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Cell Death & Disease Feb 2024Glioblastoma (GBM) cells require large amounts of iron for tumor growth and progression, which makes these cells vulnerable to destruction via ferroptosis induction....
Glioblastoma (GBM) cells require large amounts of iron for tumor growth and progression, which makes these cells vulnerable to destruction via ferroptosis induction. Mitochondria are critical for iron metabolism and ferroptosis. Sirtuin-3 (SIRT3) is a deacetylase found in mitochondria that regulates mitochondrial quality and function. This study aimed to characterize SIRT3 expression and activity in GBM and investigate the potential therapeutic effects of targeting SIRT3 while also inducing ferroptosis in these cells. We first found that SIRT3 expression was higher in GBM tissues than in normal brain tissues and that SIRT3 protein expression was upregulated during RAS-selective lethal 3 (RSL3)-induced GBM cell ferroptosis. We then observed that inhibition of SIRT3 expression and activity in GBM cells sensitized GBM cells to RSL3-induced ferroptosis both in vitro and in vivo. Mechanistically, SIRT3 inhibition led to ferrous iron and ROS accumulation in the mitochondria, which triggered mitophagy. RNA-Sequencing analysis revealed that upon SIRT3 knockdown in GBM cells, the mitophagy pathway was upregulated and SLC7A11, a critical antagonist of ferroptosis via cellular import of cystine for glutathione (GSH) synthesis, was downregulated. Forced expression of SLC7A11 in GBM cells with SIRT3 knockdown restored cellular cystine uptake and consequently the cellular GSH level, thereby partially rescuing cell viability upon RSL3 treatment. Furthermore, in GBM cells, SIRT3 regulated SLC7A11 transcription through ATF4. Overall, our study results elucidated novel mechanisms underlying the ability of SIRT3 to protect GBM from ferroptosis and provided insight into a potential combinatorial approach of targeting SIRT3 and inducing ferroptosis for GBM treatment.
Topics: Humans; Amino Acid Transport System y+; Cystine; Ferroptosis; Glioblastoma; Glutathione; Indans; Iron; Mitophagy; Sirtuin 3
PubMed: 38395990
DOI: 10.1038/s41419-024-06558-0 -
Cells Jul 2023This review aims to provide a better understanding of the emerging role of mitophagy in glaucomatous neurodegeneration, which is the primary cause of irreversible... (Review)
Review
This review aims to provide a better understanding of the emerging role of mitophagy in glaucomatous neurodegeneration, which is the primary cause of irreversible blindness worldwide. Increasing evidence from genetic and other experimental studies suggests that mitophagy-related genes are implicated in the pathogenesis of glaucoma in various populations. The association between polymorphisms in these genes and increased risk of glaucoma is presented. Reduction in intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, while clinical trials highlight the inadequacy of IOP-lowering therapeutic approaches to prevent sight loss in many glaucoma patients. Mitochondrial dysfunction is thought to increase the susceptibility of retinal ganglion cells (RGCs) to other risk factors and is implicated in glaucomatous degeneration. Mitophagy holds a vital role in mitochondrial quality control processes, and the current review explores the mitophagy-related pathways which may be linked to glaucoma and their therapeutic potential.
Topics: Humans; Mitophagy; Glaucoma; Intraocular Pressure; Retinal Ganglion Cells; Mitochondria
PubMed: 37566048
DOI: 10.3390/cells12151969 -
Cell Reports Dec 2023Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A....
Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A. Either APOL1 C-terminal truncation (APOL1Δ) or APOL3 deletion (APOL3-KO [knockout]) reduces PI4KB activity and triggers actomyosin reorganization. We report that APOL3, but not APOL1, controls PI4KB activity through interaction with PI4KB and neuronal calcium sensor-1 or calneuron-1. Both APOLs are present in Golgi-derived autophagy-related protein 9A vesicles, which are involved in PI4KB trafficking. Like APOL3-KO, APOL1Δ induces PI4KB dissociation from APOL3, linked to reduction of mitophagy flux and production of mitochondrial reactive oxygen species. APOL1 and APOL3, respectively, can interact with the mitophagy receptor prohibitin-2 and the mitophagosome membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). While APOL1 conditions PI4KB and APOL3 involvement in mitochondrion fission and mitophagy, APOL3-VAMP8 interaction promotes fusion between mitophagosomal and endolysosomal membranes. We propose that APOL3 controls mitochondrial membrane dynamics through interactions with the fission factor PI4KB and the fusion factor VAMP8.
