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Introduction: Mitochondrial Biogenesis

 
Mitochondria are organelles of endosymbiotic origin that play crucial roles in energy metabolism and many biosynthetic pathways. Moreover, they are intimately involved in regulatory circuits, such a Ca2+ signaling, and cell fate decisions, such as programmed cell death (apoptosis). Mitochondria are engulfed by two membrane systems, the inner membrane and the outer membrane, that define two aqueous compartments, the intermembrane space and the matrix. Proteomic studies have revealed that mitochondria contain more than 1,000 different proteins, more than 99% of which are encoded by nuclear DNA. Thus, these proteins are synthesized as precursors on cytosolic ribosomes, specifically targeted to mitochondria and sorted into one of the four mitochondrial subcompartments. Various protein translocation machineries of the inner and outer mitochondrial membranes accomplish the complicated task of selective protein sorting into and across lipid bilayers.
 
 

Protein Translocation und Membrane Protein Insertion at the Inner Mitochondrial Membrane

 
The presequence translocase of the inner mitochondrial membrane (TIM23 complex) mediates transport of proteins with N-terminal cleavable presequences. Presequence proteins are directly transferred from the general outer membrane translocase (TOM complex) to the TIM23 machinery. Depending on further signal information within presequence proteins, they are either inserted into the inner mitochondrial membrane or imported across the membrane into the matrix. Selective sorting of proteins to different destinations requires dynamic switches in the TIM23 machinery and the reversible association with distinct partner protein complexes at the inner membrane. For matrix translocation, TIM23 is coupled to the ATP-driven presequence translocase-associated import motor (PAM). Membrane insertion by a stop-transfer mechanism is facilitated through the association of TIM23 with the proton-pumping respiratory chain complexes via the regulatory Tim21 subunit. We are investigating, how these large-scale dynamic rearrangements in the TIM23 machinery are regulated by import signals of incoming presequence proteins.

 

 tim23

How and where are these import signals perceived and transmitted?
 
Which mechanisms trigger the signal-dependent switches in the TIM23 system?
 
How are transmembrane segments recognized by the receptor domain and/or the protein-conducting channel of the machinery and how are they laterally released into the inner mitochondrial membrane?
 
What are the distinct steps in the reaction cycle of the import motor? 
 
How is the energy derived from the membrane potential across the inner mitochondrial membrane coupled to protein transport?
 
How are the dynamic transitions modulated by auxiliary factors and the overall metabolic state of mitochondria?

 

 

Generation and Maintenance of Mitochondrial Inner Membrane Morphology

 
The inner mitochondrial membrane is characterized by a very peculiar morphology. It consists of an inner boundary membrane that is closely opposed to the outer mitochondrial membrane and large tubular invaginations termed cristae. Whereas the inner boundary membrane is enriched in protein complexes devoted to transport of metabolites and preproteins, the cristae are the main sites of oxidative phosphorylation. The border regions between inner boundary and cristae membranes are morphologically well defined and have been named crista junctions. We are interested in the question, how the characteristic morphology of the inner mitochondrial membrane is generated and maintained. Several factors, like the oligomeric F1Fo-ATP synthase, the dynamin-like GTPase Mgm1/OPA1 and proteins of the mitofilin family, have been implicated in these processes. We have recently identified a novel, evolutionary conserved inner membrane protein complex that we termed Mitochondrial INner membrane Organizing System (MINOS). MINOS consists of the core subunits Mio10/MINOS1 and Fcj1/IMMT/MINOS2 together with at least four other subunits and forms large oligomeric structures of several Megadaltons in size. Mutants with defective assembly of MINOS show dramatically altered inner membrane morphology with extended stacks of sheet-like cristae that are detached from the inner boundary membrane. Moreover, MINOS components are engaged in multiple interaction sites between inner and outer mitochondrial membranes (contact sites). We are studying the molecular mechanisms of MINOS function and dynamics. Moreover, we aim to understand the relationship between MINOS and other machineries involved in mitochondrial morphology, metabolite transport and protein biogenesis.

 

 mions

We are always interested in qualified postdocs and graduate students.
We offer diverse diploma/master thesis projects for students of Molecular Medicine!
If you are interested, please contact:
PD Dr. Martin van der Laan
Institute for Biochemistry and Molecular Biology
University of Freiburg
Stefan-Meier-Straße 17
D-79104 Freiburg
Germany
E-Mail: martin.van.der.laanbiochemie.uni-freiburg.de

 

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