The human Miro GTPases (hMiros) have recently emerged as important mediators of mitochondrial transport and may significantly contribute to the development of disorders such as Alzheimer's and schizophrenia. The hMiros represent two highly atypical members of the Ras superfamily, and exhibit several unique features: the presence of a GTPase domain at both the N-terminus and C-terminus, the presence of two calcium-binding EF-hand domains and localisation to the mitochondrial outer membrane. Here, elucidation of Miro GTPase signalling pathway components was achieved through the use of molecular biology, cell culture techniques and proteomics. An investigation of this kind has not been performed previously; we hoped, through these techniques, to enable the profiling and identification of pathways regulated by the human Miro GTPases. The results indicate several novel putative interaction partners for hMiro1 and hMiro2, including numerous proteins previously implicated in neurodegenerative pathways and the development of schizophrenia. Furthermore, we show that the N-terminal GTPase domain appears to fine-tune hMiro signalling, with GTP-bound versions of this domain associated with a diverse range of interaction partners in comparison to corresponding GDP-bound versions. Recent evidences suggest that human Miros participate in host-pathogen interactions with Vibrio Cholerae type III secretion proteins. We have undertaken a bioinformatics investigation to identify novel pathogenic effectors that might interact with Miros.
Keywords: Atypical GTPase; Endoplasmic reticulum signalling; Miro1; Miro2; Mitochondrial function; Neurodegeneration; Proteomics; RhoC; Type III secretion system; VopE.