Project Details
Projekt
Coordination of proteostasis and mitochondrial intermembrane space protein import
Applicants
Professor Dr. Thorsten Hoppe; Professor Dr. Jan Riemer
Subject Area
Biochemistry
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 541742459
Mitochondria have important functions. To do this, they have to import the majority of their approximately 1,500 proteins from the cytosol. Interestingly, many proteins destined for the mitochondrial intermembrane space (IMS) do not contain a classical N-terminal mitochondrial targeting sequence. Instead, they contain conserved cysteine residues and hydrophobic patches that allow them to interact with the so-called disulfide relay import machinery in the IMS. Notably, these proteins look like cytosolic proteins at first glance, and some have been reported to have dual localization in mitochondria and other compartments or in the cytosol. These disulfide relay-dependent proteins are synthesized on cytosolic ribosomes and imported post-translationally. Inactivation of the disulfide relay leads to their accumulation in the cytosol where they remain relatively stable before being degraded. In yeast, it has been shown that this accumulation leads to a stress response that attenuates translation and increases proteasome activity. In particular, it remains unclear how these substrates are targeted to the mitochondria, how they recognize the import pores of the outer mitochondrial membrane, how they are stabilized and what finally triggers their degradation in the cytosol. For higher eukaryotes, knowledge of these cytosolic processes is even more limited. In this project, the Riemer and the Hoppe labs, with their complementary expertise in IMS protein import and the ubiquitin/proteasome-system, respectively, will address this knowledge gap. By combining an organismal (C. elegans) and a cellular (human tissue culture cells) model, we will unravel evolutionarily conserved and specialized processes and factors in the targeting and handling of disulfide relay-dependent precursors in the cytosol. In addition, we will assess the consequences of the accumulation of disulfide relay-dependent precursors in the cytosol with respect to the initiation of stress response programs and the pathways driving the clearance of cytosolic substrates. Moreover, we will use C. elegans as a model to characterize the physiological role of the mitochondrial disulfide relay system in a multicellular organism. Overall, with this project we will unravel the cytosolic processes involved in IMS protein import and understand the consequences of impaired import from a mechanistic and organismal perspective. We will bring to the SPP our combined expertise in the mechanistic analysis of IMS protein import in human cells and an organismal perspective on mitochondrial protein import in C. elegans, and at the same time, we hope to benefit from the intensive exchange of ideas, expertise and experience in this consortium.
DFG Programme
Priority Programmes
