Brain energy homeostasis: the evolution of the astrocyte-neuron lactate shuttle hypothesis.

The brain's substantial metabolic requirements, consuming a substantial fraction of the body's total energy despite its relatively small mass, necessitate sophisticated metabolic mechanisms for efficient energy distribution and utilization. The astrocyte-neuron lactate shuttle (ANLS) hypothesis has emerged as a fundamental framework explaining the metabolic cooperation between astrocytes and neurons, whereby astrocyte-derived lactate serves as a crucial energy substrate for neurons. This review synthesizes current understanding of brain energy metabolism, focusing on the dual roles of lactate as both an energy substrate and a signaling molecule.

Genomic Insights into the Role of cAMP in Carotenoid Biosynthesis: Enhancing β-Carotene Production in via Deletion.

The gamma-ray-induced random mutagenesis of an engineered β-carotene-producing XL1-Blue resulted in the variant Ajou 45, which exhibits significantly enhanced β-carotene production. The whole-genome sequencing of Ajou 45 identified 55 mutations, notably including a reduction in the copy number of , encoding adenylate cyclase, a key enzyme regulating intracellular cyclic AMP (cAMP) levels. While the parental XL1-Blue strain harbors two copies of , Ajou 45 retains only one, potentially leading to reduced intracellular cAMP concentrations.

Diminished lactate utilization in LDHB-deficient neurons leads to impaired long-term memory retention.

Neurons' high energy demands for processing, transmitting, and storing information in the brain necessitate efficient energy metabolism to maintain normal neuronal function. The astrocyte-neuron lactate shuttle (ANLS) hypothesis suggests neurons preferentially use lactate from astrocytes over glucose for energy. This study investigated lactate dehydrogenase B (LDHB), which preferentially converts lactate to pyruvate, in neuronal energy metabolism and cognitive function.

LDHB-deficient brain exhibits resistance to ischemic neuronal cell death due to increased vasodilation.

Ischemic stroke triggers a cascade of metabolic and inflammatory events leading to neuronal death, particularly in the hippocampus. Here, we investigate the role of lactate metabolism in ischemic resistance using LDHB-deficient mice, which exhibit impaired lactate utilization. Contrary to expectations of severe neuronal damage due to metabolic defects, LDHB-deficient mice displayed significantly increased neuronal survival following ischemic insult.

Diesel-derived PM induces impairment of cardiac movement followed by mitochondria dysfunction in cardiomyocytes.

Particulate matter (PM) in polluted air can be exposed to the human body through inhalation, ingestion, and skin contact, accumulating in various organs throughout the body. Organ accumulation of PM is a growing health concern, particularly in the cardiovascular system. PM emissions are formed in the air by solid particles, liquid droplets, and fuel - particularly diesel - combustion.

The Impact of Fine Particulate Matter 2.5 on the Cardiovascular System: A Review of the Invisible Killer.

Air pollution exerts several deleterious effects on the cardiovascular system, with cardiovascular disease (CVD) accounting for 80% of all premature deaths caused by air pollution. Short-term exposure to particulate matter 2.5 (PM) leads to acute CVD-associated deaths and nonfatal events, whereas long-term exposure increases CVD-associated risk of death and reduces longevity.

LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain.

Age-related decline in mitochondrial function and oxidative stress plays a critical role in neurodegeneration. Lactate dehydrogenase-B (LDHB) is a glycolytic enzyme that catalyzes the conversion of lactate, an important brain energy substrate, into pyruvate. It has been reported that the LDHB pattern changes in the brain during ageing.

High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo.

Mitochondrial transcription factor A (TFAM) is compacting mitochondrial DNA (dmtDNA) into nucleoids and directly controls mtDNA copy number. Here, we show that the TFAM-to-mtDNA ratio is critical for maintaining normal mtDNA expression in different mouse tissues. Moderately increased TFAM protein levels increase mtDNA copy number but a normal TFAM-to-mtDNA ratio is maintained resulting in unaltered mtDNA expression and normal whole animal metabolism.

Depletion of Adipocyte Leads to Lipodystrophy and Metabolic Dysregulation.

