ATAD3B is a mitophagy receptor mediating clearance of oxidative stress-induced damaged mitochondrial DNA.

Abstract

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.

• Authors: Li Shu, Chao Hu, Meng Xu, Jianglong Yu, He He, Jie Lin, Hongying Sha, Bin Lu, Simone Engelender, Minxin Guan, Zhiyin Song
• Journal: The EMBO journal (EMBO J) Vol. 40 Issue 8 Pg. e106283 (04 15 2021) ISSN: 1460-2075 [Electronic] England
• PMID: 33665835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors.

Chemical References

• ATAD3B protein, human
• DNA, Mitochondrial
• MAP1LC3A protein, human
• Membrane Proteins
• Microtubule-Associated Proteins
• Mitochondrial Proteins
• ATPases Associated with Diverse Cellular Activities

Topics

• ATPases Associated with Diverse Cellular Activities (chemistry, genetics, metabolism)
• Animals
• Cells, Cultured
• DNA Damage
• DNA, Mitochondrial (genetics, metabolism)
• HEK293 Cells
• HeLa Cells
• Humans
• Membrane Proteins (chemistry, genetics, metabolism)
• Mice
• Microtubule-Associated Proteins (metabolism)
• Mitochondrial Proteins (chemistry, genetics, metabolism)
• Mitophagy
• Oxidative Stress
• Protein Binding