Lactylation and Central Nervous System Diseases DOI Creative Commons
Ye Chen, Dongqiong Xiao, Xihong Li

et al.

Brain Sciences, Journal Year: 2025, Volume and Issue: 15(3), P. 294 - 294

Published: March 11, 2025

As the final product of glycolysis, lactate serves as an energy substrate, metabolite, and signaling molecule in various diseases mediates lactylation, epigenetic modification that occurs under both physiological pathological conditions. Lactylation is a crucial mechanism by which exerts its functions, participating vital biological activities such glycolysis-related cellular macrophage polarization, nervous system regulation. links metabolic regulation to central (CNS) diseases, traumatic brain injury, Alzheimer’s disease, acute ischemic stroke, schizophrenia, revealing diverse functions lactylation CNS. In future, further exploration lactylation-associated enzymes proteins needed develop specific inhibitors or activators, could provide new tools strategies for treatment CNS diseases.

Language: Английский

Lactylation in cancer: Current understanding and challenges DOI
Hongde Li, Linchong Sun, Gao Ping

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(11), P. 1803 - 1807

Published: Oct. 10, 2024

Language: Английский

Citations

20
APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer’s disease DOI Creative Commons
Qiuyun Tian, Junjie Li, Bin Wu

et al.

Journal of Clinical Investigation, Journal Year: 2025, Volume and Issue: 135(1)

Published: Jan. 1, 2025

Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as novel PTM, is implicated occurrence and development AD. However, whether how APP contributes to both pathogenesis cognitive function AD remains unknown. Here, we observed reduction patients model mice cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) crucial site for lactylation, influencing amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation slowed down deficits vivo. Mechanistically, APPK612T appeared facilitate trafficking metabolism. lactylated entering endosome inhibited its binding BACE1, suppressing subsequent cleavage. Instead, it promoted interaction between CD2-associated (CD2AP), thereby accelerating endosomal-lysosomal degradation pathway APP. In APP23/PS45 double-transgenic mouse AD, APP-Kla was susceptible L-lactate regulation, which Aβ pathology repaired spatial learning memory deficits. Thus, these findings suggest targeting may be promising therapeutic strategy humans.

Language: Английский

Citations

3
Recommendations for mitochondria transfer and transplantation nomenclature and characterization DOI Creative Commons
Jonathan R. Brestoff, Keshav K. Singh, Katia Aquilano

et al.

Nature Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

Language: Английский

Citations

3
The Lactate‐Primed KAT8‒PCK2 Axis Exacerbates Hepatic Ferroptosis During Ischemia/Reperfusion Injury by Reprogramming OXSM‐Dependent Mitochondrial Fatty Acid Synthesis DOI Creative Commons
Jingsheng Yuan, Mingyang Yang,

Zhenru Wu

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Abstract Recipients often suffer from hyperlactatemia during liver transplantation (LT), but whether exacerbates hepatic ischemia‐reperfusion injury (IRI) after donor implantation remains unclear. Here, the role of in IRI is explored. In this work, found to exacerbate ferroptosis IRI. Lactate‐primed lysine acetyltransferase 8 (KAT8) determined directly lactylate mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) at Lys100 and augments PCK2 kinase activity. By using gene‐edited mice, evidence indicating that generated. Mechanistically, acts as a critical inducer by competitively inhibiting Parkin‐mediated polyubiquitination 3‐oxoacyl‐ACP synthase (OXSM), thereby leading metabolic remodeling fatty acid synthesis (mtFAS) potentiation oxidative phosphorylation tricarboxylic cycle. More importantly, targeting demonstrated markedly ameliorate hyperlactatemia‐mediated Collectively, findings support use therapeutics suppress patients with LT.

Language: Английский

Citations

2
Lactylation of histone by BRD4 regulates astrocyte polarization after experimental subarachnoid hemorrhage DOI Creative Commons
Fan Zhang,

Jian Zhou,

Peng Lü

et al.

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: July 30, 2024

Under subarachnoid hemorrhage (SAH) conditions, astrocytes undergo a marked intensification of glycolytic activity, resulting in the generation substantial amounts lactate to maintain energy demand for neurons and other brain cells. Lactate has garnered increasing attention recent years because its emerging role critical biological processes such as inflammation regulation neuroprotection, particularly through histone lactylation. Bromodomain-containing protein 4 (BRD4) plays crucial maintaining neural development promoting memory formation central nervous system. Nonetheless, function regulatory mechanism BRD4 lactylation following SAH remain elusive. Our findings indicate that BRD4, epigenetic regulator, definitive Both vitro vivo, these results demonstrated targeted silencing can significantly reduce H4K8la lactylation, thereby aggravating A1 polarization ultimately affecting recovery prognosis mice after SAH. In summary, pivotal modulating astrocyte via Targeting this might offer an efficient therapeutic strategy

Language: Английский

Citations

9
The role of astrocyte metabolic reprogramming in ischemic stroke (Review) DOI Creative Commons
Weixin Chen, Tangyou Mao, Rui Ma

et al.

