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Nature Reviews. Genetics Jun 2023Macroautophagy and microautophagy are highly conserved eukaryotic cellular processes that degrade cytoplasmic material in lysosomes. Both pathways involve characteristic... (Review)
Review
Macroautophagy and microautophagy are highly conserved eukaryotic cellular processes that degrade cytoplasmic material in lysosomes. Both pathways involve characteristic membrane dynamics regulated by autophagy-related proteins and other molecules, some of which are shared between the two pathways. Over the past few years, the application of new technologies, such as cryo-electron microscopy, coevolution-based structural prediction and in vitro reconstitution, has revealed the functions of individual autophagy gene products, especially in autophagy induction, membrane reorganization and cargo recognition. Concomitantly, mutations in autophagy genes have been linked to human disorders, particularly neurodegenerative diseases, emphasizing the potential pathogenic implications of autophagy defects. Accumulating genome data have also illuminated the evolution of autophagy genes within eukaryotes as well as their transition from possible ancestral elements in prokaryotes.
Topics: Humans; Cryoelectron Microscopy; Autophagy; Lysosomes; Proteins; Eukaryota; Biology
PubMed: 36635405
DOI: 10.1038/s41576-022-00562-w -
Molecular Metabolism Aug 2023Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, the low-grade chronic inflammation... (Review)
Review
BACKGROUND
Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, the low-grade chronic inflammation during aging, without overt infection, is defined as "inflammaging," which is associated with increased morbidity and mortality in the aging population. Emerging evidence suggests a bidirectional and cyclical relationship between chronic inflammation and the development of age-related conditions, such as cardiovascular diseases, neurodegeneration, cancer, and frailty. How the crosstalk between chronic inflammation and other hallmarks of aging underlies biological mechanisms of aging and age-related disease is thus of particular interest to the current geroscience research.
SCOPE OF REVIEW
This review integrates the cellular and molecular mechanisms of age-associated chronic inflammation with the other eleven hallmarks of aging. Extra discussion is dedicated to the hallmark of "altered nutrient sensing," given the scope of Molecular Metabolism. The deregulation of hallmark processes during aging disrupts the delicate balance between pro-inflammatory and anti-inflammatory signaling, leading to a persistent inflammatory state. The resultant chronic inflammation, in turn, further aggravates the dysfunction of each hallmark, thereby driving the progression of aging and age-related diseases.
MAIN CONCLUSIONS
The crosstalk between chronic inflammation and other hallmarks of aging results in a vicious cycle that exacerbates the decline in cellular functions and promotes aging. Understanding this complex interplay will provide new insights into the mechanisms of aging and the development of potential anti-aging interventions. Given their interconnectedness and ability to accentuate the primary elements of aging, drivers of chronic inflammation may be an ideal target with high translational potential to address the pathological conditions associated with aging.
Topics: Humans; Aged; Inflammation; Anti-Inflammatory Agents; Cardiovascular Diseases
PubMed: 37329949
DOI: 10.1016/j.molmet.2023.101755 -
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 Jan 2024Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it...
Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation. 2-DG: 2-deoxy-D-glucose; BECN1: beclin 1; CQ: chloroquine; CRC: colorectal cancer; DMOG: dimethyloxalylglycine; H3K18la: histone H3 lysine 18 lactylation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nala: sodium lactate; PDO: patient-derived orgnoid; PDX: patient-derived xenograft; RUBCNL/Pacer: rubicon like autophagy enhancer; SQSTM1/p62: sequestosome 1.
Topics: Humans; Autophagy; Beclin-1; Bevacizumab; Colorectal Neoplasms; Epigenesis, Genetic; Histones; Hypoxia; Lactic Acid; Lysine
PubMed: 37615625
DOI: 10.1080/15548627.2023.2249762 -
Autophagy Sep 2023The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions,...
