Sorting and membrane integration of mitochondrial outer membrane proteins

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Dokumentart: Dissertation
Date: 2018-10-05
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biochemie
Advisor: Rapaport, Doron (Prof. Dr.)
Day of Oral Examination: 2018-07-24
DDC Classifikation: 500 - Natural sciences and mathematics
Keywords: Mitochondrium
License: Publishing license including print on demand
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The various cellular activities of eukaryotic cells are confined in different organelles. The compartmentalization of the cytosol requires a fine regulation of the distribution of newly synthesized proteins to the destined organelle. Targeting pathways ensure the accurate sorting of protein and help to avoid mislocalization. They are organelle-specific and discriminate among the substrate proteins according to their topology and targeting signals. Tail-anchored (TA) proteins are inserted into the lipid bilayer via a single C-terminal transmembrane segment that constitutes also the targeting signal. These proteins are mainly imported into the endoplasmic reticulum (ER) and the outer mitochondrial membrane (OMM). TA proteins are targeted to the ER by the guided entry of TA proteins (GET) pathway, while it is unclear how they are directed and inserted into the OMM. Interestingly, when the mitochondrial targeting is inefficient, OMM TA proteins are mislocalized to the ER. In this study, I analysed the role of the GET pathway in the missorting of TA proteins and I proved that this machinery could recognize mitochondrial proteins and direct them to the ER. These findings suggest the existence of a, yet unknown, mitochondrial targeting pathway that under physiological conditions is more efficient and wins the kinetic competition against other pathways. One important factor that mediates the membrane insertion of several OMM α-helical proteins is the MIM complex. It is composed by the proteins Mim1 and Mim2, which have been identified only in fungi, while no homologues could be found in other eukaryotes. The MIM complex is important for mitochondrial functionality and its loss causes impaired mitochondria biogenesis, alteration of mitochondrial morphology and severe growth defects. It is still unclear how the crucial functions of this complex are mediated in other eukaryotes. In this work, I analysed the capacity of the trypanosomal OMM protein pATOM36 to rescue the phenotypes caused by the absence of the MIM complex. Reciprocal complementation studies demonstrated that this protein is a functional analogue of the MIM complex. This discovery suggests that pATOM36 and the Mim1/Mim2 complex are the result of a convergent evolution that happened after fungi and trypanosomatids diverged.

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