Project Details
Projekt
Causes, consequences and correction of mitochondrial protein misfolding
Subject Area
Biochemistry
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 541592768
Mitochondria are essential for nearly all eukaryotic life. Perhaps like no other organelle, their dysfunction is linked to human disease. A hallmark of mitochondrial dysfunction is a state of perturbed protein homeostasis (proteostasis). This can arise from an inability to properly transport, modify and fold mitochondrial precursor proteins generated in the cytosol, which must enter the organelle in an unfolded state. The consequences of the ensuing protein aggregation in the mitochondrial compartments and its triggers are poorly understood. As human mitochondria lack proteostasis factors in their own genomes, the organelle relies on mito-nuclear communication to overcome protein aggregation and sustain cellular health. If and how mitochondria are able to communicate protein aggregation to the nucleus is also largely unresolved. We will address these knowledge gaps in this tandem project, implemented as a continued collaboration between the labs of F.-Ulrich Hartl (key expertise: proteostasis, proteomics) and Lucas T. Jae (key expertise: mitochondrial protein import, genomics). Our highly complementary methodological expertise and physical proximity have been instrumental in the joint generation of the groundwork and will foster overall success of the project. We will address these specific points: 1. It is currently unclear how protein misfolding and aggregation in the mitochondrial matrix affects the organelle. Using an aggregating model protein - Mito-ß - we will determine if and how mitochondria combat matrix protein aggregates. In particular, we will decipher the role of proteases and mitophagy in the process, the latter of which can be triggered by defective precursor import and processing. We will also analyze the effects of bolstered chaperonin activity or perturbed integrated stress response (ISR) signaling in the context of matrix protein aggregates. 2. We previously unveiled that the mitoISR is set off in the mitochondrial intermembrane space (IMS). This can be accomplished by the meta-stable IMS proteins CHCHD10/2 in an unknown manner. We will elucidate the role of six mitochondrial proteins we identified to simultaneously control ISR signaling and soluble CHCHD10 levels, alongside the mitoribosome, whose activity determines the fate of CHCHD10/2 and which itself is strongly affected by matrix protein aggregates. This will clarify how matrix protein aggregation propagates into the IMS to launch the ISR mechanistically. 3. Protein aggregation can be detrimental but little is known about the specific toxicity of mitochondrial protein aggregates or the genetic landscape that modulates it. Finally, we will genetically dissect the cellular stress signaling elicited by mitochondrial protein aggregates and systematically probe the human genome for genes that bolster or worsen cellular fitness in the context of mitochondrial protein aggregation.
DFG Programme
Priority Programmes
