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DNA and Cell Biology Oct 2022Autophagy maintains intracellular homeostasis in the cardiovascular system, including in cardiomyocytes, endothelial cells (ECs), and arterial smooth muscle cells.... (Review)
Review
Autophagy maintains intracellular homeostasis in the cardiovascular system, including in cardiomyocytes, endothelial cells (ECs), and arterial smooth muscle cells. Mitophagy, a selective autophagy that specifically removes damaged and dysfunctional mitochondria, is particularly important for cardiovascular homeostasis. Dysfunctional mitophagy contributes to cardiovascular disease, particularly atherosclerosis (AS). This review focuses on the advances of regulator mechanisms of mitophagy and its potential roles in AS. The findings are beneficial to understanding the pathological processes of atherosclerotic lesions and provide new ideas for the prevention and clinical treatment of AS.
Topics: Humans; Mitophagy; Endothelial Cells; Autophagy; Mitochondria; Atherosclerosis
PubMed: 36036955
DOI: 10.1089/dna.2022.0249 -
Autophagy Jun 2024Mitophagy involves the selective elimination of defective mitochondria during chemotherapeutic stress to maintain mitochondrial homeostasis and sustain cancer growth....
Mitophagy involves the selective elimination of defective mitochondria during chemotherapeutic stress to maintain mitochondrial homeostasis and sustain cancer growth. Here, we showed that CLU (clusterin) is localized to mitochondria to induce mitophagy controlling mitochondrial damage in oral cancer cells. Moreover, overexpression and knockdown of CLU establish its mitophagy-specific role, where CLU acts as an adaptor protein that coordinately interacts with BAX and LC3 recruiting autophagic machinery around damaged mitochondria in response to cisplatin treatment. Interestingly, CLU triggers class III phosphatidylinositol 3-kinase (PtdIns3K) activity around damaged mitochondria, and inhibition of mitophagic flux causes the accumulation of excessive mitophagosomes resulting in reactive oxygen species (ROS)-dependent apoptosis during cisplatin treatment in oral cancer cells. In parallel, we determined that PPARGC1A/PGC1α (PPARG coactivator 1 alpha) activates mitochondrial biogenesis during CLU-induced mitophagy to maintain the mitochondrial pool. Intriguingly, PPARGC1A inhibition through small interfering RNA (si) and pharmacological inhibitor (SR-18292) treatment counteracts CLU-dependent cytoprotection leading to mitophagy-associated cell death. Furthermore, co-treatment of SR-18292 with cisplatin synergistically suppresses tumor growth in oral cancer xenograft models. In conclusion, CLU and PPARGC1A are essential for sustained cancer cell growth by activating mitophagy and mitochondrial biogenesis, respectively, and their inhibition could provide better therapeutic benefits against oral cancer.
Topics: Humans; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Clusterin; Mitophagy; Mitochondria; Mouth Neoplasms; Animals; Cell Survival; Cell Line, Tumor; Cisplatin; Organelle Biogenesis; Mice; Apoptosis; Mice, Nude; Reactive Oxygen Species; Autophagy
PubMed: 38447939
DOI: 10.1080/15548627.2024.2309904 -
Advances in Experimental Medicine and... 2020Pressure overload can lead to cardiac hypertrophy and heart failure. Autophagic activity could be detected in heart failure patients and animal models. However, the role... (Review)
Review
Pressure overload can lead to cardiac hypertrophy and heart failure. Autophagic activity could be detected in heart failure patients and animal models. However, the role of autophagy in heart failure is not clear. In this chapter, we will outline the role of macroautophagy and mitophagy in heart failure and the mechanisms underlying regulation.
Topics: Animals; Autophagy; Cardiomegaly; Heart Failure; Humans; Mitophagy
PubMed: 32671751
DOI: 10.1007/978-981-15-4272-5_16 -
Cells Feb 2022Mitophagy, which is able to selectively clear excess or damaged mitochondria, plays a vital role in the quality control of mitochondria and the maintenance of normal... (Review)
Review
Mitophagy, which is able to selectively clear excess or damaged mitochondria, plays a vital role in the quality control of mitochondria and the maintenance of normal mitochondrial functions in eukaryotic cells. Mitophagy is involved in many physiological and pathological processes, including apoptosis, innate immunity, inflammation, cell differentiation, signal transduction, and metabolism. Viral infections cause physical dysfunction and thus pose a significant threat to public health. An accumulating body of evidence reveals that some viruses hijack mitophagy to enable immune escape and self-replication. In this review, we systematically summarize the pathway of mitophagy initiation and discuss the functions and mechanisms of mitophagy in infection with classical swine fever virus and other specific viruses, with the aim of providing a theoretical basis for the prevention and control of related diseases.
