Characterization of inner mitochondrial membrane architecture
Role of the MICOS complex in the inner mitochondrial membrane architecture
by Mariam Barbot
Date of Examination:2016-06-02
Date of issue:2016-08-26
Advisor:Prof. Dr. Michael Meinecke
Referee:Prof. Dr. Stefan Jakobs
Referee:Prof. Dr. Tobias Moser
Referee:Prof. Dr. Ralph Kehlenbach
Referee:Prof. Dr. Dörthe Katschinski
Referee:Prof. Dr. Claudia Steinem
Files in this item
Name:PhD Thesis Mariam Barbot.pdf
Size:11.3Mb
Format:PDF
Description:Characterization of inner mitochondrial membrane architecture
Abstract
English
The inner membrane of mitochondria is extensively folded and displays a complex architecture. Cristae junctions are highly curved tubular openings that separate the cristae membrane from the inner boundary membrane. They play a central role in many vital cellular processes (e.g. apoptosis) by compartmentalizing the inner mem- brane into morphologically and functionally distinct regions. The mitochondrial con- tact site and cristae organizing system (MICOS) is a conserved multi-subunit protein complex, which is found to be enriched at cristae junctions. The complex is believed to be necessary for maintaining the physiological cristae membrane morphology by stabilizing cristae junctions. In this thesis, the role of the MICOS core subunit, Mic10, in the formation and maintenance of cristae junctions was investigated. An in vitro bottom up approach, in combination with in organello studies, was used to address the direct role and molecular mechanism by which Mic10 sculpts the inner mitochondrial membrane at cristae junctions. The reconstitution of recombinantly expressed and purified Saccha- romyces cerevisiae Mic10 into artificial model membranes led to drastic membrane morphology changes. Membrane topology studies revealed that Mic10 contains two transmembrane domains that span the inner mitochondrial membrane in a hairpin-like structure. The ability of Mic10 to sculpt membranes depends on the protein’s homo- oligomerization through highly conserved glycine-rich motifs present in both trans- membrane domains. The disruption of Mic10 oligomerization by mutating glycine residues failed to induce curvature in model membranes and resulted in abnormal inner membrane architecture when expressed in yeast cells. Collectively, these findings demonstrate that membrane sculpting by Mic10 is es- sential for both cristae junction formation and stabilization.
Keywords: MICOS; Mic10; Membrane curvature