The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions, supplies places to the hematopoietic system, and participates in complex endocrine and immune system. Not surprisingly, bones are constantly reabsorbed, formed, and remodeled under physiological conditions. Once bone metabolic homeostasis is interrupted (including inflammation, tumors, fractures, and bone metabolic diseases), the body rapidly initiates bone regeneration to maintain bone tissue structure and quality. Macroautophagy/autophagy is an essential metabolic process in eukaryotic cells, which maintains metabolic energy homeostasis and plays a vital role in bone regeneration by controlling molecular degradation and organelle renewal. One relatively new observation is that mesenchymal cells, osteoblasts, osteoclasts, osteocytes, chondrocytes, and vascularization process exhibit autophagy, and the molecular mechanisms and targets involved are being explored and updated. The role of autophagy is also emerging in degenerative diseases (intervertebral disc degeneration [IVDD], osteoarthritis [OA], etc.) and bone metabolic diseases (osteoporosis [OP], osteitis deformans, osteosclerosis). The use of autophagy regulators to modulate autophagy has benefited bone regeneration, including MTOR (mechanistic target of rapamycin kinase) inhibitors, AMPK activators, and emerging phytochemicals. The application of biomaterials (especially nanomaterials) to trigger autophagy is also an attractive research direction, which can exert superior therapeutic properties from the material-loaded molecules/drugs or the material's properties such as shape, roughness, surface chemistry, etc. All of these have essential clinical significance with the discovery of autophagy associated signals, pathways, mechanisms, and treatments in bone diseases in the future. Δψm: mitochondrial transmembrane potential AMPK: AMP-activated protein kinase ARO: autosomal recessive osteosclerosis ATF4: activating transcription factor 4 ATG: autophagy-related β-ECD: β-ecdysone BMSC: bone marrow mesenchymal stem cell ER: endoplasmic reticulum FOXO: forkhead box O GC: glucocorticoid HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha HSC: hematopoietic stem cell HSP: heat shock protein IGF1: insulin like growth factor 1 IL1B/IL-1β: interleukin 1 beta IVDD: intervertebral disc degradation LPS: lipopolysaccharide MAPK: mitogen-activated protein kinase MSC: mesenchymal stem cell MTOR: mechanistic target of rapamycin kinase NP: nucleus pulposus NPWT: negative pressure wound therapy OA: osteoarthritis OP: osteoporosis PTH: parathyroid hormone ROS: reactive oxygen species SIRT1: sirtuin 1 SIRT3: sirtuin 3 SQSTM1/p62: sequestosome 1 TNFRSF11B/OPG: TNF receptor superfamily member 11b TNFRSF11A/RANK: tumor necrosis factor receptor superfamily, member 11a TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11 TSC1: tuberous sclerosis complex 1 ULK1: unc-51 like autophagy activating kinase 1.
Topics: Humans; Autophagy; Signal Transduction; AMP-Activated Protein Kinases; Clinical Relevance; Osteoarthritis; TOR Serine-Threonine Kinases; Osteoporosis; Metabolic Diseases
PubMed: 36858962
DOI: 10.1080/15548627.2023.2186112 -
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 -
Autophagy Jul 2023Ferroptosis is a newly characterized form of programmed cell death, which is driven by the lethal accumulation of lipid peroxides catalyzed by the intracellular...
