ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts

Qi, Yongmei; Qiu, Qian; Gu, Xueyan; Tian, Ye; Zhang, Yingmei

doi:10.1038/srep24700

Cited by 96 publications

(77 citation statements)

References 57 publications

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“…COX IV often serves as a marker of mitochondrial mass and has also been used to monitor the last step in the degradation process of mitophagy 42. Hence, it is possible mitophagy may contribute to the overall changes in autophagy we observed.…”

Section: Discussionmentioning

confidence: 88%

B355252, A Novel Small Molecule, Confers Neuroprotection Against Cobalt Chloride Toxicity In Mouse Hippocampal Cells Through Altering Mitochondrial Dynamics And Limiting Autophagy Induction

Chimeh¹,

Zimmerman²,

Gilyazova³

et al. 2018

Int. J. Med. Sci.

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Cerebral hypoxia as often occurs in cases of stroke, hemorrhage, or other traumatic brain injuries, is one of the leading causes of death worldwide and a main driver of disabilities in the elderly. Using a chemical mimetic of hypoxia, cobalt chloride (CoCl2), we tested the ability of a novel small molecule, 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B355252), to alleviate CoCl2-induced damage in mouse hippocampal HT22 cells. A dose-dependent decrease in cell viability was observed during CoCl2 treatment along with increases in mitochondrial membrane potential and generation of reactive oxygen species (ROS). B355252 conferred protection against these changes. We further found that mitochondrial dynamics, the balance between mitochondrial fusion and fission, were perturbed by CoCl2 treatment. Mitochondrial fusion, which was assessed by measuring the expression of proteins optic atrophy protein 1 (OPA1) and mitofusin 2 (Mfn2), declined due to CoCl2 exposure, but B355252 addition was able to elevate Mfn2 expression while OPA1 expression was unchanged. Mitochondrial fission, measured by phosphorylated dynamin-related protein 1 (p-DRP1) and fission protein 1 (FIS1) expression, also decreased following CoCl2 exposure, and was stabilized by B355252 addition. Finally, autophagy was assessed by measuring the conversion of cytosolic microtubule-associated protein 1A/1B-light chain three-I (LC3-I) to autophagosome-bound microtubule-associated protein 1A/1B-light chain three-II (LC3-II) and was found to be increased by CoCl2. B355252 addition significantly reduced autophagy induction. Taken together, our results indicate B355252 has therapeutic potential to reduce the damaging effects caused by CoCl2 and should be further evaluated for applications in cerebral ischemia therapy.

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Section: Discussionmentioning

confidence: 88%

B355252, A Novel Small Molecule, Confers Neuroprotection Against Cobalt Chloride Toxicity In Mouse Hippocampal Cells Through Altering Mitochondrial Dynamics And Limiting Autophagy Induction

Chimeh¹,

Zimmerman²,

Gilyazova³

et al. 2018

Int. J. Med. Sci.

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“…It has been reported that ionizing radiation induces ATM-dependent G2/M arrest in human ESCs (Momcilovic et al., 2009). We treated R1 cells with 50 nM doxorubicin for either 12, 24, or 36 hr in the presence of KU55933, an ATM inhibitor (Qi et al., 2016). Consistent with previous reports (Hickson et al., 2004), inhibition of ATM reduced the level of p53 comparable with that in control cells (compare lane 5 with lane 1, Figure S3).…”

Section: Resultsmentioning

confidence: 99%

p53 and p73 Regulate Apoptosis but Not Cell-Cycle Progression in Mouse Embryonic Stem Cells upon DNA Damage and Differentiation

Wang

Dai

et al. 2016

Stem Cell Reports

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SummaryEmbryonic stem cells (ESCs) are fast proliferating cells capable of differentiating into all somatic cell types. In somatic cells, it is well documented that p53 is rapidly activated upon DNA damage to arrest the cell cycle and induce apoptosis. In mouse ESCs, p53 can also be functionally activated, but the precise biological consequences are not well characterized. Here, we demonstrated that doxorubicin treatment initially led to cell-cycle arrest at G2/M in ESCs, followed by the occurrence of massive apoptosis. Neither p53 nor its target gene p73 was required for G2/M arrest. Instead, p53 and p73 were fully responsible for apoptosis. p53 and p73 were also required for differentiation-induced apoptosis in mouse ESCs. In addition, doxorubicin treatment induced the expression of retinoblastoma protein in a p53-dependent manner. Therefore, both p53 and p73 are critical in apoptosis induced by DNA damage and differentiation.

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“…Spermidine feeding protects from age‐induced memory impairment in an autophagy‐dependent manner . Spermidine induces the formation of mitophagosomes and decreases the aggregation of dysfunctional mitochondrial through the PINK1/Parkin pathway …”

Section: Methods To Enhance Mitochondrial Functionmentioning

confidence: 99%

Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure

et al. 2019

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Summary Mitochondria not only supply the energy for cell function, but also take part in cell signaling. This review describes the dysfunctions of mitochondria in aging and neurodegenerative diseases, and the signaling pathways leading to mitochondrial biogenesis (including PGC‐1 family proteins, SIRT1, AMPK) and mitophagy (parkin‐Pink1 pathway). Understanding the regulation of these mitochondrial pathways may be beneficial in finding pharmacological approaches or lifestyle changes (caloric restrict or exercise) to modulate mitochondrial biogenesis and/or to activate mitophagy for the removal of damaged mitochondria, thus reducing the onset and/or severity of neurodegenerative diseases.

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ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts

Cited by 96 publications

References 57 publications

B355252, A Novel Small Molecule, Confers Neuroprotection Against Cobalt Chloride Toxicity In Mouse Hippocampal Cells Through Altering Mitochondrial Dynamics And Limiting Autophagy Induction

B355252, A Novel Small Molecule, Confers Neuroprotection Against Cobalt Chloride Toxicity In Mouse Hippocampal Cells Through Altering Mitochondrial Dynamics And Limiting Autophagy Induction

p53 and p73 Regulate Apoptosis but Not Cell-Cycle Progression in Mouse Embryonic Stem Cells upon DNA Damage and Differentiation

Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure

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