A Biochemical and Structural Understanding of TOM Complex Interactions and Implications for Human Health and Disease.

Ashley S Pitt,Susan K Buchanan

doi:10.3390/cells10051164

Abstract

The central role mitochondria play in cellular homeostasis has made its study critical to our understanding of various aspects of human health and disease. Mitochondria rely on the translocase of the outer membrane (TOM) complex for the bulk of mitochondrial protein import. In addition to its role as the major entry point for mitochondrial proteins, the TOM complex serves as an entry pathway for viral proteins. TOM complex subunits also participate in a host of interactions that have been studied extensively for their function in neurodegenerative diseases, cardiovascular diseases, innate immunity, cancer, metabolism, mitophagy and autophagy. Recent advances in our structural understanding of the TOM complex and the protein import machinery of the outer mitochondrial membrane have made structure-based therapeutics targeting outer mitochondrial membrane proteins during mitochondrial dysfunction an exciting prospect. Here, we describe advances in understanding the TOM complex, the interactome of the TOM complex subunits, the implications for the development of therapeutics, and our understanding of the structure/function relationship between components of the TOM complex and mitochondrial homeostasis.

Highlights

Mitochondria are double membrane-bound organelles primarily responsible for energy production in eukaryotes
While advances in our understanding of the yeast the outer membrane (TOM) complex have served as the foundation for much of the knowledge of mitochondrial protein import in humans, the increased complexity of humans reveals some distinct differences in how components of the TOM complex are able to function (Figure 2)
Targeted studies on the TOM complex components in humans reveal a broad interactome that serves the various needs of mitochondria across cell types and disease states

Summary

Introduction

Mitochondria are double membrane-bound organelles primarily responsible for energy production in eukaryotes. The importance of mitochondria to cellular function and homeostasis makes the organelle an essential target for understanding human health and disease. Most studies on the TOM complex have focused on the fungal homologs; some studies in humans show that various subunits play specific roles in neurodegeneration, innate immunity, hepatic regeneration, and cellular stress response. As the general import pathway for mitochondrial proteins, in addition to interacting with proteins during translocation, TOM complex subunits interact with mature proteins to carry out mitochondrial functions. We discuss advances in our understanding of the mitochondrial import machinery, of the interactome of TOM subunits as it relates to human health and disease, and of mitochondrial protein import dysregulation that teaches us about pathology and the development of therapeutics (Figure 2).

Structure and Functional Data on the TOM Complex

Observed Structural Arrangements of the TOM Complex and Interplay with Other

The Role of the TOM Complex Subunits in Human Health and Disease

Conclusions