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Autophagy Nov 2023LAMP2 (lysosomal associated membrane protein 2) is one of the major protein components of the lysosomal membrane. There currently exist three LAMP2 isoforms, LAMP2A,... (Review)
Review
LAMP2 (lysosomal associated membrane protein 2) is one of the major protein components of the lysosomal membrane. There currently exist three LAMP2 isoforms, LAMP2A, LAMP2B and LAMP2C, and they vary in distribution and function. LAMP2A serves as a receptor and channel for transporting cytosolic proteins in a process called chaperone-mediated autophagy (CMA). LAMP2B is required for autophagosome-lysosome fusion in cardiomyocytes and is one of the components of exosome membranes. LAMP2C is primarily implicated in a novel type of autophagy in which nucleic acids are taken up into lysosomes for degradation. In this review, the current evidence for the function of each LAMP2 isoform in various pathophysiological processes and human diseases, as well as their possible mechanisms, are comprehensively summarized. We discuss the evolutionary patterns of the three isoforms in vertebrates and provide technical guidance on investigating these isoforms. We are also concerned with the newly arising questions in this particular research area that remain unanswered. Advances in the functions of the three LAMP2 isoforms will uncover new links between lysosomal dysfunction, autophagy and human diseases. ACSL4: acyl-CoA synthetase long-chain family member 4; AD: Alzheimer disease; Ag: antigens; APP: amyloid beta precursor protein; ATG14: autophagy related 14; AVSF: autophagic vacuoles with unique sarcolemmal features; BBC3/PUMA: BCL2 binding component 3; CCD: C-terminal coiled coil domain; CMA: chaperone-mediated autophagy; CVDs: cardiovascular diseases; DDIT4/REDD1: DNA damage inducible transcript 4; ECs: endothelial cells; ER: endoplasmic reticulum; ESCs: embryonic stem cells; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA/β-glucocerebrosidase: glucosylceramidase beta; GSCs: glioblastoma stem cells; HCC: hepatocellular carcinoma; HD: Huntington disease; HSCs: hematopoietic stem cells; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; IL3: interleukin 3; IR: ischemia-reperfusion; LAMP2: lysosomal associated membrane protein 2; LDs: lipid droplets; LRRK2: leucine rich repeat kinase 2; MA: macroautophagy; MHC: major histocompatibility complex; MST1: macrophage stimulating 1; NAFLD: nonalcoholic fatty liver disease; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NLRP3: NLR family pyrin domain containing 3; PARK7: Parkinsonism associated deglycase; PD: Parkinson disease; PEA15/PED: proliferation and apoptosis adaptor protein 15; PKM/PKM2: pyruvate kinase M1/2; RA: rheumatoid arthritis; RARA: retinoic acid receptor alpha; RCAN1: regulator of calcineurin 1; RCC: renal cell carcinoma; RDA: RNautophagy and DNautophagy; RNAi: RNA interference; RND3: Rho Family GTPase 3; SG-NOS3/eNOS: deleterious glutathionylated NOS3; SLE: systemic lupus erythematosus; TAMs: tumor-associated macrophages; TME: tumor microenvironment; UCHL1: ubiquitin C-terminal hydrolase L1; VAMP8: vesicle associated membrane protein 8.
Topics: Animals; Humans; Autophagy; Lysosomal-Associated Membrane Protein 2; Amyloid beta-Peptides; Carcinoma, Hepatocellular; Endothelial Cells; Liver Neoplasms; Lysosomes; Protein Isoforms; Tumor Microenvironment; Apoptosis Regulatory Proteins
PubMed: 37469132
DOI: 10.1080/15548627.2023.2235196 -
Autophagy Dec 2023Lactate is a glycolysis product that is produced from pyruvate by LDH (lactate dehydrogenase) and plays an important role in physiological and pathological processes....
Lactate is a glycolysis product that is produced from pyruvate by LDH (lactate dehydrogenase) and plays an important role in physiological and pathological processes. However, whether lactate regulates autophagy is still unknown. We recently reported that LDHA is phosphorylated at serine 196 by ULK1 (unc-51 like kinase 1) under nutrient-deprivation conditions, promoting lactate production. Then, lactate mediates PIK3C3/VPS34 lactylation at lysine 356 and lysine 781 via acyltransferase KAT5/TIP60. PIK3C3/VPS34 lactylation enhances the association of PIK3C3/VPS34 with BECN1 (beclin 1, autophagy related), ATG14 and UVRAG, increases PIK3C3/VPS34 lipid kinase activity, promotes macroautophagy/autophagy and facilitates the endolysosomal degradation pathway. PIK3C3/VPS34 hyperlactylation induces autophagy and plays an essential role in skeletal muscle homeostasis and cancer progression. Overall, this study describes an autophagy regulation mechanism and the integration of two highly conserved life processes: glycolysis and autophagy.
