Mitophagy, the selective autophagy of damaged mitochondria, is mediated by several receptors, including BNIP3 and NIX, and is important for mitochondrial homeostasis. Mitochondria are also the major source of reactive oxygen species (ROS); mitochondrial ROS (mtROS) can give rise to lipid peroxides, which, in turn, induce ferroptosis, a specific type of cell death. In this study, Kanki and co-workers provide direct evidence that mitophagy mediated by BNIP3 and NIX protects cells against ferroptosis by reducing mtROS.

The authors show that BNIP3 and NIX are essential for mitophagy as cells with double knockout of BNIP3 and NIX are impaired in mitophagy and exhibit reduced mitochondrial function, including reduced basal respiration and ATP production. Interestingly, these mitophagy-deficient cells are highly sensitive to ferroptosis, which can be rescued with expression of BNIP3 and NIX, or by treating cells with a mitochondrial superoxide scavenger. These findings point to an increase in mtROS levels, owing to the absence of mitophagy as an inducer of ferroptosis.

线粒体自噬是受损线粒体的选择性自噬，由 BNIP3 和 NIX 等多种受体介导，对线粒体稳态非常重要。线粒体也是活性氧 (ROS) 的主要来源；线粒体活性氧 (mtROS) 可以产生脂质过氧化物，进而诱导铁死亡（一种特定类型的细胞死亡）。在这项研究中，Kanki 及其同事提供了直接证据，证明 BNIP3 和 NIX 介导的线粒体自噬通过减少 mtROS 来保护细胞免于铁死亡。

作者表明，BNIP3 和 NIX 对于线粒体自噬至关重要，因为 BNIP3 和 NIX 双敲除的细胞线粒体自噬受损，并表现出线粒体功能降低，包括基础呼吸和 ATP 产生减少。有趣的是，这些线粒体自噬缺陷的细胞对铁死亡高度敏感，可以通过表达 BNIP3 和 NIX 或用线粒体超氧化物清除剂处理细胞来挽救铁死亡。这些发现表明，由于缺乏线粒体自噬作为铁死亡的诱导剂，mtROS 水平增加。