Topics: Animals; Apoptosis; Immunity, Innate; Mitochondria; Mitophagy; Swine; Virus Diseases
PubMed: 35203359
DOI: 10.3390/cells11040711 -
Endokrynologia Polska 2023Mitophagy is a specific type of autophagy and a selective form of autophagy on a larger scale. It selectively eliminates damaged, misfolded, and surplus mitochondria,... (Review)
Review
Mitophagy is a specific type of autophagy and a selective form of autophagy on a larger scale. It selectively eliminates damaged, misfolded, and surplus mitochondria, particularly those that are cytotoxic, by using autophagic lysosomes. This process is crucial for maintaining a balance of both the quality and quantity of mitochondria, which is necessary for normal cell function and tissue development. However, in certain abnormal situations, such as nutritional deficiencies and hypoxia, the function of mitophagy becomes impaired. This leads to a failure to clear damaged mitochondria in a timely manner, resulting in the production of a large number of reactive oxygen species. These reactive oxygen species further contribute to an inflammatory response and the release of factors that induce apoptosis. Moreover, abnormal mitophagy can also cause mitochondrial dysfunction, disrupt metabolic reprogramming during stress responses, alter cell fate decisions and differentiation, and consequently impact the development and progression of diseases, including cancer. Therefore, mitophagy plays a crucial role in controlling the quality of cancer cells, making it imperative to study its function and impact. Numerous proteins and molecules are involved in the regulation of mitophagy, with Parkin and PTEN-induced kinase 1 (PINK1) serving as key mediators, and the hypoxia-related proteins hypoxia-inducible factor la (HIF1a) and FUN14 domain-containing 1 (FUNDC1) also playing a role. Additionally, proteins such as chromatin licensing and DNA replication factor 1 (CDT-1), insulin-like growth factor 1 (IGF-1), caveolin 1 (Cav-1), and others contribute to the regulation of mitophagy in various ways. This article aims to explore the dual role of mitophagy in tumourigenesis by examining the factors and proteins associated with mitophagy and their regulatory effects. The objective of this review is to provide a new theoretical foundation and direction for cancer treatment.
Topics: Humans; Autophagy; Hypoxia; Mitophagy; Neoplasms; Reactive Oxygen Species
PubMed: 37902014
DOI: 10.5603/ep.95652 -
Identification of mitophagy-related biomarkers and immune infiltration in major depressive disorder.BMC Genomics Apr 2023Major depressive disorder (MDD) is a life-threatening and debilitating mental health condition. Mitophagy, a form of selective autophagy that eliminates dysfunctional...
BACKGROUND
Major depressive disorder (MDD) is a life-threatening and debilitating mental health condition. Mitophagy, a form of selective autophagy that eliminates dysfunctional mitochondria, is associated with depression. However, studies on the relationship between mitophagy-related genes (MRGs) and MDD are scarce. This study aimed to identify potential mitophagy-related biomarkers for MDD and characterize the underlying molecular mechanisms.
METHODS
The gene expression profiles of 144 MDD samples and 72 normal controls were retrieved from the Gene Expression Omnibus database, and the MRGs were extracted from the GeneCards database. Consensus clustering was used to determine MDD clusters. Immune cell infiltration was evaluated using CIBERSORT. Functional enrichment analyses were performed to determine the biological significance of mitophagy-related differentially expressed genes (MR-DEGs). Weighted gene co-expression network analysis, along with a network of protein-protein interactions (PPI), was used to identify key modules and hub genes. Based on the least absolute shrinkage and selection operator analysis and univariate Cox regression analysis, a diagnostic model was constructed and evaluated using receiver operating characteristic curves and validated with training data and external validation data. We reclassified MDD into two molecular subtypes according to biomarkers and evaluated their expression levels.