Topics: Autophagy; Autophagy-Related Proteins; Lactic Acid; Lysine; Beclin-1; Class III Phosphatidylinositol 3-Kinases; Glycolysis
PubMed: 37565742
DOI: 10.1080/15548627.2023.2246356 -
PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.Nature Metabolism Nov 2023Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate...
Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4 stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer.
Topics: Lactic Acid; Protein Kinases; Up-Regulation; Cellular Senescence; Neoplasms
PubMed: 37903887
DOI: 10.1038/s42255-023-00912-w -
Advanced Science (Weinheim,... Nov 2023Mitochondrial bioenergetic deficits and their resulting glucose hypometabolism are the key pathophysiological modulators that promote neurodegeneration. However, there...
Mitochondrial bioenergetic deficits and their resulting glucose hypometabolism are the key pathophysiological modulators that promote neurodegeneration. However, there are no specific potential molecules that have been identified to treat neurological diseases by regulating energy metabolism and repairing mitochondrial damage. Pyruvate dehydrogenase (PDH) complex (PDC), which can be phosphorylated by pyruvate dehydrogenase kinase (PDK), is the gate-keeping enzyme for mitochondrial glucose oxidation. In this study, a small-molecule scutellarin (SG) is discovered that can significantly alleviate the neuropathological changes in hippocampal CA1 of cerebral hypoperfusion model rats, rescued the morphological changes of abnormal mitochondria, and restored mitochondrial homeostasis. Mitochondrial proteomics, energy metabolism monitoring, and C-metabolic flux analysis targeted SG activity on PDK2, thus regulating PDK-PDC-mediated glycolytic metabolism to TCA cycle during mitochondrial OXPHOS damage. The knockdown of PDK2 in the SK-N-SH cells validated that SG could rescue mitochondrial damage via the PDK-PDC axis, promote the MMP level and reduce the mitochondria-dependent apoptosis. Collectively, this study explored the novel therapeutic approach: the PDK-PDC axis for neurological injury and cognitive impairment and uncovered the effect of SG on mitochondrial protection via the PDK-PDC axis and mitochondrial glucose oxidation. The findings indicate that active components ameliorating mitochondrial bioenergetic deficits could be of significant value for neurological disease therapy.
Topics: Rats; Animals; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Protein Serine-Threonine Kinases; Glucose; Mitochondria
PubMed: 37750289
DOI: 10.1002/advs.202303584 -
Signal Transduction and Targeted Therapy Aug 2023Reprogrammed cellular metabolism is essential for maintaining cancer stem cells (CSCs) state. Here, we report that mitochondrial D-lactate catabolism is a necessary...
Reprogrammed cellular metabolism is essential for maintaining cancer stem cells (CSCs) state. Here, we report that mitochondrial D-lactate catabolism is a necessary initiating oncogenic event during tumorigenesis of esophageal squamous cell carcinoma (ESCC). We discover that cyclin-dependent kinase 7 (CDK7) phosphorylates nuclear Yes-associated protein 1 (YAP) at S127 and S397 sites and enhances its transcription function, which promotes D-lactate dehydrogenase (LDHD) protein expression. Moreover, LDHD is enriched significantly in ESCC-CSCs rather than differentiated tumor cells and high LDHD status is connected with poor prognosis in ESCC patients. Mechanistically, the CDK7-YAP-LDHD axis helps ESCC-CSCs escape from ferroptosis induced by D-lactate and generates pyruvate to satisfy energetic demands for their elevated self-renewal potential. Hence, we conclude that esophageal CSCs adopt a D-lactate elimination and pyruvate accumulation mode dependent on CDK7-YAP-LDHD axis, which drives stemness-associated hallmarks of ESCC-CSCs. Reasonably, targeting metabolic checkpoints may serve as an effective strategy for ESCC therapy.
Topics: Humans; Adaptor Proteins, Signal Transducing; Cell Line, Tumor; Cyclin-Dependent Kinases; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Ferroptosis; L-Lactate Dehydrogenase; Lactic Acid; Neoplastic Stem Cells; Transcription Factors
PubMed: 37582812
DOI: 10.1038/s41392-023-01555-9 -
Cardiovascular Research Jul 2023Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic...
