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Frontiers in Pharmacology 2024Retinal pigment epithelial cell and neuroretinal damage in age-related macular degeneration (AMD) can lead to serious visual impairments and blindness. Studies have... (Review)
Review
Retinal pigment epithelial cell and neuroretinal damage in age-related macular degeneration (AMD) can lead to serious visual impairments and blindness. Studies have shown that mitophagy, a highly specialized cellular degradation system, is implicated in the pathogenesis of AMD. Mitophagy selectively eliminates impaired or non-functioning mitochondria via several pathways, such as the phosphatase and tensin homolog-induced kinase 1/Parkin, BCL2-interacting protein 3 and NIP3-like protein X, FUN14 domain-containing 1, and AMP-activated protein kinase pathways. This has a major impact on the maintenance of mitochondrial homeostasis. Therefore, the regulation of mitophagy could be a promising therapeutic strategy for AMD. Traditional Chinese medicine (TCM) uses natural products that could potentially prevent and treat various diseases, such as AMD. This review aims to summarize recent findings on mitophagy regulation pathways and the latest progress in AMD treatment targeting mitophagy, emphasizing methods involving TCM.
PubMed: 38828456
DOI: 10.3389/fphar.2024.1410998 -
Acta Pharmaceutica Sinica. B Jun 2024The clinical efficacy of current cancer therapies falls short, and there is a pressing demand to integrate new targets with conventional therapies. Autophagy, a highly... (Review)
Review
The clinical efficacy of current cancer therapies falls short, and there is a pressing demand to integrate new targets with conventional therapies. Autophagy, a highly conserved self-degradation process, has received considerable attention as an emerging therapeutic target for cancer. With the rapid development of nanomedicine, nanomaterials have been widely utilized in cancer therapy due to their unrivaled delivery performance. Hence, considering the potential benefits of integrating autophagy and nanotechnology in cancer therapy, we outline the latest advances in autophagy-based nanotherapeutics. Based on a brief background related to autophagy and nanotherapeutics and their impact on tumor progression, the feasibility of autophagy-based nanotherapeutics for cancer treatment is demonstrated. Further, emerging nanotherapeutics developed to modulate autophagy are reviewed from the perspective of cell signaling pathways, including modulation of the mammalian target of rapamycin (mTOR) pathway, autophagy-related (ATG) and its complex expression, reactive oxygen species (ROS) and mitophagy, interference with autophagosome-lysosome fusion, and inhibition of hypoxia-mediated autophagy. In addition, combination therapies in which nano-autophagy modulation is combined with chemotherapy, phototherapy, and immunotherapy are also described. Finally, the prospects and challenges of autophagy-based nanotherapeutics for efficient cancer treatment are envisioned.
PubMed: 38828133
DOI: 10.1016/j.apsb.2024.03.019 -
Journal of Lipid and Atherosclerosis May 2024The aim of this study was to evaluate the effect of the m.15059G>A mitochondrial nonsense mutation on cellular functions related to atherosclerosis, such as lipidosis,...
OBJECTIVE
The aim of this study was to evaluate the effect of the m.15059G>A mitochondrial nonsense mutation on cellular functions related to atherosclerosis, such as lipidosis, pro-inflammatory response, and mitophagy. Heteroplasmic mutations have been proposed as a potential cause of mitochondrial dysfunction, potentially disrupting the innate immune response and contributing to the chronic inflammation associated with atherosclerosis.
METHODS
The human monocytic cell line THP-1 and cytoplasmic hybrid cell line TC-HSMAM1 were used. An original approach based on the CRISPR/Cas9 system was developed and used to eliminate mitochondrial DNA (mtDNA) copies carrying the m.15059G>A mutation in the gene. The expression levels of genes encoding enzymes related to cholesterol metabolism were analyzed using quantitative polymerase chain reaction. Pro-inflammatory cytokine secretion was assessed using enzyme-linked immunosorbent assays. Mitophagy in cells was detected using confocal microscopy.
RESULTS
In contrast to intact TC-HSMAM1 cybrids, Cas9-TC-HSMAM1 cells exhibited a decrease in fatty acid synthase () gene expression following incubation with atherogenic low-density lipoprotein. TC-HSMAM1 cybrids were found to have defective mitophagy and an inability to downregulate the production of pro-inflammatory cytokines (to establish immune tolerance) upon repeated lipopolysaccharide stimulation. Removal of mtDNA harboring the m.15059G>A mutation resulted in the re-establishment of immune tolerance and the activation of mitophagy in the cells under investigation.
CONCLUSION
The m.15059G>A mutation was found to be associated with defective mitophagy, immune tolerance, and impaired metabolism of intracellular lipids due to upregulation of in monocytes and macrophages.
PubMed: 38826184
DOI: 10.12997/jla.2024.13.2.166 -
Journal of Experimental & Clinical... Jun 2024Studies have shown that oxidative stress and its resistance plays important roles in the process of tumor metastasis, and mitochondrial dysfunction caused by...
