Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
EMBO J. 2021 Apr 15;40(8):e106283. doi: 10.15252/embj.2020106283. Epub 2021 Mar 5.
Mitochondrial DNA (mtDNA) encodes several key components of respiratory chain complexes that produce cellular energy through oxidative phosphorylation. mtDNA is vulnerable to damage under various physiological stresses, especially oxidative stress. mtDNA damage leads to mitochondrial dysfunction, and dysfunctional mitochondria can be removed by mitophagy, an essential process in cellular homeostasis. However, how damaged mtDNA is selectively cleared from the cell, and how damaged mtDNA triggers mitophagy, remain mostly unknown. Here, we identified a novel mitophagy receptor, ATAD3B, which is specifically expressed in primates. ATAD3B contains a LIR motif that binds to LC3 and promotes oxidative stress-induced mitophagy in a PINK1-independent manner, thus promoting the clearance of damaged mtDNA induced by oxidative stress. Under normal conditions, ATAD3B hetero-oligomerizes with ATAD3A, thus promoting the targeting of the C-terminal region of ATAD3B to the mitochondrial intermembrane space. Oxidative stress-induced mtDNA damage or mtDNA depletion reduces ATAD3B-ATAD3A hetero-oligomerization and leads to exposure of the ATAD3B C-terminus at the mitochondrial outer membrane and subsequent recruitment of LC3 for initiating mitophagy. Furthermore, ATAD3B is little expressed in m.3243A > G mutated cells and MELAS patient fibroblasts showing endogenous oxidative stress, and ATAD3B re-expression promotes the clearance of m.3243A > G mutated mtDNA. Our findings uncover a new pathway to selectively remove damaged mtDNA and reveal that increasing ATAD3B activity is a potential therapeutic approach for mitochondrial diseases.
线粒体 DNA（mtDNA）编码呼吸链复合物的几个关键组成部分，这些复合物通过氧化磷酸化产生细胞能量。mtDNA 在各种生理应激下，特别是氧化应激下，容易受到损伤。mtDNA 损伤导致线粒体功能障碍，功能障碍的线粒体可以通过自噬被清除，自噬是细胞内稳态的一个重要过程。然而，受损的 mtDNA 如何被选择性地从细胞中清除，以及受损的 mtDNA 如何引发自噬，在很大程度上仍然未知。在这里，我们鉴定了一种新的自噬受体 ATAD3B，它在灵长类动物中特异性表达。ATAD3B 含有一个 LIR 基序，该基序与 LC3 结合，并以 PINK1 非依赖性的方式促进氧化应激诱导的自噬，从而促进氧化应激诱导的受损 mtDNA 的清除。在正常情况下，ATAD3B 与 ATAD3A 异源寡聚化，从而促进 ATAD3B C 端区域靶向线粒体膜间隙。氧化应激诱导的 mtDNA 损伤或 mtDNA 耗竭减少了 ATAD3B-ATAD3A 异源寡聚化，并导致 ATAD3B C 端在线粒体外膜上暴露，随后招募 LC3 以启动自噬。此外，m.3243A>G 突变细胞和表现出内源性氧化应激的 MELAS 患者成纤维细胞中 ATAD3B 的表达量很少，而 ATAD3B 的重新表达促进了 m.3243A>G 突变 mtDNA 的清除。我们的发现揭示了一种选择性清除受损 mtDNA 的新途径，并表明增加 ATAD3B 的活性可能是治疗线粒体疾病的一种潜在方法。