AIMS
Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear.
METHODS AND RESULTS
Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe-/- mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque.
CONCLUSIONS
We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe-/- mice. These results point toward a promising treatment to combat atherosclerosis.
Topics: Animals; Humans; Mice; Atherosclerosis; Cardiovascular Diseases; Heart Disease Risk Factors; Inflammation; Mice, Knockout, ApoE; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Risk Factors
PubMed: 36866436
DOI: 10.1093/cvr/cvad038 -
Advanced Science (Weinheim,... Nov 2023Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that...
Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that ovariectomized mice exhibit reduced blood vessel density in the bone and reduced expression of the endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Endothelial cell (EC)-specific deletion of Pkm2 impairs osteogenesis and worsens osteoporosis in mice. This is attributed to the impaired ability of bone mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. Mechanistically, EC-specific deletion of Pkm2 reduces serum lactate levels secreted by ECs, which affect histone lactylation in BMSCs. Using joint CUT&Tag and RNA sequencing analyses, collagen type I alpha 2 chain (COL1A2), cartilage oligomeric matrix protein (COMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7 like 2 (TCF7L2) as osteogenic genes regulated by histone H3K18la lactylation are identified. PKM2 overexpression in ECs, lactate addition, and exercise restore the phenotype of endothelial PKM2-deficient mice. Furthermore, serum metabolomics indicate that patients with osteoporosis have relatively low lactate levels. Additionally, histone lactylation and related osteogenic genes of BMSCs are downregulated in patients with osteoporosis. In conclusion, glycolysis in ECs fuels BMSC differentiation into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis by increasing serum lactate levels.
Topics: Humans; Animals; Mice; Histones; Lactic Acid; Osteoporosis; Mesenchymal Stem Cells; Endothelial Cells
PubMed: 37752768
DOI: 10.1002/advs.202301300 -
Annals of the Rheumatic Diseases Sep 2023The activator protein-1 (AP-1) transcription factor component c-Fos regulates chondrocyte proliferation and differentiation, but its involvement in osteoarthritis (OA)...
OBJECTIVES
The activator protein-1 (AP-1) transcription factor component c-Fos regulates chondrocyte proliferation and differentiation, but its involvement in osteoarthritis (OA) has not been functionally assessed.
METHODS
c-Fos expression was evaluated by immunohistochemistry on articular cartilage sections from patients with OA and mice subjected to the destabilisation of the medial meniscus (DMM) model of OA. Cartilage-specific c-Fos knockout (c-Fos) mice were generated by crossing to mice. Articular cartilage was evaluated by histology, immunohistochemistry, RNA sequencing (RNA-seq), quantitative reverse transcription PCR (qRT-PCR) and metabolic enzyme assays. The effect of dichloroacetic acid (DCA), an inhibitor of pyruvate dehydrogenase kinase (Pdk), was assessed in c-Fos mice subjected to DMM.
RESULTS
FOS-positive chondrocytes were increased in human and murine OA cartilage during disease progression. Compared with c-Fos mice, c-Fos mice exhibited exacerbated DMM-induced cartilage destruction. Chondrocytes lacking c-Fos proliferate less, have shorter collagen fibres and reduced cartilage matrix. Comparative RNA-seq revealed a prominent anaerobic glycolysis gene expression signature. Consistently decreased pyruvate dehydrogenase (Pdh) and elevated lactate dehydrogenase (Ldh) enzymatic activities were measured , which are likely due to higher expression of hypoxia-inducible factor-1α, , and Pdk1 in chondrocytes. treatment of c-Fos mice with DCA restored Pdh/Ldh activity, chondrocyte proliferation, collagen biosynthesis and decreased cartilage damage after DMM, thereby reverting the deleterious effects of c-Fos inactivation.
CONCLUSIONS
c-Fos modulates cellular bioenergetics in chondrocytes by balancing pyruvate flux between anaerobic glycolysis and the tricarboxylic acid cycle in response to OA signals. We identify a novel metabolic adaptation of chondrocytes controlled by c-Fos-containing AP-1 dimers that could be therapeutically relevant.
Topics: Animals; Humans; Mice; Cartilage, Articular; Chondrocytes; Collagen; Disease Models, Animal; Osteoarthritis; Transcription Factor AP-1; Proto-Oncogene Proteins c-fos
PubMed: 37344157
DOI: 10.1136/ard-2023-224002