No abstract

No 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.

Selenium is an essential nutrient widely distributed in organic forms in certain foods and inorganic forms in soil. Selenium exerts its anticarcinogenic effects mainly through selenoproteins at nutritional levels and through selenium metabolites, including reactive oxygen species (ROS), 3 at supranutritional levels (1, 2). Animal and epidemiological studies strongly implicate selenium as an effective chemoprevention agent against colon cancer (3-6); however, the Nutritional Prevention of Cancer Trial and the recent Selenium and Vitamin E Cancer Prevention Trial reported mixed results on the efficacy of selenium in suppressing prostate cancer (7-9). Whatever the reason, the molecular mechanism by which selenium mitigates colorectal tumorigenesis is largely unknown.The majority of colorectal cancers are characterized by microsatellite instability due to a defective MMR system (10, 11). The MMR system senses DNA base mismatch after DNA replication and provokes repair, checkpoint and apoptotic responses (12). Among the many human MMR proteins, hMLH1 (human MutL homologue-1) and hPMS2 (human post-meiotic segregation protein-2) form a complex that recognizes and stabilizes mismatched DNA at an early stage and facilitates the DNA damage response (13). Somatic mutations in MMR genes and epigenetic silencing of hMLH1 expression are observed in a significant portion of sporadic colorectal cancers (8, 14), whereas germ line mutations in hMLH1 account for 60% of the autosomal dominant nonpolyposis colon cancer. Loss of both hMLH1 and hMSH2 (human MutS homologue-2) is associated with complete inactivation of MMR, whereas defects in other MMR proteins result in only partial MMR deficiency (15).The G 2 /M checkpoint prevents damaged cells from entering mitosis by coordinating DNA repair and/or apoptosis pathways. In response to DNA damage, hMLH1 can regulate G 2 /M transition through Cdc2 protein (16), and ATM kinase is implicated in G 2 /M checkpoint response (17-19). Moreover, a linkage between hMLH1 and ATM after DNA damage has been demonstrated (20,21). We have shown recently that selenium compounds at doses Յ LD 50 can activate DNA damage response through ATM and ROS in noncancerous but not in cancerous cells (22). In the current study, we hypothesized that lack of a G 2 /M checkpoint response renders the hMLH1-deficient HCT 116 cells resistant to selenium-induced DNA damage response. By employing isogenic cell lines with or without hMLH1 expression, we show herein that hMLH1 is required for

No abstract

The results showed that Cd significantly induced MMP collapse and typical mitophagosomes formation, increased LC3-II/LC3-I ratio and PINK1 level, and decreased mitochondrial mass, revealing that Cd could induce mitophagy. However, NAC or ALC pretreatment markedly decreased Cd-induced ROS and simultaneously rescued MMP and mitochondrial mass, suggesting ROS played a crucial role in regulating mitophagy. NAC or ALC also dramatically lessened PINK1 level and mitochondrial accumulation of Parkin, indicating that ROS were related to PINK1/Parkin pathway. Notably, CsA compromised Cd-induced mitophagy, PINK1 accumulation and Parkin translocation while failed to block ROS increase, suggesting ROS functioned as an upstream signal for PINK1/Parkin pathway. Taken together, the results indicated that Cd induced ROS-mediated mitophagy through PINK1/Parkin pathway in kidneys of mice. The present study proposes a new perspective to evaluate the nephrotoxicity and its molecular mechanism under Cd exposure in vivo.

No abstract

No abstract