Endosymbiosis in Monoxenous Trypanosomatids: Biological and Metabolic Aspects

Endosymbiosis is a necessary process in eukaryotic evolution, yet the steps leading to full integration remain poorly understood. Trypanosomatids provide a comparative framework to study this transition through two independent systems representing distinct levels of integration. Strigomonadinae comprises a subfamily derived from a single ancestral acquisition, which maintains a single cytosolic bacterium closely synchronized with the host cell cycle. In contrast, Novymonas esmeraldas harbors multiple bacteria within symbiontophorous vacuoles, presenting a more limited coordination of division. The generation of aposymbiotic strains enables direct functional assessment of endosymbiont contributions to host biology. Comparative analyses reveal strong metabolic interdependence, with the endosymbiont supplying essential amino acids, heme, vitamins, and purines, while relying on the host for key metabolic resources including non-essential amino acids, cofactors, energy metabolism, and lipid biosynthesis. Beyond metabolism, the endosymbiont impacts protein homeostasis and cellular regulation, modulating proteolytic pathways such as GP63, cysteine peptidases, and the ubiquitin–proteasome system, as well as host networks involving kinetoplast-associated proteins (KAPs). Host-encoded endosymbiont-targeted proteins (ETPs) further mediate endosymbiont positioning, organization, and coordinated maintenance and division. Here, we critically synthesize current knowledge on mEHTs using a comparative framework based on interconnected dimensions of host–endosymbiont integration.