A dynamic gateway: Uncovering the expanded human TOM complex interactome and its regulatory complexity

Area of Science:

• Cell Biology
• Mitochondrial Biology
• Proteomics

Background:

• The translocase of the outer mitochondrial membrane (TOM) complex is essential for importing nuclear-encoded proteins into mitochondria.
• The human TOM complex functions within a highly complex cellular environment compared to simpler organisms.
• Understanding the human TOM interactome is crucial for elucidating mitochondrial function in health and disease.

Purpose of the Study:

• To generate a high-confidence map of the human TOM complex interactome.
• To identify both stable and transient protein interactions within the human TOM complex.
• To uncover human-specific interactors and understand their roles in mitochondrial regulation.

Main Methods:

• Utilized a membrane-permeable cross-linker to capture protein interactions.
• Employed mass spectrometry-based proteomics to identify interactors.
• Analyzed interprotein cross-links to map complex organization and conformational flexibility.

Main Results:

• Identified a comprehensive map of the human TOM interactome with significant overlap with yeast partners.
• Discovered novel human-specific interactors, including regulatory factors and quality control proteins.
• Revealed conformational flexibility in TOM20 and identified FKBP8 as a human-specific interactor that organizes the TOM complex.

Conclusions:

• The human TOM complex is a dynamic hub integrating protein biogenesis, quality control, and signaling pathways.
• The identified human-specific interactors highlight unique aspects of mitochondrial regulation in humans.
• This expanded interactome provides a valuable resource for studying mitochondrial dysfunction in diseases.