RESULTS
In total, 315 MDD-related MR-DEGs were identified. Functional enrichment analyses revealed that MR-DEGs were mainly enriched in mitophagy-related biological processes and multiple neurodegenerative disease pathways. Two distinct clusters with diverse immune infiltration characteristics were identified in the 144 MDD samples. MATR3, ACTL6A, FUS, BIRC2, and RIPK1 have been identified as potential biomarkers of MDD. All biomarkers showed varying degrees of correlation with immune cells. In addition, two molecular subtypes with distinct mitophagy gene signatures were identified.
CONCLUSIONS
We identified a novel five-MRG gene signature that has excellent diagnostic performance and identified an association between MRGs and the immune microenvironment in MDD.
Topics: Humans; Depressive Disorder, Major; Mitophagy; Neurodegenerative Diseases; Biomarkers; Cluster Analysis; Actins; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins; RNA-Binding Proteins; Nuclear Matrix-Associated Proteins
PubMed: 37098514
DOI: 10.1186/s12864-023-09304-6 -
Journal of Cachexia, Sarcopenia and... Aug 2022Maintaining healthy mitochondria is mandatory for muscle viability and function. An essential surveillance mechanism targeting defective and harmful mitochondria to...
BACKGROUND
Maintaining healthy mitochondria is mandatory for muscle viability and function. An essential surveillance mechanism targeting defective and harmful mitochondria to degradation is the selective form of autophagy called mitophagy. Ambra1 is a multifaceted protein with well-known autophagic and mitophagic functions. However, the study of its role in adult tissues has been extremely limited due to the embryonic lethality caused by full-body Ambra1 deficiency.
METHODS
To establish the role of Ambra1 as a positive regulator of mitophagy, we exploited in vivo overexpression of a mitochondria-targeted form of Ambra1 in skeletal muscle. To dissect the consequence of Ambra1 inactivation in skeletal muscle, we generated muscle-specific Ambra1 knockout (Ambra1 :Mlc1f-Cre) mice. Mitochondria-enriched fractions were obtained from muscles of fed and starved animals to investigate the dynamics of the mitophagic flux.
RESULTS
Our data show that Ambra1 has a critical role in the mitophagic flux of adult murine skeletal muscle and that its genetic inactivation leads to mitochondria alterations and myofibre remodelling. Ambra1 overexpression in wild-type muscles is sufficient to enhance mitochondria clearance through the autophagy-lysosome system. Consistently with this, Ambra1-deficient muscles display an abnormal accumulation of the mitochondrial marker TOMM20 by +76% (n = 6-7; P < 0.05), a higher presence of myofibres with swollen mitochondria by +173% (n = 4; P < 0.05), and an alteration in the maintenance of the mitochondrial membrane potential and a 34% reduction in the mitochondrial respiratory complex I activity (n = 4; P < 0.05). Lack of Ambra1 in skeletal muscle leads to impaired mitophagic flux, without affecting the bulk autophagic process. This is due to a significantly decreased recruitment of DRP1 (n = 6-7 mice; P < 0.01) and Parkin (n = 6-7 mice; P < 0.05) to the mitochondrial compartment, when compared with controls. Ambra1-deficient muscles also show a marked dysregulation of the endolysosome compartment, as the incidence of myofibres with lysosomal accumulation is 20 times higher than wild-type muscles (n = 4; P < 0.05). Histologically, Ambra1-deficient muscles of both 3- and 6-month-old animals display a significant decrease of myofibre cross-sectional area and a 52% reduction in oxidative fibres (n = 6-7; P < 0.05), thus highlighting a role for Ambra1 in the proper structure and activity of skeletal muscle.
CONCLUSIONS
Our study indicates that Ambra1 is critical for skeletal muscle mitophagy and for the proper maintenance of functional mitochondria.
Topics: Adaptor Proteins, Signal Transducing; Animals; Autophagy; Lysosomes; Mice; Mitochondria; Mitophagy; Muscle, Skeletal
PubMed: 35593053
DOI: 10.1002/jcsm.13010 -
Molecular Cell Mar 2024To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress...
To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.
Topics: Mitophagy; Protein Kinases; Autophagy; Ubiquitin-Protein Ligases; Protein Processing, Post-Translational; Signal Transduction
PubMed: 38340717
DOI: 10.1016/j.molcel.2024.01.016 -
Autophagy Apr 2024Intervertebral disc degeneration (IDD) is the most critical pathological factor in the development of low back pain. The maintenance of nucleus pulposus (NP) cell and...