BACKGROUND
Studies have shown that oxidative stress and its resistance plays important roles in the process of tumor metastasis, and mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) damage is an important molecular event in oxidative stress. In lung cancer, the normal fibroblasts (NFs) are activated as cancer-associated fibroblasts (CAFs), and act in the realms of the tumor microenvironment (TME) with consequences for tumor growth and metastasis. However, its activation mechanism and whether it participates in tumor metastasis through antioxidative stress remain unclear.
METHODS
The role and signaling pathways of tumor cell derived extracellular vesicles (EVs) activating NFs and the characteristic of induced CAFs (iCAFs) were measured by the transmission electron microscopy, nanoparticle tracking analysis, immunofluorescence, collagen contraction assay, quantitative PCR, immunoblotting, luciferase reporter assay and mitochondrial membrane potential detection. Mitochondrial genome and single nucleotide polymorphism sequencing were used to investigate the transport of mtDNA from iCAFs to ρ cells, which were tumor cells with mitochondrial dysfunction caused by depletion of mtDNA. Further, the effects of iCAFs on mitochondrial function, growth and metastasis of tumor cells were analysed in co-culture models both in vitro and in vivo, using succinate dehydrogenase, glutathione and oxygen consumption rate measurements, CCK-8 assay, transwell assay, xenotransplantation and metastasis experiments as well as in situ hybridization and immunohistochemistry.
RESULTS
Our findings revealed that EVs derived from high-metastatic lung cancer cells packaged miR-1290 that directly targets MT1G, leading to activation of AKT signaling in NFs and inducing NFs conversion to CAFs. The iCAFs exhibit higher levels of autophagy and mitophagy and more mtDNA release, and reactive oxygen species (ROS) could further promote this process. After cocultured with the conditioned medium (CM) of iCAFs, the ρ cells may restore its mitochondrial function by acquisition of mtDNA from CAFs, and further promotes tumor metastasis.
CONCLUSIONS
These results elucidate a novel mechanism that CAFs activated by tumor-derived EVs can promote metastasis by transferring mtDNA and restoring mitochondrial function of tumor cells which result in resistance of oxidative stress, and provide a new therapeutic target for lung cancer metastasis.
Topics: Extracellular Vesicles; Lung Neoplasms; Humans; DNA, Mitochondrial; Cancer-Associated Fibroblasts; Mice; Animals; Mitophagy; Neoplasm Metastasis; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38825680
DOI: 10.1186/s13046-024-03077-w -
Biological Research Jun 2024It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and... (Review)
Review
It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.
Topics: Humans; Hormesis; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Animals; Osteoarthritis; Signal Transduction
PubMed: 38824571
DOI: 10.1186/s40659-024-00494-1 -
Cellular & Molecular Biology Letters May 2024Hepatic stellate cells (HSCs) play a crucial role in the development of fibrosis in non-alcoholic fatty liver disease (NAFLD). Small extracellular vesicles (sEV) act as...
BACKGROUND
Hepatic stellate cells (HSCs) play a crucial role in the development of fibrosis in non-alcoholic fatty liver disease (NAFLD). Small extracellular vesicles (sEV) act as mediators for intercellular information transfer, delivering various fibrotic factors that impact the function of HSCs in liver fibrosis. In this study, we investigated the role of lipotoxic hepatocyte derived sEV (LTH-sEV) in HSCs activation and its intrinsic mechanisms.
METHODS
High-fat diet (HFD) mice model was constructed to confirm the expression of LIMA1. The relationship between LIMA1-enriched LTH-sEV and LX2 activation was evaluated by measurement of fibrotic markers and related genes. Levels of mitophagy were detected using mt-keima lentivirus. The interaction between LIMA1 and PINK1 was discovered through database prediction and molecular docking. Finally, sEV was injected to investigate whether LIMA1 can accelerate HFD induced liver fibrosis in mice.
RESULTS
LIMA1 expression was upregulated in lipotoxic hepatocytes and was found to be positively associated with the expression of the HSCs activation marker α-SMA. Lipotoxicity induced by OPA led to an increase in both the level of LIMA1 protein in LTH-sEV and the release of LTH-sEV. When HSCs were treated with LTH-sEV, LIMA1 was observed to hinder LX2 mitophagy while facilitating LX2 activation. Further investigation revealed that LIMA1 derived from LTH-sEV may inhibit PINK1-Parkin-mediated mitophagy, consequently promoting HSCs activation. Knocking down LIMA1 significantly attenuates the inhibitory effects of LTH-sEV on mitophagy and the promotion of HSCs activation.
CONCLUSIONS
Lipotoxic hepatocyte-derived LIMA1-enriched sEVs play a crucial role in promoting HSCs activation in NAFLD-related liver fibrosis by negatively regulating PINK1 mediated mitophagy. These findings provide new insights into the pathological mechanisms involved in the development of fibrosis in NAFLD.
