Simultaneous Zn2+ tracking in multiple organelles using super-resolution morphology-correlated organelle identification in living cells

Fang, Hongbao; Geng, Shanshan; Hao, Mingang; Chen, Qixin; Liu, Minglun; Liu, Chunyan; Tian, Ze; Wang, Chengjun; Takebe, Takanori; Guan, Jun‐Lin; Chen, Yuncong; Guo, Zijian; He, Weijiang; Diao, Jiajie

doi:10.1038/s41467-020-20309-7

Cited by 87 publications

(45 citation statements)

References 67 publications

(36 reference statements)

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“…The surprising necessity of autophagy to degrade SIRTs may be related to a conserved tetrathiolate. Indeed, high levels of free Zn 2+ have been observed in autolysosomes, and cells starved for Zn 2+ demonstrate increased autophagy of Zn 2+ binding proteins [ 49 , 50 ]. Since different SIRTs occur more frequently in different cellular compartments, a future approach, which may allow distinguishing between mitophagy and nucleophagy may help gain an even better understanding of these processes.…”

Section: Discussionmentioning

confidence: 99%

The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

et al. 2021

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The sirtuin (SIRT) protein family has been of major research interest over the last decades because of their involvement in aging, cancer, and cell death. SIRTs have been implicated in gene and metabolic regulation through their capacity to remove acyl groups from lysine residues in proteins in an NAD+-dependent manner, which may alter individual protein properties as well as the histone–DNA interaction. Since SIRTs regulate a wide range of different signaling cascades, a fine-tuned homeostasis of these proteins is imperative to guarantee the function and survival of the cell. So far, however, how exactly this homeostasis is established has remained unknown. Here, we provide evidence that neuronal SIRT degradation in Parkinson’s disease (PD) models is executed by autophagy rather than the proteasome. In neuronal Lund human mesencephalic (LUHMES) cells, all seven SIRTs were substrates for autophagy and showed an accelerated autophagy-dependent degradation upon 1-methyl-4-phenylpyridinium (MPP+) mediated oxidative insults in vitro, whereas the proteasome did not contribute to the removal of oxidized SIRTs. Through blockade of endogenous H2O2 generation and supplementation with the selective radical scavenger phenothiazine (PHT), we could identify H2O2-derived species as the responsible SIRT-oxidizing agents. Analysis of all human SIRTs suggested a conserved regulatory motif based on cysteine oxidation, which may have triggered their degradation via autophagy. High amounts of H2O2, however, rapidly carbonylated selectively SIRT2, SIRT6, and SIRT7, which were found to accumulate carbonylation-prone amino acids. Our data may help in finding new strategies to maintain and modify SIRT bioavailability in neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

et al. 2021

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“…Recently, Ji et al (2020) reported that using MCU knock-out or pharmacologic blockers significantly reduced mitochondrial Zn 2+ accumulation, and attenuated Zn 2+ -triggered mitochondrial dysfunction and cortical neuron cell death. Using structured illumination microscopy and a new single Zn 2+ fluorescent probe, Fang et al (2021) revealed that CCCP-induced mitophagy in living HeLa cells was associated with mobile Zn 2+ enhancement. It would be interesting to further explore whether mitophagy is deleterious under this probable mechanism in the early state of glaucoma.…”

Section: Mitochondria Of Rgcs: Critical Target Of Metal Ionsmentioning

confidence: 99%

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Tang

Zhuo

2021

Front. Cell Dev. Biol.

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Glaucoma is the most substantial cause of irreversible blinding, which is accompanied by progressive retinal ganglion cell damage. Retinal ganglion cells are energy-intensive neurons that connect the brain and retina, and depend on mitochondrial homeostasis to transduce visual information through the brain. As cofactors that regulate many metabolic signals, iron and zinc have attracted increasing attention in studies on neurons and neurodegenerative diseases. Here, we summarize the research connecting iron, zinc, neuronal mitochondria, and glaucomatous injury, with the aim of updating and expanding the current view of how retinal ganglion cells degenerate in glaucoma, which can reveal novel potential targets for neuroprotection.

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“…To study lysosomal dynamics in autophagy, we used SIM to image lysosomes upon inducing autophagy by several different agents. First, HeLa cells were treated with 10 μM carbonyl cyanide mchlorophenylhydrazone (CCCP) [23][24][25], a common inducer of mitophagy, for 12 h before using staining to monitor lysosome cluster under SIM (Fig. 1a).…”

Section: Super-resolution Imaging Allows Tracking the Formation Of Lysosome Clusters Upon Stimulationmentioning

confidence: 99%

Prefused lysosomes cluster on autophagosomes regulated by VAMP8

et al. 2021

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Lysosome–autophagosome fusion is critical to autophagosome maturation. Although several proteins that regulate this fusion process have been identified, the prefusion architecture and its regulation remain unclear. Herein, we show that upon stimulation, multiple lysosomes form clusters around individual autophagosomes, setting the stage for membrane fusion. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein on lysosomes—vesicle-associated membrane protein 8 (VAMP8)—plays an important role in forming this prefusion state of lysosomal clusters. To study the potential role of phosphorylation on spontaneous fusion, we investigated the effect of phosphorylation of C-terminal residues of VAMP8. Using a phosphorylation mimic, we observed a decrease of fusion in an ensemble lipid mixing assay and an increase of unfused lysosomes associated with autophagosomes. These results suggest that phosphorylation not only reduces spontaneous fusion for minimizing autophagic flux under normal conditions, but also preassembles multiple lysosomes to increase the fusion probability for resuming autophagy upon stimulation. VAMP8 phosphorylation may thus play an important role in chemotherapy drug resistance by influencing autophagosome maturation.

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Simultaneous Zn2+ tracking in multiple organelles using super-resolution morphology-correlated organelle identification in living cells

Cited by 87 publications

References 67 publications

The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Prefused lysosomes cluster on autophagosomes regulated by VAMP8

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