Intervertebral disc degeneration (IDD) is the most critical pathological factor in the development of low back pain. The maintenance of nucleus pulposus (NP) cell and intervertebral disc integrity benefits largely from well-controlled mitochondrial quality, surveilled by mitochondrial dynamics (fission and fusion) and mitophagy, but the outcome is cellular context-dependent that remain to be clarified. Our studies revealed that the loss of NLRX1 is correlated with NP cell senescence and IDD progression, which involve disordered mitochondrial quality. Further using animal and in vitro tissue and cell models, we demonstrated that NLRX1 could facilitate mitochondrial quality by coupling mitochondrial dynamic factors (p-DNM1L, L-OPA1:S-OPA1, OMA1) and mitophagy activity. Conversely, mitochondrial collapse occurred in NLRX1-defective NP cells and switched on the compensatory PINK1-PRKN pathway that led to excessive mitophagy and aggressive NP cell senescence. Mechanistically, NLRX1 was originally shown to interact with zinc transporter SLC39A7 and modulate mitochondrial Zn trafficking via the formation of an NLRX1-SLC39A7 complex on the mitochondrial membrane of NP cells, subsequently orchestrating mitochondrial dynamics and mitophagy. The restoration of NLRX1 function by gene overexpression or pharmacological agonist (NX-13) treatment showed great potential for regulating mitochondrial fission with synchronous fusion and mitophagy, thus sustaining mitochondrial homeostasis, ameliorating NP cell senescence and rejuvenating intervertebral discs. Collectively, our findings highlight a working model whereby the NLRX1-SLC39A7 complex coupled mitochondrial dynamics and mitophagy activity to surveil and target damaged mitochondria for degradation, which determines the beneficial function of the mitochondrial surveillance system and ultimately rejuvenates intervertebral discs. 3-MA: 3-methyladenine; Baf-A: bafilomycin A; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; DNM1L/DRP1: dynamin 1 like; EdU: 5-Ethynyl-2'-deoxyuridine; HE: hematoxylin-eosin; IDD: intervertebral disc degeneration; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MKI67/Ki67: marker of proliferation Ki-67; LBP: low back pain; MMP: mitochondrial membrane potential; MFN1: mitofusin 1; MFN2: mitofusin 2; MFF: mitochondrial fission factor; NP: nucleus pulposus; NLRX1: NLR family member X1; OMA1: OMA1 zinc metallopeptidase; OPA1: OPA1 mitochondrial dynamin like GTPase; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxidative species; SASP: senescence-associated secretory phenotype; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SO: safranin o; TBHP: tert-butyl hydroperoxide; TP53/p53: tumor protein p53; SLC39A7/ZIP7: solute carrier family 39 member 7; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23.
Topics: Mitophagy; Mitochondrial Dynamics; Mitochondria; Animals; Zinc; Intervertebral Disc Degeneration; Mitochondrial Proteins; Cellular Senescence; Nucleus Pulposus; Humans; Intervertebral Disc; Cation Transport Proteins; Mice; Protein Kinases
PubMed: 37876250
DOI: 10.1080/15548627.2023.2274205 -
Mitochondrion Mar 2020Autophagy is a ubiquitous homeostatic mechanism for the degradation or turnover of cellular components. Degradation of mitochondria via autophagy (mitophagy) is involved... (Review)
Review
Autophagy is a ubiquitous homeostatic mechanism for the degradation or turnover of cellular components. Degradation of mitochondria via autophagy (mitophagy) is involved in a number of physiological processes including cellular homeostasis, differentiation and aging. Upon stress or injury, mitophagy prevents the accumulation of damaged mitochondria and the increased steady state levels of reactive oxygen species leading to oxidative stress and cell death. A number of human diseases, particularly neurodegenerative disorders, have been linked to the dysregulation of mitophagy. In this mini-review, we aimed to review the molecular mechanisms involved in the regulation of mitophagy and their relationship with redox signaling and oxidative stress.
Topics: Aging; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Dynamics; Mitophagy; Neurodegenerative Diseases; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species
PubMed: 31972372
DOI: 10.1016/j.mito.2020.01.002