Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress

  • Proteins need to be folded into their native conformation to fulfill their function. However, perturbations of the transport, folding, and assembly lead to the misfolding of proteins and challenge cellular protein homeostasis (proteostasis). Therefore, cells evolved an elaborate chaperone and protease network to deal with such conditions. Chaperone-mediated protein folding and proteasomal degradation clear the cytosol from misfolded proteins. Moreover, misfolded proteins can be sequestered into aggregates to lower the proteostasis network's workload and reduce toxic effects. Proteins imported into mitochondria fold and assemble only upon successful import and are, therefore, no longer subject to cytosolic quality control. Mitochondrial chaperones and proteases that are part of the mitochondrial proteostasis network have been identified and characterized. Still, factors that facilitate, control, and resolve aggregates for the sequestration of misfolded proteins are largely unknown. In this study, I aimed to characterize the formation of protein aggregates in the mitochondrial matrix. On the one hand, I elucidated the role of the matrix disaggregase, Hsp78. Hsp78 associates with protein aggregates upon the induction of heat stress or when misfolded model proteins are imported into the mitochondrial matrix. By employing microscopy and proteomic analysis, I showed that Hsp78 interacts with protein aggregates and helps to recover from stress by refolding them. At the same time, non-productive refolding of aggregates leads to proteolytic degradation via the matrix master protease Pim1. On the other hand, I identified the mitochondrially encoded protein Var1 as a novel component of the matrix proteostasis network. Var1 is a mitochondrially encoded protein of the mitochondrial ribosome, but I discovered that Var1 has a second, independent function as it induces the formation of aggregates, which I named Var1 bodies. This aggregation-prone behavior is associated with the proteins' unusual sequence of many asparagine repeats. Hsp78 and Var1 bodies are distinct structures, absorbing different sets of proteins. Moreover, whereas Hsp78 aggregates form only transiently, Var1 bodies are persistent and are not resolved once stress conditions are over. My findings show that the formation of aggregates in the matrix shows clear parallels to that in the cytosol: Hsp78, like Hsp104, binds various protein aggregates from which some get un- and refolded while others are degraded by the Pim1 protease. Var1, on the other hand, acts like the cytosolic prion-protein Rnq1 that forms insoluble protein deposits that absorb and sequester other cellular proteins.

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Metadaten
Author:Lea Tamara BertgenORCiD
URN:urn:nbn:de:hbz:386-kluedo-76141
Advisor:Johannes M. Herrmann
Document Type:Doctoral Thesis
Cumulative document:No
Language of publication:English
Date of Publication (online):2024/01/11
Year of first Publication:2024
Publishing Institution:Rheinland-Pfälzische Technische Universität Kaiserslautern-Landau
Granting Institution:Rheinland-Pfälzische Technische Universität Kaiserslautern-Landau
Acceptance Date of the Thesis:2023/12/18
Date of the Publication (Server):2025/01/23
Page Number:XII, 117
Faculties / Organisational entities:Kaiserslautern - Fachbereich Biologie
DDC-Cassification:5 Naturwissenschaften und Mathematik / 570 Biowissenschaften, Biologie
Licence (German):Creative Commons 4.0 - Namensnennung, nicht kommerziell, keine Bearbeitung (CC BY-NC-ND 4.0)