Analysis of MICOS independent Contact Sites between the inner and the outer membrane of mitochondria
Final Report Abstract
Mitochondria are characterized by their complex membrane architecture. Their aqueous reaction compartments are delimited from the cytosol by an envelope consisting of two membranes, the mitochondrial inner and outer membranes. Importantly, most of the reactions catalyzed within mitochondria occur in the matrix, the most inner compartment. Thus, a huge number of metabolites and signals has to be transported across these membranes to allow the communication between mitochondria and the rest of the cell. Specialized protein-protein interactions, so called contact sites, were thought to be essential for this communication. Most of the so far identified mitochondrial contact sites depend on the MICOS (mitochondrial contact site and cristae organizing system) complex, however, additional MICOS independent contact sites have to exist. The here reported projects aimed at the identification and characterization of these MICOS independent contact sites. In the first project we used an improved version of the previously applied method for isolation of mitochondrial contact sites to identify Cqd1 as a potential candidate. Cqd1, like Cqd2 and Coq8 is a member of the highly conserved UbiB protein kinase-like family. It was recently shown that Cqd1 in cooperation with Cqd2 is important for the distribution of coenzyme Q within the cell by a yet unknown mechanism. We localized Cqd1 in the mitochondrial inner membrane and identified a novel, MICOS independent contact site that is formed by Cqd1 and the outer membrane complex Por1-Om14. Our data suggested that Cqd1 is involved in the homeostasis of phospholipids, in addition to its role in coenzyme Q homeostasis. Thereby, Cqd1 and Cqd2 antagonistically contribute to mitochondrial biogenesis. Furthermore, we obtained evidence that a defined level of Cqd1 is essential for the maintenance of mitochondrial membrane architecture and the correct interaction of mitochondria with the endoplasmic reticulum. This additionally supports a function of Cqd1 in the formation of membrane contact sites. In the second project we initially characterized two largely uncharacterized mitochondrial proteins, Min8 and Mix17. Mix17 is particularly interesting since mutations in the mammalian homolog Mic14/ChChD10 were identified in patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) indicating a causal connection. Min8 was recently shown to be involved the assembly of the cytochrome c oxidase. Unexpectedly, we found that the N-Terminus of Mix17 is exposed to the cytosol in an energy dependent manner. Our data indicated that Mix17 spans the outer membrane through the TOM complex. Moreover, we showed that Mix17 interacts transiently with the inner membrane protein Min8. This transient, MICOS independent contact site might assist in the import of complex IV subunits and thus might support the efficient assembly and maximal activity of the respiratory chain. Importantly, this model would be in line with previous results and would help to explain the phenotype observed in ALS and FTD patients.
Publications
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The MICOS complex, a structural element of mitochondria with versatile functions. Biological Chemistry, 401(6-7), 765-778.
Khosravi, Siavash & Harner, Max E.
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Evidence of a role for cAMP in mitochondrial regulation in ovarian granulosa cells. Molecular Human Reproduction, 28(10).
Kaseder, Melanie; Schmid, Nina; Eubler, Katja; Goetz, Katharina; Müller-Taubenberger, Annette; Dissen, Gregory A.; Harner, Max; Wanner, Gerhard; Imhof, Axel; Forne, Ignasi & Mayerhofer, Artur
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RNA supply drives physiological granule assembly in neurons. Nature Communications, 13(1).
Bauer, Karl E.; Bargenda, Niklas; Schieweck, Rico; Illig, Christin; Segura, Inmaculada; Harner, Max & Kiebler, Michael A.
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The dsRBP Staufen2 governs RNP assembly of neuronal Argonaute proteins. Nucleic Acids Research, 50(12), 7034-7047.
Ehses, Janina; Schlegel, Melina; Schröger, Luise; Schieweck, Rico; Derdak, Sophia; Bilban, Martin; Bauer, Karl; Harner, Max & Kiebler, Michael A.
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An Improved Method to Isolate Mitochondrial Contact Sites. Journal of Visualized Experiments(196).
Khosravi, Siavash; Frickel, Johanna & Harner, Max E.
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The UbiB family member Cqd1 forms a novel membrane contact site in mitochondria. Journal of Cell Science, 136(10).
Khosravi, Siavash; Chelius, Xenia; Unger, Ann-Katrin; Rieger, Daniela; Frickel, Johanna; Sachsenheimer, Timo; Lüchtenborg, Christian; Schieweck, Rico; Brügger, Britta; Westermann, Benedikt; Klecker, Till; Neupert, Walter & Harner, Max E.
