Iron Supply via NCOA4-Mediated Ferritin Degradation Maintains Mitochondrial Functions
Iron Supply via NCOA4-Mediated Ferritin Degradation Maintains Mitochondrial Functions
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DOI：
10.1128/mcb.00010-19
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发表时间：
2019-07-01
影响因子：
5.3
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
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作者：
Fujimaki, Motoki;Furuya, Norihiko;Hattori, Nobutaka
铁是线粒体代谢过程（包括线粒体呼吸）的必需营养素。铁蛋白复合物储存多余的铁，保护细胞免受铁毒性。因此，储存在铁蛋白复合物中的铁可以在铁耗尽的条件下被利用。在这项研究中，我们表明，通过巴弗洛霉素A1抑制溶酶体依赖性蛋白质降解和敲除铁蛋白自噬受体NCOA 4，减少线粒体呼吸，呼吸链复合物组装和膜电位在铁充足的条件下。然而，自噬并没有导致铁蛋白复合物在铁充足条件下的降解。敲除铁蛋白轻链（铁蛋白复合物的一个亚基）通过减少与NCOA 4的相互作用抑制铁蛋白降解。然而，铁蛋白轻链敲除并不影响线粒体功能，铁充足的条件下，铁蛋白轻链敲除细胞表现出快速减少的线粒体功能与野生型细胞相比，铁耗尽的条件下。这些结果表明铁蛋白复合物的组成性降解有助于线粒体功能的维持。
Iron is an essential nutrient for mitochondrial metabolic processes, including mitochondrial respiration. Ferritin complexes store excess iron and protect cells from iron toxicity. Therefore, iron stored in the ferritin complex might be utilized under iron-depleted conditions. In this study, we show that the inhibition of lysosome-dependent protein degradation by bafilomycin A1 and the knockdown of NCOA4, an autophagic receptor for ferritin, reduced mitochondrial respiration, respiratory chain complex assembly, and membrane potential under iron-sufficient conditions. However, autophagy did not contribute to degradation of the ferritin complex under iron-sufficient conditions. Knockout of the ferritin light chain, a subunit of the ferritin complex, inhibited ferritin degradation by decreasing interactions with NCOA4. However, ferritin light chain knockout did not affect mitochondrial functions under ironsufficient conditions, and ferritin light chain knockout cells showed a rapid reduction of mitochondrial functions compared with wild-type cells under iron-depleted conditions. These results indicate that the constitutive degradation of the ferritin complex contributes to the maintenance of mitochondrial functions.