Evolutionary Divergence and Essentiality of the Single Tim17‐Centered Translocase of the Mitochondrial Inner Membrane in Trypanosoma brucei

Abstract

ABSTRACT Translocase of the mitochondrial inner membrane (TIM) is essential for importing nuclear‐encoded proteins, a critical process for organelle biogenesis and function. While TIM is well‐characterized in a wide range of eukaryotes, it is remarkably divergent in the parasitic protozoan Trypanosoma brucei , the causative agent of human and animal African trypanosomiasis. Unlike the canonical TIM23 and TIM22 complexes found in opisthokonts, T. brucei possesses a single, essential TIM complex built around a central subunit, TbTim17. This review synthesizes recent research to delineate the unique composition, assembly, and multifaceted functions of this complex. The core components have been described, including the trypanosome‐specific subunits TbTim54 and TbTim62, and the essential roles of accessory factors like the intermembrane space protein TbTim15, the chaperone TbTRAP1, and the divergent small Tim network. Furthermore, we explore the complex's unexpected versatility in importing not only presequence‐containing proteins and carrier proteins but also cytosolic tRNAs. The phosphatase activity of TbTim50 and its role in cellular signaling and infectivity are also highlighted. The essential nature of the trypanosomal TIM complex across all life cycle stages, coupled with its significant structural differences from the host machinery, positions it as a promising source of novel therapeutic targets against trypanosomiases.