Topics: Animals; Humans; Male; Mice; Diet, High-Fat; Disease Models, Animal; Extracellular Vesicles; Hepatic Stellate Cells; Hepatocytes; Liver Cirrhosis; Mice, Inbred C57BL; Mitophagy; Non-alcoholic Fatty Liver Disease; Protein Kinases
PubMed: 38822260
DOI: 10.1186/s11658-024-00596-4 -
Molecular Medicine (Cambridge, Mass.) May 20248-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1...
BACKGROUND
8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified.
METHODS
A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1.
RESULTS
In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells.
CONCLUSION
OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.
Topics: Animals; Mitophagy; Pulmonary Fibrosis; DNA Glycosylases; Mice; Macrophages; Protein Kinases; Bleomycin; Disease Models, Animal; Male; Ubiquitin-Protein Ligases; Oxidative Stress; Mice, Inbred C57BL; Macrophage Activation; Humans; Quinazolinones
PubMed: 38822247
DOI: 10.1186/s10020-024-00843-6 -
Scientific Reports May 2024Sirtuin1 (SIRT1) activity decreases the tuberous sclerosis complex 2 (TSC2) lysine acetylation status, inhibiting the mechanistic target of rapamycin complex 1 (mTORC1)...
Sirtuin1 (SIRT1) activity decreases the tuberous sclerosis complex 2 (TSC2) lysine acetylation status, inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) signalling and concomitantly, activating autophagy. This study analyzes the role of TSC2 acetylation levels in its translocation to the lysosome and the mitochondrial turnover in both mouse embryonic fibroblast (MEF) and in mouse insulinoma cells (MIN6) as a model of pancreatic β cells. Resveratrol (RESV), an activator of SIRT1 activity, promotes TSC2 deacetylation and its translocation to the lysosome, inhibiting mTORC1 activity. An improvement in mitochondrial turnover was also observed in cells treated with RESV, associated with an increase in the fissioned mitochondria, positive autophagic and mitophagic fluxes and an enhancement of mitochondrial biogenesis. This study proves that TSC2 in its deacetylated form is essential for regulating mTORC1 signalling and the maintenance of the mitochondrial quality control, which is involved in the homeostasis of pancreatic beta cells and prevents from several metabolic disorders such as Type 2 Diabetes Mellitus.
Topics: Tuberous Sclerosis Complex 2 Protein; Animals; Acetylation; Lysosomes; Mice; Mitochondria; Mechanistic Target of Rapamycin Complex 1; Sirtuin 1; Autophagy; Protein Transport; Resveratrol; Signal Transduction; Fibroblasts; Insulin-Secreting Cells; Cell Line, Tumor
PubMed: 38822085
DOI: 10.1038/s41598-024-63525-7 -
Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models.Cell Death & Disease May 2024Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in...
Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in actively respiring cells has also been shown to trigger metabolic collapse mediated by the depletion of nicotinamide adenine dinucleotide (NAD) pools, resulting in cell death. Here we found that the deficit in the autophagy-NAD axis underpins the loss of viability in cell models of a neurodegenerative lysosomal storage disorder, Niemann-Pick type C1 (NPC1) disease. Defective autophagic flux in NPC1 cells resulted in mitochondrial dysfunction due to impairment of mitophagy, leading to the depletion of both the reduced and oxidised forms of NAD as identified via metabolic profiling. Consequently, exhaustion of the NAD pools triggered mitochondrial depolarisation and apoptotic cell death. Our chemical screening identified two FDA-approved drugs, celecoxib and memantine, as autophagy activators which effectively restored autophagic flux, NAD levels, and cell viability of NPC1 cells. Of biomedical relevance, either pharmacological rescue of the autophagy deficiency or NAD precursor supplementation restored NAD levels and improved the viability of NPC1 patient fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons. Together, our findings identify the autophagy-NAD axis as a mechanism of cell death and a target for therapeutic interventions in NPC1 disease, with a potential relevance to other neurodegenerative disorders.
Topics: Niemann-Pick Disease, Type C; Humans; Autophagy; NAD; Induced Pluripotent Stem Cells; Fibroblasts; Mitochondria; Memantine; Neurons; Cell Death; Cell Survival; Mitophagy; Apoptosis
PubMed: 38821960
DOI: 10.1038/s41419-024-06770-y -
Journal of Molecular Biology May 2024Mitophagy is a specific type of autophagy responsible for the selective elimination of dysfunctional or superfluous mitochondria, ensuring the maintenance of...
Mitophagy is a specific type of autophagy responsible for the selective elimination of dysfunctional or superfluous mitochondria, ensuring the maintenance of mitochondrial quality control. The initiation of mitophagy is coordinated by the ULK1 kinase complex, which engages mitophagy receptors via its FIP200 subunit. Whether FIP200 performs additional functions in the subsequent later phases of mitophagy beyond this initial step and how its regulation occurs, remains unclear. Our findings reveal that multiple phosphorylation events on FIP200 differentially control the early and late stages of mitophagy. Furthermore, these phosphorylation events influence FIP200's interaction with ATG16L1. In summary, our results highlight the necessity for precise and dynamic regulation of FIP200, underscoring its importance in the progression of mitophagy.
PubMed: 38821350
DOI: 10.1016/j.jmb.2024.168631