Choline dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy

Area of Science:

• Cell Biology
• Mitochondrial Biology
• Autophagy Research

Background:

• Choline dehydrogenase (CHDH) is primarily known for its role in choline metabolism within mitochondria.
• Mitophagy, the selective degradation of damaged mitochondria, is crucial for cellular health.
• The precise mechanisms regulating mitophagy, particularly the role of specific mitochondrial proteins, are still being elucidated.

Purpose of the Study:

• To investigate the novel role of CHDH in the process of mitophagy.
• To determine how CHDH influences PARK2/parkin-mediated mitochondrial clearance.
• To elucidate the molecular interactions of CHDH during mitophagy.

Main Methods:

• Utilized knockdown and overexpression of CHDH in mammalian cell lines (HeLa, SN4741).
• Assessed mitophagy induction using CCCP and MPP+ treatments.
• Investigated protein-protein interactions using co-immunoprecipitation and analyzed protein localization via cell imaging.

Main Results:

• CHDH knockdown impaired mitophagy, while its overexpression accelerated it.
• CHDH localizes to mitochondrial membranes and accumulates on the outer membrane during mitophagy.
• CHDH interacts with SQSTM1 independently of PARK2 and forms a ternary complex with SQSTM1 and LC3 to recruit cargo to damaged mitochondria.

Conclusions:

• CHDH is a critical component of the mitophagy pathway, acting independently of its metabolic function.
• CHDH facilitates the recruitment of SQSTM1 and LC3 to depolarized mitochondria, enabling cargo recognition for degradation.
• These findings reveal a new regulatory mechanism in PARK2-mediated mitophagy involving CHDH.