Ferroptosis is a newly characterized form of programmed cell death, which is driven by the lethal accumulation of lipid peroxides catalyzed by the intracellular bioactive iron. Targeted induction of ferroptotic cell death holds great promise for therapeutic design against other therapy-resistant cancers. To date, multiple post-translational modifications have been elucidated to impinge on the ferroptotic sensitivity. Here we report that the Ser/Thr protein kinase ATM, the major sensor of DNA double-strand break damage, is indispensable for ferroptosis execution. Pharmacological inhibition or genetic ablation of ATM significantly antagonizes ferroptosis. Besides, ATM ablation-induced ferroptotic resistance is largely independent of its downstream target TRP53, as cells defective in both and are still more insensitive to ferroptotic inducers than the single knockout cells. Mechanistically, ATM dominates the intracellular labile free iron by phosphorylating NCOA4, facilitating NCOA4-ferritin interaction and therefore sustaining ferritinophagy, a selective type of macroautophagy/autophagy specifically degrading ferritin for iron recycling. Our results thus uncover a novel regulatory circuit of ferroptosis comprising ATM-NCOA4 in orchestrating ferritinophagy and iron bioavailability. AMPK: AMP-activated protein kinase; ATM: ataxia telangiectasia mutated; BSO: buthionine sulphoximine; CDKN1A: cyclin-dependent kinase inhibitor 1A (P21); CQ: chloroquine; DFO: deferoxamine; DFP: deferiprone; Fer: ferrostatin-1; FTH1: ferritin heavy polypeptide 1; GPX4: glutathione peroxidase 4; GSH: glutathione; MEF: mouse embryonic fibroblast; NCOA4: nuclear receptor coactivator 4; PFTα: pifithrin-α; PTGS2: prostaglandin-endoperoxide synthase 2; Slc7a11: solute carrier family 7 member 11; Sul: sulfasalazine; TFRC: transferrin receptor; TRP53: transformation related protein 53.
Topics: Animals; Mice; Ferroptosis; Autophagy; Fibroblasts; Transcription Factors; Ferritins; Iron; Buthionine Sulfoximine
PubMed: 36752571
DOI: 10.1080/15548627.2023.2170960 -
Autophagy Jul 2023Eukaryotic stress granules (SGs) are highly dynamic assemblies of untranslated mRNAs and proteins that form through liquid-liquid phase separation (LLPS) under cellular...
Eukaryotic stress granules (SGs) are highly dynamic assemblies of untranslated mRNAs and proteins that form through liquid-liquid phase separation (LLPS) under cellular stress. SG formation and elimination process is a conserved cellular strategy to promote cell survival, although the precise regulation of this process is poorly understood. Here, we screened six E3 ubiquitin ligases present in SGs and identified TRIM21 (tripartite motif containing 21) as a central regulator of SG homeostasis that is highly enriched in SGs of cells under arsenite-induced oxidative stress. Knockdown of promotes SG formation whereas overexpression of inhibits the formation of physiological and pathological SGs associated with neurodegenerative diseases. TRIM21 catalyzes K63-linked ubiquitination of the SG core protein, G3BP1 (G3BP stress granule assembly factor 1), and G3BP1 ubiquitination can effectively inhibit LLPS, . Recent reports suggested the involvement of macroautophagy/autophagy, as a stress response pathway, in the regulation of SG homeostasis. We systematically investigated well-defined autophagy receptors and identified SQSTM1/p62 (sequestosome 1) and CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2) as the primary receptors that directly interact with G3BP1 during arsenite-induced stress. Endogenous SQSTM1 and CALCOCO2 localize to the periphery of SGs under oxidative stress and mediate SG elimination, as single knockout of each receptor causes accumulation of physiological and pathological SGs. Collectively, our study broadens the understanding in the regulation of SG homeostasis by showing that TRIM21 and autophagy receptors modulate SG formation and elimination respectively, suggesting the possibility of clinical targeting of these molecules in therapeutic strategies for neurodegenerative diseases. ACTB: actin beta; ALS: amyotrophic lateral sclerosis; BafA1: bafilomycin A; BECN1: beclin 1; C9orf72: C9orf72-SMCR8 complex subunit; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; Co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2-phenylindole; FTD: frontotemporal dementia; FUS: FUS RNA binding protein; G3BP1: G3BP stress granule assembly factor 1; GFP: green fluorescent protein; LLPS: liquid-liquid phase separation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NBR1: NBR1 autophagy cargo receptor; NES: nuclear export signal; OPTN: optineurin; RFP: red fluorescent protein; SQSTM1/p62: sequestosome 1; SG: stress granule; TAX1BP1: Tax1 binding protein 1; TOLLIP: toll interacting protein; TRIM21: tripartite motif containing 21; TRIM56: tripartite motif containing 56; UB: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.
