Mitophagy alleviates AIF-mediated spleen apoptosis induced by AlCl3 through Parkin stabilization in mice

Aluminium (Al) accumulates in the spleen and causes spleen apoptosis. Mitochondrial dyshomeostasis represents primary mechanisms of spleen apoptosis induced by Al. Apoptosis-inducing factor (AIF) is located in the gap of the mitochondrial membrane and can be released into the nucleus, leading to apoptosis. Phosphatase and tensin homolog (PTEN)-induced putative kinase1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy maintains mitochondrial homeostasis by removing damaged mitochondria, but its function in AIF-mediated spleen apoptosis induced by Al is not clear. In our study, aluminium trichloride (AlCl3) was diluted in water for 90 d and administered to 75 male C57BL/6N mice at 0, 44.8, 59.8, 89.7, and 179.3 mg/kg body weight. AlCl3 triggered PINK1/Parkin pathway-mediated mitophagy, induced AIF release and AIF-mediated spleen apoptosis. AlCl3 was administered to sixty male C57BL/6N mice of wild type and Parkin knockout for 90 d at 0 and 179.3 mg/kg body weight. The results indicated that Parkin deficiency decreased mitophagy, aggravated mitochondrial damage, AIF release and AIF-mediated spleen apoptosis induced by AlCl3. According to our results, PINK1/ Parkin-mediated mitophagy and AIF-mediated spleen apoptosis are caused by AlCl3, whereas mitophagy is protective in AIF-mediated apoptosis induced by AlCl3.

Automated summary

Aluminium (Al) accumulation in the spleen leads to apoptosis, primarily through mitochondrial dyshomeostasis and the release of apoptosis-inducing factor (AIF). The role of phosphatase and tensin homolog (PTEN)-induced putative kinase1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy in AIF-mediated spleen apoptosis induced by Al is uncertain. In this study, AlCl3 administration resulted in PINK1/Parkin-mediated mitophagy, AIF release, and AIF-mediated spleen apoptosis. Parkin deficiency exacerbated mitochondrial damage, AIF release, and AIF-mediated spleen apoptosis induced by AlCl3. Our findings suggest that mitophagy and AIF-mediated spleen apoptosis are both caused by AlCl3, but mitophagy is protective in AIF-mediated apoptosis induced by AlCl3.