Interconnectivity of mitochondrial protein biogenesis and homeostasis
Abstract: To ensure correct protein function, the cells are equipped with a tightly regulated network of chaperones that support protein folding and actively participate in protein quality control (PQC) and turnover. Due to the dual origin of the mitochondrial proteome, the cytosolic and mitochondrial PQC networks coordinate to ensure protein import and assembly in the organelle. In particular, chaperones play crucial roles during protein synthesis and de novo folding, but also during protein import and insertion into membranes. Despite the increasing knowledge on the involvement of the cytosolic chaperone networks on surveilling mitochondrial proteins prior and during import, many aspects of the function of the mitochondrial PQC systems are still enigmatic.In this thesis I focused on shedding light on the molecular mechanisms underlying protein aggregate handling and chaperone-dependent folding capacity in mitochondria as well as understanding the effect of metals on mitochondrial protein stability and the dual origin of some mitochondrial proteins. Paper I, studies the relevance of the metabolic status of the cells in protein aggregate handling and identifies newly synthetized proteins as the main source of aggregates. In line with this, in Paper II we have developed a novel reporter that allows us to study the capacity of the folding chaperones in vivo under acute or chronic stress. Paper III, analyses the effects of Mn2+ overdose on protein stability and its implications in mitochondrial homeostasis and Paper IV, explores the dual origin of the novel component of the α-ketoglutarate dehydrogenase complex, Kgd4.
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