytes, the specific pathways involved in the complete oxidation of glutamate and the energy provided by each reaction.
It is well established that astrocytes can utilize many substrates to support oxidative energy metabolism; however, use of energy substrates in the presence of other substrates, as would occur in ...vivo, has not been systematically evaluated. Substrate competition studies were used to determine changes in the rates of
14
CO
2
production since little is known about the interaction of energy substrates in astrocytes. The rates of
14
CO
2
production from 1 mM D-6-
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Cglucose,
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-U-
14
Cglutamate,
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-U-
14
Cglutamine,
d
-3-hydroxy3-
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Cbutyrate,
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-U-
14
Clactate and
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-U-
14
Cmalate by primary cultures of astrocytes from rat brain were determined to be 1.17 ± 0.19, 85.30 ± 12.25, 28.04 ± 2.84, 13.55 ± 4.56, 14.84 ± 2.40 and 5.20 ± 1.20 nmol/h/mg protein (mean ± SEM), respectively. The rate of
14
CO
2
production from glutamate oxidation was higher than that of the other substrates Addition of unlabeled glutamate significantly decreased the rates of
14
CO
2
production from all other substrates studied; however, glutamate oxidation was not altered by the addition of any of the other substrates. The rate of
14
CO
2
production of glutamine was decreased by glutamate, but not altered by other substrates. The rate of
14
CO
2
production from glucose was significantly decreased by the addition of unlabeled glutamate, glutamine or lactate, but not by 3-hydroxybutyrate or malate. Addition of unlabeled glucose did not significantly alter the
14
CO
2
production from any other substrate.
14
CO
2
production from lactate was decreased by the addition of unlabeled glutamine or glutamate and increased by addition of malate. The
14
CO
2
production from malate was decreased by the addition of unlabeled glutamate or lactate, but was not altered by the other substrates. The substrate utilization for oxidative energy metabolism in astrocytes is very different than the profile previously reported for synaptic terminals. These studies demonstrate the potential use of multiple substrates including glucose, glutamate, glutamine, lactate and 3-hydroxybutyrate as energy substrates for astrocytes. The data also provide evidence of interactions of substrates and multiple compartments of TCA cycle activity in cultured astrocytes.
This Preface introduces the Special Issue entitled, "Energy Substrates and Microbiome Govern Brain Bioenergetics and Cognitive Function with Aging", which is comprised of manuscripts contributed by ...invited speakers and program/organizing committee members who participated in the 14th International Conference on Brain Energy Metabolism (ICBEM) held on October 24-27, 2022 in Santa Fe, New Mexico, USA. The conference covered the latest developments in research related to neuronal energetics, emerging roles for glycogen in higher brain functions, the impact of dietary intervention on aging, memory, and Alzheimer's disease, roles of the microbiome in gut-brain signaling, astrocyte-neuron interactions related to cognition and memory, novel roles for mitochondria and their metabolites, and metabolic neuroimaging in aging and neurodegeneration. The special issue contains 25 manuscripts on these topics plus three tributes to outstanding scientists who have made important contributions to brain energy metabolism and participated in numerous ICBEM conferences. In addition, two of the manuscripts describe important directions and the rationale for future research in many thematic areas covered by the conference.
Brain development is a highly orchestrated complex process. The developing brain utilizes many substrates including glucose, ketone bodies, lactate, fatty acids and amino acids for energy, cell ...division and the biosynthesis of nucleotides, proteins and lipids. Metabolism is crucial to provide energy for all cellular processes required for brain development and function including ATP formation, synaptogenesis, synthesis, release and uptake of neurotransmitters, maintaining ionic gradients and redox status, and myelination. The rapidly growing population of infants and children with neurodevelopmental and cognitive impairments and life-long disability resulting from developmental brain injury is a significant public health concern. Brain injury in infants and children can have devastating effects because the injury is superimposed on the high metabolic demands of the developing brain. Acute injury in the pediatric brain can derail, halt or lead to dysregulation of the complex and highly regulated normal developmental processes. This paper provides a brief review of metabolism in developing brain and alterations found clinically and in animal models of developmental brain injury. The metabolic changes observed in three major categories of injury that can result in life-long cognitive and neurological disabilities, including neonatal hypoxia–ischemia, pediatric traumatic brain injury, and brain injury secondary to prematurity are reviewed.