Topics: Apolipoprotein L1; Mitochondrial Membranes; Golgi Apparatus; Mitochondria; 1-Phosphatidylinositol 4-Kinase; Apolipoproteins; Mitochondrial Dynamics
PubMed: 38041817
DOI: 10.1016/j.celrep.2023.113528 -
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 -
Cell Death & Disease Nov 2023Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system (CNS) that is characterized by myelin damage, followed by axonal and...
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system (CNS) that is characterized by myelin damage, followed by axonal and ultimately neuronal loss, which has been found to be associated with mitophagy. The etiology and pathology of MS remain elusive. However, the role of FK506 binding protein 5 (FKBP5, also called FKBP51), a newly identified gene associated with MS, in the progression of the disease has not been well defined. Here, we observed that the progress of myelin loss and regeneration in Fkbp5 mice treated with demyelination for the same amount of time was significantly slower than that in wild-type mice, and that mitophagy plays an important regulatory role in this process. To investigate the mechanism, we discovered that the levels of FKBP5 protein were greatly enhanced in the CNS of cuprizone (CPZ) mice and the myelin-denuded environment stimulates significant activation of the PINK1/Parkin-mediated mitophagy, in which the important regulator, PPAR-γ, is critically regulated by FKBP5. This study reveals the role of FKBP5 in regulating a dynamic pathway of natural restorative regulation of mitophagy through PPAR-γ in pathological demyelinating settings, which may provide potential targets for the treatment of demyelinating diseases.
Topics: Animals; Mice; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice, Inbred C57BL; Mitophagy; Multiple Sclerosis; Myelin Sheath; Neurodegenerative Diseases; PPAR gamma; Remyelination
PubMed: 37952053
DOI: 10.1038/s41419-023-06260-7 -
Autophagy Sep 2023Despite growing evidence that has declared the importance of circRNAs in neurodegenerative diseases, the clinical significance of circRNAs in dopaminergic (DA) neuronal...
Despite growing evidence that has declared the importance of circRNAs in neurodegenerative diseases, the clinical significance of circRNAs in dopaminergic (DA) neuronal degeneration in the pathogenesis of Parkinson disease (PD) remains unclear. Here, we performed rRNA-depleted RNA sequencing and detected more than 10,000 circRNAs in the plasma samples of PD patients. In consideration of ROC and the correlation between Hohen-Yahr stage (H-Y stage) and Unified Parkinson Disease Rating Scale-motor score (UPDRS) of 40 PD patients, was selected for further research. Low expression of was found in PD patients and there was a negative positive correlation between the level and severity of PD motor symptoms, while overexpression of protected DA neurons against neurotoxin-induced PD-like neurodegeneration and . Mechanistically, acted as a sponge to promote the stable expression of target gene , thus enhancing PINK1-PRKN-dependent mitophagy to eliminate damaged mitochondria and maintain mitochondrial homeostasis. Thus, rescued DA neuronal degeneration through the -PINK1 axis-mediated improvement of mitochondrial function. This study reveals that exerts a critical role in participating in PD pathogenesis, and may give us an insight into the novel avenue to develop potential biomarkers and therapeutic targets for PD. AAV: adeno-associated virus; DA: dopaminergic; FISH: fluorescence in situ hybridizations; HPLC: high-performance liquid chromatography; H-Y stage: Hohen-Yahr stage; LDH: lactate dehydrogenase; MMP: mitochondrial membrane potential; MPTP/p: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid; NC: negative control; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PBS: phosphate-buffered saline; ROS: reactive oxygen species; SNpc: substantia nigra pars compacta; TEM: transmission electron microscopy; UPDRS: Unified Parkinson's Disease Rating Scale-motor score.
Topics: Humans; Parkinson Disease; Mitophagy; RNA, Circular; Autophagy; Dopamine; Dopaminergic Neurons; Protein Kinases; Ubiquitin-Protein Ligases; MicroRNAs
PubMed: 37014258
DOI: 10.1080/15548627.2023.2196889 -
Burns & Trauma 2023Burn injuries are a significant cause of death worldwide, leading to systemic inflammation, multiple organ failure and sepsis. The progression of burn injury is... (Review)
Review
Burn injuries are a significant cause of death worldwide, leading to systemic inflammation, multiple organ failure and sepsis. The progression of burn injury is explicitly correlated with mitochondrial homeostasis, which is disrupted by the hyperinflammation induced by burn injury, leading to mitochondrial dysfunction and cell death. Mitophagy plays a crucial role in maintaining cellular homeostasis by selectively removing damaged mitochondria. A growing body of evidence from various disease models suggest that pharmacological interventions targeting mitophagy could be a promising therapeutic strategy. Recent studies have shown that mitophagy plays a crucial role in wound healing and burn injury. Furthermore, chemicals targeting mitophagy have also been shown to improve wound recovery, highlighting the potential for novel therapeutic strategies based on an in-depth exploration of the molecular mechanisms regulating mitophagy and its association with skin wound healing.