International Journal of Molecular Medicine, Journal Year: 2025, Volume and Issue: 55(3)

Published: Jan. 21, 2025

Ischemic stroke, a leading cause of disability and mortality worldwide, is characterized by the sudden loss blood flow in specific area brain. Intravenous thrombolysis with recombinant tissue plasminogen activator only approved pharmacological treatment for acute ischemic stroke; however, aforementioned has significant clinical limitations, thus there an urgent need development novel mechanisms therapeutic strategies stroke. Astrocytes, abundant versatile cells central nervous system, offer crucial support to neurons nutritionally, structurally physically. They also contribute blood‑brain barrier formation regulate neuronal extracellular ion concentrations. Accumulated evidence revealed involvement astrocytes regulation host neurotransmitter metabolism, immune response repair, different metabolic characteristics can process suggesting that targeted astrocyte reprogramming may prognosis In present review, current understanding multifaceted along its regulatory factors pathways, as well promote polarization balance, which hold promise immunometabolism‑targeted therapies were summarized.

Language: Английский

Citations

1
Non-histone lactylation: unveiling its functional significance DOI Creative Commons
Peng Shi, Yongjie Ma, Shangzhe Zhang

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 24, 2025

Lactylation, a newly discovered protein posttranslational modification (PTM) in 2019, primarily occurs on lysine residues. Lactylation of histones was initially identified, and subsequent studies have increasingly demonstrated its widespread presence non-histone proteins. Recently, high-throughput proteomics identified large number lactylated proteins sites, revealing their global regulatory role disease development. Notably, this is catalyzed by lactyltransferase reversed delactylase, with numerous new enzymes, such as AARS1/2, reported to be involved. Specifically, these revealed how lactylation exerts influence through alterations spatial conformation, molecular interactions, enzyme activity subcellular localization. Indeed, implicated various physiological pathological processes, including tumor development, cardiovascular cerebrovascular diseases, immune cell activation psychiatric disorders. This review provides the latest advancements research roles lactylation, highlighting crucial scientific importance for future studies.

Language: Английский

Citations

1
Multi-omic profiling of sarcopenia identifies disrupted branched-chain amino acid catabolism as a causal mechanism and therapeutic target DOI
Xinrong Zuo, Rui Zhao, Minming Wu

et al.

Nature Aging, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Language: Английский

Citations

1
JZL-184 Alleviate Neurological Impairment through Regulation of Mitochondrial Transfer and Lipid Droplet Accumulation after Cardiac Arrest DOI
Qiang Zhang, Chenyu Zhang, Yuanzheng Lu

et al.

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 24, 2024

Language: Английский

Citations

7
Exploring the prognostic significance of lactate-mitochondria-related genes in prostate cancer DOI Creative Commons
Yuan Wang,

Ronghui Chen,

Fengle Jiang

et al.

Frontiers in Genetics, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 6, 2025

Prostate cancer (PCa) is a common and serious health issue among older men globally. Metabolic reprogramming, particularly involving lactate mitochondria, plays key role in PCa progression, but studies linking these factors to prognosis are limited. To identify novel prognostic markers of based on lactate-mitochondria-related genes (LMRGs), RNA sequencing data clinical information from The Cancer Genome Atlas (TCGA) the cBioPortal database were used construct risk signature. Here, we established nine-LMRG signature for PCa, Kaplan-Meier curves confirmed worse high-risk subgroups TCGA dataset. Meanwhile, nomogram that effectively predicts patients was also constructed. Next, close associations between immune microenvironment examined clarify LMRGs shaping landscape. Furthermore, as only lactate-related gene nine genes, myeloperoxidase (MPO) identified factor mediates production vitro vivo through attenuation glycolytic pathway. More importantly, MPO significantly inhibited cell migration, invasion, epithelial-mesenchymal transition (EMT), indicating its potential an anticancer gene. Additionally, with high expression highly sensitive chemotherapeutic agents mitochondrial inhibitors, highlighting improved therapeutic strategy management.

Language: Английский

Citations

0