/ is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of in white adipose tissue and related metabolic diseases remains elusive. In this study, we show that adipocyte-specific knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, and insulin resistance.

Suppressed expression of LDHB promotes age-related hearing loss via aerobic glycolysis.

Age-dependent decrease of mitochondrial energy production and cellular redox imbalance play significant roles in age-related hearing loss (ARHL). Lactate dehydrogenase B (LDHB) is a key glycolytic enzyme that catalyzes the interconversion of pyruvate and lactate. LDH activity and isoenzyme patterns are known to be changed with aging, but the role of LDHB in ARHL has not been studied yet.

Expression of Cellular Receptors in the Ischemic Hemisphere of Mice with Increased Glucose Uptake.

Many previous studies have shown reduced glucose uptake in the ischemic brain. In contrast, in a permanent unilateral common carotid artery occlusion (UCCAO) mouse model, our pilot experiments using 18F-fluorodeoxyglucose positron emission tomography (FDG PET) revealed that a subset of mice exhibited conspicuously high uptake of glucose in the ipsilateral hemisphere at 1 week post-occlusion (asymmetric group), whereas other mice showed symmetric uptake in both hemispheres (symmetric group). Thus, we aimed to understand the discrepancy between the two groups.

Silica-coated magnetic nanoparticles induce glucose metabolic dysfunction in vitro via the generation of reactive oxygen species.

Nanoparticles are a useful material in biomedicine given their unique properties and biocompatibility; however, there is increasing concern regarding the potential toxicity of nanoparticles with respect to cell metabolism. Some evidence suggests that nanoparticles can disrupt glucose and energy homeostasis. In this study, we investigated the metabolomic, transcriptomic, and integrated effects of silica-coated magnetic nanoparticles containing rhodamine B isothiocyanate dye [MNPs@SiO(RITC)] on glucose metabolism in human embryonic kidney 293 (HEK293) cells.

Identification of a rare homozygous c.790C>T variation in the TFB2M gene in Korean patients with autism spectrum disorder.

Mitochondrial dysfunction and subsequent enhanced oxidative stress is implicated in the pathogenesis of autism spectrum disorder (ASD). Mitochondrial transcription factor B2 (TFB2M) is an essential protein in mitochondrial gene expression. No reports have described TFB2M mutations and variations involved in any human diseases.

Expanding the genetic code of Mus musculus.

Here we report the expansion of the genetic code of Mus musculus with various unnatural amino acids including N-acetyl-lysine. Stable integration of transgenes encoding an engineered N-acetyl-lysyl-tRNA synthetase (AcKRS)/tRNA pair into the mouse genome enables site-specific incorporation of unnatural amino acids into a target protein in response to the amber codon. We demonstrate temporal and spatial control of protein acetylation in various organs of the transgenic mouse using a recombinant green fluorescent protein (GFPuv) as a model protein.

Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid.

Mammalian mitochondrial DNA (mtDNA) is packaged by mitochondrial transcription factor A (TFAM) into mitochondrial nucleoids that are of key importance in controlling the transmission and expression of mtDNA. Nucleoid ultrastructure is poorly defined, and therefore we used a combination of biochemistry, superresolution microscopy, and electron microscopy to show that mitochondrial nucleoids have an irregular ellipsoidal shape and typically contain a single copy of mtDNA. Rotary shadowing electron microscopy revealed that nucleoid formation in vitro is a multistep process initiated by TFAM aggregation and cross-strand binding.

Perturbation of NCOA6 leads to dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a progressive heart disease characterized by left ventricular dilation and contractile dysfunction. Although many candidate genes have been identified with mouse models, few of them have been shown to be associated with DCM in humans. Germline depletion of Ncoa6, a nuclear hormone receptor coactivator, leads to embryonic lethality and heart defects.

Proposed cytotoxic mechanisms of the saffron carotenoids crocin and crocetin on cancer cell lines.

We investigated the cytotoxic activities of crocin and crocetin, 2 major carotenoids isolated from the stigma of Crocus sativus (saffron), on 5 human cancer cell lines and proposed their possible anticancer mechanisms. Crocetin, a glycosylated carotenoid, showed approximately 5- to 18-fold higher cytotoxicity than crocin, a carboxylic carotenoid (IC50 of 0.16-0.

