"ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane"

Area of Science:

• Mitochondrial biology
• Cellular biochemistry
• Genetics

Background:

• Mitochondrial ATPase Associated with diverse cellular Activities (AAA) domain containing enzyme ATAD3A is crucial for inner mitochondrial membrane organization and linked to childhood diseases.
• Human evolution resulted in ATAD3A paralogs: ATAD3B and ATAD3C, with ATAD3C largely considered a pseudogene.

Purpose of the Study:

• To investigate the cellular activities and functional role of the ATAD3C paralog.
• To determine ATAD3C's impact on mitochondrial structure and function, particularly in relation to ATAD3A.

Main Methods:

• Detection of ATAD3C peptides in HEK 293T cells and human tissues.
• Characterization of ATAD3C as an integral membrane protein.
• Overexpression studies in fibroblasts to assess effects on cell proliferation, oxygen consumption, and reactive oxygen species (ROS) production.
• Analysis of ATAD3A complex size and respiratory chain assembly.

Main Results:

• ATAD3C is expressed in cells and tissues and functions as an integral membrane protein.
• Overexpression of ATAD3C, unlike ATAD3A, reduced cell proliferation and oxygen consumption while increasing ROS.
• ATAD3C monomers incorporated into the ATAD3A complex, reducing its size and altering mitochondrial membrane organization.
• ATAD3C expression promoted the accumulation of dimeric CIII in the inner membrane, hindering supercomplex formation.

Conclusions:

• ATAD3C exhibits a negative dominant role, regulating ATAD3A function in mitochondrial membranes.
• ATAD3C impacts mitochondrial oxidative phosphorylation (OXPHOS) and cellular energy metabolism.
• The findings suggest ATAD3C plays a significant regulatory role in mitochondrial function, challenging its pseudogene status.