PubMed: 37465279
DOI: 10.1093/burnst/tkad029 -
Pharmacological Research Aug 2023Maintaining mitochondrial homeostasis is a potential therapeutic strategy for various diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic... (Review)
Review
Maintaining mitochondrial homeostasis is a potential therapeutic strategy for various diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, and cancer. Selective degradation of mitochondria by autophagy (mitophagy) is a fundamental mitochondrial quality control mechanism conserved from yeast to humans. Indeed, small-molecule modulators of mitophagy are valuable pharmaceutical tools that can be used to dissect complex biological processes and turn them into potential drugs. In the past few years, pharmacological regulation of mitophagy has shown promising therapeutic efficacy in various disease models. However, with the increasing number of chemical mitophagy modulator studies, frequent methodological flaws can be observed, leading some studies to draw unreliable or misleading conclusions. This review attempts (a) to summarize the molecular mechanisms of mitophagy; (b) to propose a Mitophagy Modulator Characterization System (MMCS); (c) to perform a comprehensive analysis of methods used to characterize mitophagy modulators, covering publications over the past 20 years; (d) to provide novel targets for pharmacological intervention of mitophagy. We believe this review will provide a panorama of current research on chemical mitophagy modulators and promote the development of safe and robust mitophagy modulators with therapeutic potential by introducing high methodological standards.
Topics: Humans; Mitophagy; Autophagy; Mitochondria; Cardiovascular Diseases; Neoplasms
PubMed: 37348691
DOI: 10.1016/j.phrs.2023.106835 -
Frontiers in Neuroscience 2023Neurons in the central nervous system are among the most metabolically active cells in the body, characterized by high oxygen consumption utilizing glucose both... (Review)
Review
Neurons in the central nervous system are among the most metabolically active cells in the body, characterized by high oxygen consumption utilizing glucose both aerobically and anaerobically. Neurons have an abundance of mitochondria which generate adequate ATP to keep up with the high metabolic demand. One consequence of the oxidative phosphorylation mechanism of ATP synthesis, is the generation of reactive oxygen species which produces cellular injury as well as damage to mitochondria. Mitochondria respond to injury by fusion which serves to ameliorate the damage through genetic complementation. Mitochondria also undergo fission to meet an increased energy demand. Loss of mitochondria is also compensated by increased biogenesis to generate new mitochondria. Damaged mitochondria are removed by mitophagy, an autophagic process, in which damaged mitochondria are surrounded by a membrane to form an autophagosome which ultimately fuses with the lysosome resulting in degradation of faulty mitochondria. Dysregulation of mitophagy has been reported in several central nervous system disorders, including, Alzheimer's disease and Parkinson's disease. Recent studies point to aberrant mitophagy in ocular neurodegenerative disorders which could be an important contributor to the disease etiology/pathology. This review article highlights some of the recent findings that point to dysregulation of mitophagy and it's underlying mechanisms in ocular neurodegenerative diseases, including, glaucoma, age-related macular degeneration and diabetic retinopathy.
PubMed: 37965225
DOI: 10.3389/fnins.2023.1299552 -
Cells Nov 2023Autophagy is an essential lysosome-mediated degradation pathway that maintains cellular homeostasis and viability in response to various intra- and extracellular... (Review)
Review
Autophagy is an essential lysosome-mediated degradation pathway that maintains cellular homeostasis and viability in response to various intra- and extracellular stresses. Mitophagy is a type of autophagy that is involved in the intricate removal of dysfunctional mitochondria during conditions of metabolic stress. In this review, we describe the multifaceted roles of autophagy and mitophagy in normal physiology and the field of cancer biology. Autophagy and mitophagy exhibit dual context-dependent roles in cancer development, acting as tumor suppressors and promoters. We also discuss the important role of autophagy and mitophagy within the cancer microenvironment and how autophagy and mitophagy influence tumor host-cell interactions to overcome metabolic deficiencies and sustain the activity of cancer-associated fibroblasts (CAFs) in a stromal environment. Finally, we explore the dynamic interplay between autophagy and the immune response in tumors, indicating their potential as immunomodulatory targets in cancer therapy. As the field of autophagy and mitophagy continues to evolve, this comprehensive review provides insights into their important roles in cancer and cancer microenvironment.
Topics: Humans; Mitophagy; Autophagy; Neoplasms; Biology; Tumor Microenvironment
PubMed: 38067169
DOI: 10.3390/cells12232742