title: ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts.
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.
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.|Qibo Medical School, Longdong University, Qingyang 745000, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Gu
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology*; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D063306:Mitophagy / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism*; D013095:Spermidine / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D011494:Protein Kinases; D013095:Spermidine; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C576324:ATM protein, human