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

Area of Science:

• Cellular Biology
• Mitochondrial Biology
• Genetics

Background:

• Mitochondrial DNA (mtDNA) is crucial for cellular energy production via oxidative phosphorylation.
• Oxidative stress can damage mtDNA, leading to mitochondrial dysfunction and impaired cellular homeostasis.
• The mechanisms for selective clearance of damaged mtDNA through mitophagy are largely unknown.

Purpose of the Study:

• To identify novel mitophagy receptors involved in the selective removal of damaged mtDNA.
• To elucidate the mechanism by which damaged mtDNA triggers mitophagy.
• To explore the therapeutic potential of targeting this pathway for mitochondrial diseases.

Main Methods:

• Identification and characterization of the ATAD3B protein as a mitophagy receptor.
• Investigation of ATAD3B's interaction with LC3 and its role in mitophagy.
• Analysis of ATAD3B expression and function in cells with mtDNA mutations (e.g., m.3243A>G) and MELAS patient fibroblasts.
• Assessment of ATAD3B's role in targeting damaged mtDNA for clearance.

Main Results:

• ATAD3B, a primate-specific protein, acts as a mitophagy receptor, promoting the clearance of oxidative stress-induced damaged mtDNA.
• ATAD3B binds to LC3 via a LIR motif, initiating mitophagy independently of PINK1.
• Under oxidative stress, reduced ATAD3B-ATAD3A hetero-oligomerization exposes ATAD3B, facilitating LC3 recruitment and mitophagy.
• ATAD3B re-expression in cells with mtDNA mutations (m.3243A>G) enhances the clearance of mutated mtDNA.

Conclusions:

• ATAD3B is a novel mitophagy receptor that selectively clears damaged mtDNA in response to oxidative stress.
• The ATAD3B-mediated pathway provides a new mechanism for maintaining mitochondrial quality control.
• Enhancing ATAD3B activity presents a potential therapeutic strategy for mitochondrial disorders associated with mtDNA damage.