Leif Hertz, M.D., D.Sc. (honōris causā) (1930–2018), was one of the original and noteworthy participants in the International Conference on Brain Energy Metabolism (ICBEM) series since its inception ...in 1993. The biennial ICBEM conferences are organized by neuroscientists interested in energetics and metabolism underlying neural functions; they have had a high impact on conceptual and experimental advances in these fields and on promoting collaborative interactions among neuroscientists. Leif made major contributions to ICBEM discussions and understanding of metabolic and signaling characteristics of astrocytes and their roles in brain function. His studies ranged from uptake of K+ from extracellular fluid and its stimulation of astrocytic respiration, identification, and regulation of enzymes specifically or preferentially expressed in astrocytes in the glutamate–glutamine cycle of excitatory neurotransmission, a requirement for astrocytic glycogenolysis for fueling K+ uptake, involvement of glycogen in memory consolidation in the chick, and pharmacology of astrocytes. This tribute to Leif Hertz highlights his major discoveries, the high impact of his work on astrocyte–neuron interactions, and his unparalleled influence on understanding the cellular basis of brain energy metabolism. His work over six decades has helped integrate the roles of astrocytes into neurotransmission where oxidative and glycogenolytic metabolism during neurotransmitter glutamate turnover are key aspects of astrocytic energetics. Leif recognized that brain astrocytic metabolism is greatly underestimated unless the volume fraction of astrocytes is taken into account. Adjustment for pathway rates expressed per gram tissue for volume fraction indicates that astrocytes have much higher oxidative rates than neurons and astrocytic glycogen concentrations and glycogenolytic rates during sensory stimulation in vivo are similar to those in resting and exercising muscle, respectively. These novel insights are typical of Leif's astute contributions to the energy metabolism field, and his publications have identified unresolved topics that provide the neuroscience community with challenges and opportunities for future research.
Astrocytes have many critical roles in essential brain functions; they are not simply structures that help glue brain cells together. Important roles of astrocytes include energy metabolism, neurotransmission, signaling, K+ buffering, and cognitive functions. This tribute to Leif Hertz's lifetime research emphasizes many critical functions of astrocytes and provides a historical context to stimulate future studies in important, unresolved topics that are necessary for better understanding of brain images and disorders. Gln, glutamine; glu, glutamate; TCA, tricarboxylic acid cycle. For further abbreviations, refer to the main manuscript.
Increased male susceptibility to long‐term cognitive deficits is well described in clinical and experimental studies of neonatal hypoxic‐ischemic encephalopathy. While cell death signaling pathways ...are known to be sexually dimorphic, a sex‐dependent pathophysiological mechanism preceding the majority of secondary cell death has yet to be described. Mitochondrial dysfunction contributes to cell death following cerebral hypoxic‐ischemia (HI). Several lines of evidence suggest that there are sex differences in the mitochondrial metabolism of adult mammals. Therefore, this study tested the hypothesis that brain mitochondrial respiratory impairment and associated oxidative stress is more severe in males than females following HI. Maximal brain mitochondrial respiration during oxidative phosphorylation was two‐fold more impaired in males following HI. The endogenous antioxidant glutathione was 30% higher in the brain of sham females compared to males. Females also exhibited increased glutathione peroxidase (GPx) activity following HI injury. Conversely, males displayed a reduction in mitochondrial GPx4 protein levels and mitochondrial GPx activity. Moreover, a 3–4‐fold increase in oxidative protein carbonylation was observed in the cortex, perirhinal cortex, and hippocampus of injured males, but not females. These data provide the first evidence for sex‐dependent mitochondrial respiratory dysfunction and oxidative damage, which may contribute to the relative male susceptibility to adverse long‐term outcomes following HI.
Lower basal GSH levels, lower post‐hypoxic mitochondrial glutathione peroxidase (mtGPx) activity, and mitochondrial glutathione peroxidase 4 (mtGPx4) protein levels may contribute to the susceptibility of the male brain to oxidative damage and mitochondrial dysfunction following neonatal hypoxic‐ischemia (HI). Treatment of male pups with acetyl‐L‐carnitine (ALCAR) protects against the loss of mtGPx activity, mtGPx4 protein, and increases in protein carbonylation after HI. These findings provide novel insight into the pathophysiology of sexually dimorphic outcomes following HI.
Lower basal GSH levels, lower post‐hypoxic mitochondrial glutathione peroxidase (mtGPx) activity, and mitochondrial glutathione peroxidase 4 (mtGPx4) protein levels may contribute to the susceptibility of the male brain to oxidative damage and mitochondrial dysfunction following neonatal hypoxic‐ischemia (HI). Treatment of male pups with acetyl‐L‐carnitine (ALCAR) protects against the loss of mtGPx activity, mtGPx4 protein, and increases in protein carbonylation after HI. These findings provide novel insight into the pathophysiology of sexually dimorphic outcomes following HI.
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