Topics: Sequestosome-1 Protein; DNA Helicases; Arsenites; Stress Granules; C9orf72 Protein; Calcium; Autophagy; RNA Helicases; RNA Recognition Motif Proteins; Poly-ADP-Ribose Binding Proteins; Ubiquitination; Carrier Proteins; Apoptosis Regulatory Proteins; Homeostasis; Ubiquitins
PubMed: 36692217
DOI: 10.1080/15548627.2022.2164427 -
Autophagy Aug 2023Copper is an essential trace element in biological systems, maintaining the activity of enzymes and the function of transcription factors. However, at high... (Review)
Review
Copper is an essential trace element in biological systems, maintaining the activity of enzymes and the function of transcription factors. However, at high concentrations, copper ions show increased toxicity by inducing regulated cell death, such as apoptosis, paraptosis, pyroptosis, ferroptosis, and cuproptosis. Furthermore, copper ions can trigger macroautophagy/autophagy, a lysosome-dependent degradation pathway that plays a dual role in regulating the survival or death fate of cells under various stress conditions. Pathologically, impaired copper metabolism due to environmental or genetic causes is implicated in a variety of human diseases, such as rare Wilson disease and common cancers. Therapeutically, copper-based compounds are potential chemotherapeutic agents that can be used alone or in combination with other drugs or approaches to treat cancer. Here, we review the progress made in understanding copper metabolic processes and their impact on the regulation of cell death and autophagy. This knowledge may help in the design of future clinical tools to improve cancer diagnosis and treatment. ACSL4, acyl-CoA synthetase long chain family member 4; AIFM1/AIF, apoptosis inducing factor mitochondria associated 1; AIFM2, apoptosis inducing factor mitochondria associated 2; ALDH, aldehyde dehydrogenase; ALOX, arachidonate lipoxygenase; AMPK, AMP-activated protein kinase; APAF1, apoptotic peptidase activating factor 1; ATF4, activating transcription factor 4; ATG, autophagy related; ATG13, autophagy related 13; ATG5, autophagy related 5; ATOX1, antioxidant 1 copper chaperone; ATP, adenosine triphosphate; ATP7A, ATPase copper transporting alpha; ATP7B, ATPase copper transporting beta; BAK1, BCL2 antagonist/killer 1; BAX, BCL2 associated X apoptosis regulator; BBC3/PUMA, BCL2 binding component 3; BCS, bathocuproinedisulfonic acid; BECN1, beclin 1; BID, BH3 interacting domain death agonist; BRCA1, BRCA1 DNA repair associated; BSO, buthionine sulphoximine; CASP1, caspase 1; CASP3, caspase 3; CASP4/CASP11, caspase 4; CASP5, caspase 5; CASP8, caspase 8; CASP9, caspase 9; CCS, copper chaperone for superoxide dismutase; CD274/PD-L1, CD274 molecule; CDH2, cadherin 2; CDKN1A/p21, cyclin dependent kinase inhibitor 1A; CDKN1B/p27, cyclin-dependent kinase inhibitor 1B; COMMD10, COMM domain containing 10; CoQ10, coenzyme Q 10; CoQ10H2, reduced coenzyme Q 10; COX11, cytochrome c oxidase copper chaperone COX11; COX17, cytochrome c oxidase copper chaperone COX17; CP, ceruloplasmin; CYCS, cytochrome c, somatic; DBH, dopamine beta-hydroxylase; DDIT3/CHOP, DNA damage inducible transcript 3; DLAT, dihydrolipoamide S-acetyltransferase; DTC, diethyldithiocarbamate; EIF2A, eukaryotic translation initiation factor 2A; EIF2AK3/PERK, eukaryotic translation initiation