The immune-stimulating peptide WKYMVm has therapeutic effects against ulcerative colitis.

In this study, we examined the therapeutic effects of an immune-stimulating peptide, WKYMVm, in ulcerative colitis. The administration of WKYMVm to dextran sodium sulfate (DSS)-treated mice reversed decreases in body weight, bleeding score and stool score in addition to reversing DSS-induced mucosa destruction and shortened colon. The WKYMVm-induced therapeutic effect against ulcerative colitis was strongly inhibited by a formyl peptide receptor (FPR) 2 antagonist, WRWWWW, indicating the crucial role of FPR2 in this effect.

MTERF1 binds mtDNA to prevent transcriptional interference at the light-strand promoter but is dispensable for rRNA gene transcription regulation.

Mitochondrial transcription termination factor 1, MTERF1, has been reported to couple rRNA gene transcription initiation with termination and is therefore thought to be a key regulator of mammalian mitochondrial ribosome biogenesis. The prevailing model is based on a series of observations published over the last two decades, but no in vivo evidence exists to show that MTERF1 regulates transcription of the heavy-strand region of mtDNA containing the rRNA genes. Here, we demonstrate that knockout of Mterf1 in mice has no effect on mitochondrial rRNA levels or mitochondrial translation.

TWINKLE is an essential mitochondrial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication.

Replication of the mammalian mitochondrial DNA (mtDNA) is dependent on the minimal replisome, consisting of the heterotrimeric mtDNA polymerase (POLG), the hexameric DNA helicase TWINKLE and the tetrameric single-stranded DNA-binding protein (mtSSB). TWINKLE has been shown to unwind DNA during the replication process and many disease-causing mutations have been mapped to its gene. Patients carrying Twinkle mutations develop multiple deletions of mtDNA, deficient respiratory chain function and neuromuscular symptoms.

MTERF3 regulates mitochondrial ribosome biogenesis in invertebrates and mammals.

Regulation of mitochondrial DNA (mtDNA) expression is critical for the control of oxidative phosphorylation in response to physiological demand, and this regulation is often impaired in disease and aging. We have previously shown that mitochondrial transcription termination factor 3 (MTERF3) is a key regulator that represses mtDNA transcription in the mouse, but its molecular mode of action has remained elusive. Based on the hypothesis that key regulatory mechanisms for mtDNA expression are conserved in metazoans, we analyzed Mterf3 knockout and knockdown flies.

LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs.

Regulation of mtDNA expression is critical for maintaining cellular energy homeostasis and may, in principle, occur at many different levels. The leucine-rich pentatricopeptide repeat containing (LRPPRC) protein regulates mitochondrial mRNA stability and an amino-acid substitution of this protein causes the French-Canadian type of Leigh syndrome (LSFC), a neurodegenerative disorder characterized by complex IV deficiency. We have generated conditional Lrpprc knockout mice and show here that the gene is essential for embryonic development.

Mitochondrial DNA mutations in disease and aging.

The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level.

MTERF4 regulates translation by targeting the methyltransferase NSUN4 to the mammalian mitochondrial ribosome.

Precise control of mitochondrial DNA gene expression is critical for regulation of oxidative phosphorylation capacity in mammals. The MTERF protein family plays a key role in this process, and its members have been implicated in regulation of transcription initiation and site-specific transcription termination. We now demonstrate that a member of this family, MTERF4, directly controls mitochondrial ribosomal biogenesis and translation.

Enhanced cardiomyocyte Ca(2+) cycling precedes terminal AV-block in mitochondrial cardiomyopathy Mterf3 KO mice.

Aims: Heart disease is commonly associated with altered mitochondrial function and signs of oxidative stress. This study elucidates whether primary cardiac mitochondrial dysfunction causes changes in cardiomyocyte handling of reactive oxygen species (ROS) and Ca(2+). We used a mouse model with a tissue-specific ablation of the recently discovered mtDNA transcription regulator Mterf3 (Mterf3 KO).