Project Details
Projekt
Role of interorgan communication in balancing proteostasis and mitochondrial function
Applicant
Professorin Dr. Aleksandra Trifunovic
Subject Area
Cell Biology
Biochemistry
Biochemistry
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 531902955
To manage the buildup of misfolded proteins, cells activate compartment-specific quality control pathways that coordinate proteostasis maintenance and cell death. The mitochondrial stress response (MSR) is initiated when respiratory chain biogenesis is disrupted or mitochondrial proteostasis is compromised. MSR is characterized by transcriptional activation resembling the integrated stress response (ISR), which is followed by the upregulation of the mitochondrial unfolded protein response (UPRmt), occurring only in the late stages of MSR. Recent findings have shown that mitochondrial disturbances in individual tissues can lead to cell non-autonomous, systemic metabolic changes, potentially triggered by the cytokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), released in response to mitochondrial dysfunction. Our recent findings demonstrated that cardiac-specific FGF21 exerts a cell-non-autonomous effect on peripheral tissues, that is cell-type and dose dependent Additionally, our unpublished data suggest significant crosstalk between brown and white adipocytes, influencing proteostatic fitness even in the tissue not directly affected by mitochondrial dysfunction. Together, these findings form the foundation of our project, which aims to identify cell non-autonomous regulatory mechanisms that coordinate proteostasis with impaired mitochondrial function through interorgan communication. We will utilize our newly developed cell-specific mouse models with disrupted mitochondrial proteostasis, in combination with FGF21 and GDF15 mitokine depletion, to explore these mechanisms.
DFG Programme
Research Units
