Mitophagy is a cargo-specific autophagic process that recycles damaged mitochondria to promote mitochondrial turnover. PTEN-induced putative kinase 1 (PINK1) mediates the canonical mitophagic pathway. We show that PINK1 expression is positively correlated with decreased colon cancer survival, and mitophagy is required for colon cancer growth following nutrient stress. However, the mechanism by which PINK1 maintains colon cancer growth remains equivocal. Inducible knockdown (KD) of PINK1 in a panel of colon cancer cell lines inhibited colon cancer cell proliferation, whereas disruption of other mitophagy receptors did not similarly impact cellular proliferation. Mechanistically, we observed a decrease in mitochondrial respiration, membrane hyperpolarization, accumulation of mitochondrial DNA, and depletion of antioxidant glutathione following PINK1 KD. Mitochondria are important hubs for storing iron and synthesizing iron-dependent cofactors such as heme and iron sulfur clusters. An increase iron storage protein ferritin and a decrease labile iron pool was observed in PINK1 KD cells. However, neither total cellular iron nor markers of iron starvation/overload were affected. Cellular iron storage and the labile iron pool are maintained via autophagic degradation of ferritin (ferritinophagy). Overexpressing nuclear receptor coactivator 4 (NCOA4), a key adaptor for ferritinophagy, rescued cell growth and the labile iron pool in PINK1 KD cells. We demonstrate that PINK1 regulates intracellular iron availability by integrating mitophagy to ferritinophagy. In conclusion, these results indicate that PINK1 is essential for maintaining intracellular iron homeostasis to support survival and growth in colorectal cancer cells.

中文翻译：

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PINK1 通过调节不稳定铁池来支持结直肠癌的生长。

线粒体自噬是一种货物特异性自噬过程，可回收受损的线粒体以促进线粒体周转。PTEN 诱导的假定激酶 1 (PINK1) 介导经典线粒体自噬通路。我们表明 PINK1 表达与结肠癌存活率降低呈正相关，并且营养应激后结肠癌生长需要线粒体自噬。然而，PINK1 维持结肠癌生长的机制仍然模棱两可。一组结肠癌细胞系中 PINK1 的可诱导敲低 (KD) 抑制了结肠癌细胞增殖，而其他线粒体自噬受体的破坏并没有类似地影响细胞增殖。从机制上讲，我们观察到线粒体呼吸减少、膜超极化、线粒体 DNA 积累、和 PINK1 KD 后抗氧化剂谷胱甘肽的消耗。线粒体是储存铁和合成铁依赖性辅助因子（如血红素和铁硫簇）的重要枢纽。在 PINK1 KD 细胞中观察到铁储存蛋白铁蛋白增加和不稳定铁池减少。然而，总细胞铁和铁饥饿/超负荷的标志物都没有受到影响。细胞铁储存和不稳定铁池通过铁蛋白的自噬降解（铁蛋白吞噬）来维持。过表达核受体共激活因子 4 (NCOA4) 是吞噬铁蛋白的关键适配器，可挽救 PINK1 KD 细胞中的细胞生长和不稳定铁池。我们证明 PINK1 通过将 mitophagy 整合到 ferritinophagy 来调节细胞内铁的可用性。综上所述，