factor 2 alpha kinase 3; ER, endoplasmic reticulum; ESCRT-III, endosomal sorting complex required for transport-III; ETC, electron transport chain; FABP3, fatty acid binding protein 3; FABP7, fatty acid binding protein 7; FADD, Fas associated via death domain; FAS, Fas cell surface death receptor; FASL, Fas ligand; FDX1, ferredoxin 1; GNAQ/11, G protein subunit alpha q/11; GPX4, glutathione peroxidase 4; GSDMD, gasdermin D; GSH, glutathione; HDAC, histone deacetylase; HIF1, hypoxia inducible factor 1; HIF1A, hypoxia inducible factor 1 subunit alpha; HMGB1, high mobility group box 1; IL1B, interleukin 1 beta; IL17, interleukin 17; KRAS, KRAS proto-oncogene, GTPase; LOX, lysyl oxidase; LPCAT3, lysophosphatidylcholine acyltransferase 3; MAP1LC3, microtubule associated protein 1 light chain 3; MAP2K1, mitogen-activated protein kinase kinase 1; MAP2K2, mitogen-activated protein kinase kinase 2; MAPK, mitogen-activated protein kinases; MAPK14/p38, mitogen-activated protein kinase 14; MEMO1, mediator of cell motility 1; MT-CO1/COX1, mitochondrially encoded cytochrome c oxidase I; MT-CO2/COX2, mitochondrially encoded cytochrome c oxidase II; MTOR, mechanistic target of rapamycin kinase; MTs, metallothioneins; NAC, N-acetylcysteine; NFKB/NF-Κb, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; NPLOC4/NPL4, NPL4 homolog ubiquitin recognition factor; PDE3B, phosphodiesterase 3B; PDK1, phosphoinositide dependent protein kinase 1; PHD, prolyl-4-hydroxylase domain; PIK3C3/VPS34, phosphatidylinositol 3-kinase catalytic subunit type 3; PMAIP1/NOXA, phorbol-12-myristate-13-acetate-induced protein 1; POR, cytochrome P450 oxidoreductase; PUFA-PL, PUFA of phospholipids; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; SCO1, synthesis of cytochrome C oxidase 1; SCO2, synthesis of cytochrome C oxidase 2; SLC7A11, solute carrier family 7 member 11; SLC11A2/DMT1, solute carrier family 11 member 2; SLC31A1/CTR1, solute carrier family 31 member 1; SLC47A1, solute carrier family 47 member 1; SOD1, superoxide dismutase; SP1, Sp1 transcription factor; SQSTM1/p62, sequestosome 1; STEAP4, STEAP4 metalloreductase; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TFEB, transcription factor EB; TM, tetrathiomolybdate; TP53/p53, tumor protein p53; TXNRD1, thioredoxin reductase 1; UCHL5, ubiquitin C-terminal hydrolase L5; ULK1, Unc-51 like autophagy activating kinase 1; ULK1, unc-51 like autophagy activating kinase 1; ULK2, unc-51 like autophagy activating kinase 2; USP14, ubiquitin specific peptidase 14; VEGF, vascular endothelial gro wth factor; XIAP, X-linked inhibitor of apoptosis.
Topics: Humans; Autophagy; Tumor Suppressor Protein p53; Apoptosis Inducing Factor; Copper; Ubiquinone; Electron Transport Complex IV; Autophagy-Related Protein-1 Homolog; Proto-Oncogene Proteins p21(ras); Apoptosis; Caspases; Hypoxia-Inducible Factor 1; Superoxide Dismutase; Neoplasms; Ions; Proto-Oncogene Proteins c-bcl-2
PubMed: 37055935
DOI: 10.1080/15548627.2023.2200554 -
Nature Communications Jan 2024Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective...
Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.
Topics: Humans; Mice; Animals; Aged; DNA, Mitochondrial; Mitophagy; Mitochondria; Inflammation; Nucleotidyltransferases; Aging
PubMed: 38280852
DOI: 10.1038/s41467-024-45044-1