Depletion of mitochondria in mammalian cells through enforced mitophagy

Correia‐Melo, Clara; Ichim, Gabriel; Tait, Stephen W.G.; Passos, João F.

doi:10.1038/nprot.2016.159

Cited by 43 publications

(39 citation statements)

References 38 publications

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“…S2b , left) and subjected to a short-term CCCP treatment for widespread mitophagy induction. 33 In these cells, mitophagy, indicated by the co-localization of mitochondria with LC3, was clearly observed (Supplementary information, Fig. S2a , right), and mitochondrial proteins or mitochondrial DNA (mtDNA) could be hardly detected (Supplementary information, Fig.…”

Section: Resultsmentioning

confidence: 99%

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

et al. 2018

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Iron has been shown to trigger oxidative stress by elevating reactive oxygen species (ROS) and to participate in different modes of cell death, such as ferroptosis, apoptosis and necroptosis. However, whether iron-elevated ROS is also linked to pyroptosis has not been reported. Here, we demonstrate that iron-activated ROS can induce pyroptosis via a Tom20-Bax-caspase-GSDME pathway. In melanoma cells, iron enhanced ROS signaling initiated by CCCP, causing the oxidation and oligomerization of the mitochondrial outer membrane protein Tom20. Bax is recruited to mitochondria by oxidized Tom20, which facilitates cytochrome c release to cytosol to activate caspase-3, eventually triggering pyroptotic death by inducing GSDME cleavage. Therefore, ROS acts as a causative factor and Tom20 senses ROS signaling for iron-driven pyroptotic death of melanoma cells. Since iron activates ROS for GSDME-dependent pyroptosis induction and melanoma cells specifically express a high level of GSDME, iron may be a potential candidate for melanoma therapy. Based on the functional mechanism of iron shown above, we further demonstrate that iron supplementation at a dosage used in iron-deficient patients is sufficient to maximize the anti-tumor effect of clinical ROS-inducing drugs to inhibit xenograft tumor growth and metastasis of melanoma cells through GSDME-dependent pyroptosis. Moreover, no obvious side effects are observed in the normal tissues and organs of mice during the combined treatment of clinical drugs and iron. This study not only identifies iron as a sensitizer amplifying ROS signaling to drive pyroptosis, but also implicates a novel iron-based intervention strategy for melanoma therapy.

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Section: Resultsmentioning

confidence: 99%

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

et al. 2018

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“…Ototoxic drugs are a common cause of sensorineural hearing loss, and aminoglycosides are the most commonly used ototoxic drugs. Cochlear HCs are susceptible to aminoglycoside-mediated cytotoxicity and cannot be regenerated once damaged, and thus aminoglycoside ototoxicity is usually associated with permanent sensorineural deafness ( Nadol, 1993 ; Lazarou et al, 2015 ; Correia-Melo et al, 2017 ). Recent studies have reported that HCs in the mouse cochlea have a very limited ability to regenerate during the neonatal period, but this limited spontaneous HC regeneration is not sufficient to restore hearing ability once HCs are destroyed by aminoglycosides, and all regenerative ability is lost a few days after birth ( Li et al, 2016 ; Ni et al, 2016 ; Waqas et al, 2016 ; Lu et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage

Zhong

et al. 2020

Front. Cell Dev. Biol.

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Aminoglycoside-induced hair cell (HC) loss is one of the most important causes of hearing loss. After entering the inner ear, aminoglycosides induce the production of high levels of reactive oxygen species (ROS) that subsequently activate apoptosis in HCs. Citicoline, a nucleoside derivative, plays a therapeutic role in central nervous system injury and in neurodegenerative disease models, including addictive disorders, stroke, head trauma, and cognitive impairment in the elderly, and has been widely used in the clinic as an FDA approved drug. However, its effect on auditory HCs remains unknown. Here, we used HC-like HEI-OC-1 cells and whole organ explant cultured mouse cochleae to explore the effect of citicoline on aminoglycoside-induced HC damage. Consistent with previous reports, both ROS levels and apoptosis were significantly increased in neomycin-induced cochlear HCs and HEI-OC-1 cells compared to undamaged controls. Interestingly, we found that co-treatment with citicoline significantly protected against neomycin-induced HC loss in both HEI-OC-1 cells and whole organ explant cultured cochleae. Furthermore, we demonstrated that citicoline could significantly reduce neomycin-induced mitochondrial dysfunction and inhibit neomycin-induced ROS accumulation and subsequent apoptosis. Thus, we conclude that citicoline can protect against neomycin-induced HC loss by inhibiting ROS aggregation and thus preventing apoptosis in HCs, and this suggests that citicoline might serve as a potential therapeutic drug in the clinic to protect HCs.

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“…Mitochondria have traditionally been viewed as the powerhouse of the cell due to their central role in metabolism and energy production. More recently, mitochondria have been implicated in other cellular roles including calcium storage, migration, cell death, senescence, and inflammation [19]. Sustaining mitochondria is one of the important functions of astrocyte in CNS.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of mitochondria demonstrated more energy support for astrocytes and neurons. Moreover, mitochondria have been implicated in inflammation, cell death, and senescence [19].…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture and Moxibustion Regulate Hippocampus Glia and Mitochondria Activation in DSS-Induced Colitis Mice

Zhang

Xie

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Objectives. To study the influence of electroacupuncture (EA) and moxibustion on the hippocampus astrocyte and microglia activation in the ulcerative colitis model and to evaluate the mitochondria activity. Methods. 2.5% dextran sodium sulfate-induced colitis mice were treated by EA or moxibustion. Intestinal pathological structure was observed by hematoxylin and eosin (H&E) staining; the expression of GFAP or S100b (markers for astrocyte), Iba-1 (a marker for microglia), and Mitofilin (a marker for mitochondria) in hippocampus was detected by immunofluorescence staining or western blot. Results. The results demonstrated that both EA and moxibustion could improve the morphology of distal colonic mucosal epithelia in DSS-induced colitis mice. Expression of GFAP in the hippocampus was significantly increased after EA or moxibustion treatment. The effects were further supported by WB results. Meanwhile, expression of mitofilin in the hippocampus CA1 and CA3 regions showed the same trend as that of GFAP. Expression of Iba-1 in the hippocampus showed no significant difference after EA or moxibustion treatment, while the state of microglia changed from resting in control mice to activated state in colitis mice. Conclusion. EA and moxibustion were able to modulate the activation of astrocyte, microglial, and mitochondria in the hippocampus area in the colitis model.

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Depletion of mitochondria in mammalian cells through enforced mitophagy

Cited by 43 publications

References 38 publications

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage

Electroacupuncture and Moxibustion Regulate Hippocampus Glia and Mitochondria Activation in DSS-Induced Colitis Mice

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