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

Qi Y, Qiu Q, Gu X, Tian Y, Zhang Y - Sci Rep (2016)

Bottom Line: Our results indicate that spermidine induces mitophagy by eliciting mitochondrial depolarization, which triggers the formation of mitophagosomes and mitolysosomes, thereby promoting the accumulation of PINK1 and translocation of Parkin to damaged mitochondria, finally leading to the decreased mitochondrial mass in GM00637 cells.These results suggest that ATM drives the initiation of the mitophagic cascade.These findings underscore the importance of a mitophagy regulatory network of ATM and PINK1/Parkin and elucidate a novel mechanism by which ATM influences spermidine-induced mitophagy.

View Article: PubMed Central - PubMed

Affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.

ABSTRACT
The ATM (ataxia telangiectasia mutated) protein has recently been proposed to play critical roles in the response to mitochondrial dysfunction by initiating mitophagy. Here, we have used ATM-proficient GM00637 cells and ATM-deficient GM05849 cells to investigate the mitophagic effect of spermidine and to elucidate the role of ATM in spermdine-induced mitophagy. Our results indicate that spermidine induces mitophagy by eliciting mitochondrial depolarization, which triggers the formation of mitophagosomes and mitolysosomes, thereby promoting the accumulation of PINK1 and translocation of Parkin to damaged mitochondria, finally leading to the decreased mitochondrial mass in GM00637 cells. However, in GM05849 cells or GM00637 cells pretreated with the ATM kinase inhibitor KU55933, the expression of full-length PINK1 and the translocation of Parkin are blocked, and the colocalization of Parkin with either LC3 or PINK1 is disrupted. These results suggest that ATM drives the initiation of the mitophagic cascade. Our study demonstrates that spermidine induces mitophagy through ATM-dependent activation of the PINK1/Parkin pathway. These findings underscore the importance of a mitophagy regulatory network of ATM and PINK1/Parkin and elucidate a novel mechanism by which ATM influences spermidine-induced mitophagy.

No MeSH data available.


Related in: MedlinePlus

ATM impacted the accumulation of PINK1 and translocation of Parkin.KU55933-pretreated GM00637 cells and GM05849 cells were exposed to spermidine or CCCP. Immunoblotting and immunofluorescence analyses were performed as described in the legend to Fig. 3 (a–k), except for l and m, which show the colocalization of PINK1 and p-ATM Ser 1981.
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f5: ATM impacted the accumulation of PINK1 and translocation of Parkin.KU55933-pretreated GM00637 cells and GM05849 cells were exposed to spermidine or CCCP. Immunoblotting and immunofluorescence analyses were performed as described in the legend to Fig. 3 (a–k), except for l and m, which show the colocalization of PINK1 and p-ATM Ser 1981.

Mentions: To further study the involvement of ATM kinase activation in spermidine-induced mitophagy, we determined whether ATM targets the PINK1/Parkin pathway. We show that the expression of PINK1 was inhibited in GM00637 cells pretreated with KU55933 (Fig. 5a) and not detectable in GM05849 cells (Fig. 5b). The translocation of Parkin was blocked in KU55933-pretreated GM00637 cells (Fig. 5c) and GM05849 cells (Fig. 5d). Furthermore, colocalization of Parkin with either LC3 (Fig. 5f,g) or PINK1 (Fig. 5i,j) was also compromised. Notably, spermidine promoted the colocalization of PINK1 and p-ATM (Fig. 5l). The quantitative analyses of Parkin/mitochondria (Fig. 5e), Parkin/LC3B (Fig. 5h), Parkin/PINK1 (Fig. 5k) and PINK1/p-ATM (Fig. 5m) colocalizations fully supported the above observations.


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

Qi Y, Qiu Q, Gu X, Tian Y, Zhang Y - Sci Rep (2016)

ATM impacted the accumulation of PINK1 and translocation of Parkin.KU55933-pretreated GM00637 cells and GM05849 cells were exposed to spermidine or CCCP. Immunoblotting and immunofluorescence analyses were performed as described in the legend to Fig. 3 (a–k), except for l and m, which show the colocalization of PINK1 and p-ATM Ser 1981.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835770&req=5

f5: ATM impacted the accumulation of PINK1 and translocation of Parkin.KU55933-pretreated GM00637 cells and GM05849 cells were exposed to spermidine or CCCP. Immunoblotting and immunofluorescence analyses were performed as described in the legend to Fig. 3 (a–k), except for l and m, which show the colocalization of PINK1 and p-ATM Ser 1981.
Mentions: To further study the involvement of ATM kinase activation in spermidine-induced mitophagy, we determined whether ATM targets the PINK1/Parkin pathway. We show that the expression of PINK1 was inhibited in GM00637 cells pretreated with KU55933 (Fig. 5a) and not detectable in GM05849 cells (Fig. 5b). The translocation of Parkin was blocked in KU55933-pretreated GM00637 cells (Fig. 5c) and GM05849 cells (Fig. 5d). Furthermore, colocalization of Parkin with either LC3 (Fig. 5f,g) or PINK1 (Fig. 5i,j) was also compromised. Notably, spermidine promoted the colocalization of PINK1 and p-ATM (Fig. 5l). The quantitative analyses of Parkin/mitochondria (Fig. 5e), Parkin/LC3B (Fig. 5h), Parkin/PINK1 (Fig. 5k) and PINK1/p-ATM (Fig. 5m) colocalizations fully supported the above observations.

Bottom Line: Our results indicate that spermidine induces mitophagy by eliciting mitochondrial depolarization, which triggers the formation of mitophagosomes and mitolysosomes, thereby promoting the accumulation of PINK1 and translocation of Parkin to damaged mitochondria, finally leading to the decreased mitochondrial mass in GM00637 cells.These results suggest that ATM drives the initiation of the mitophagic cascade.These findings underscore the importance of a mitophagy regulatory network of ATM and PINK1/Parkin and elucidate a novel mechanism by which ATM influences spermidine-induced mitophagy.

View Article: PubMed Central - PubMed

Affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.

ABSTRACT
The ATM (ataxia telangiectasia mutated) protein has recently been proposed to play critical roles in the response to mitochondrial dysfunction by initiating mitophagy. Here, we have used ATM-proficient GM00637 cells and ATM-deficient GM05849 cells to investigate the mitophagic effect of spermidine and to elucidate the role of ATM in spermdine-induced mitophagy. Our results indicate that spermidine induces mitophagy by eliciting mitochondrial depolarization, which triggers the formation of mitophagosomes and mitolysosomes, thereby promoting the accumulation of PINK1 and translocation of Parkin to damaged mitochondria, finally leading to the decreased mitochondrial mass in GM00637 cells. However, in GM05849 cells or GM00637 cells pretreated with the ATM kinase inhibitor KU55933, the expression of full-length PINK1 and the translocation of Parkin are blocked, and the colocalization of Parkin with either LC3 or PINK1 is disrupted. These results suggest that ATM drives the initiation of the mitophagic cascade. Our study demonstrates that spermidine induces mitophagy through ATM-dependent activation of the PINK1/Parkin pathway. These findings underscore the importance of a mitophagy regulatory network of ATM and PINK1/Parkin and elucidate a novel mechanism by which ATM influences spermidine-induced mitophagy.

No MeSH data available.


Related in: MedlinePlus