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  Proteome and metabolome changes associated with mitochondrial diseases

Aretz, I. (2016). Proteome and metabolome changes associated with mitochondrial diseases. PhD Thesis.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-F1E7-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-F1E8-0
Genre: Thesis

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Mitochondrial diseases are a group of metabolic disorders with heterogeneous phe-notypes that are frequently characterized by anomalies of oxidative phosphorylation (OXPHOS). To date, hundreds of mutations affecting the nuclear and mitochondrial DNA (mtDNA) have been associated with mitochondrial disease, but with little in-vestigation of the underlying pathogenic mechanisms. This thesis presents a holistic view of regulatory mechanisms in mitochondrial diseases by integrating quantitative metabolome and proteome data derived from a cell line with a complex I deficiency induced by rotenone and a cell line lacking mtDNA (ρ0 cells). In rotenone treated cells, energy producing pathways such as the respiratory chain, glycolysis, the pen-tose phosphate pathway (PPP), the galactose metabolism and the tricarboxylic acid (TCA) cycle were down-regulated. A protein-protein interaction (PPI) and pathway analysis revealed that proteins involved in cell division processes were increased, while proteins related to the cytoskeleton were decreased. Furthermore, a deficiency of complex I causes a disruption in the iron-sulfur (Fe-S) cluster assembly, resulting in an impairment of redox reactions. In cells lacking mtDNA, mitochondrial energy pathways were down-regulated as well, but data integration revealed that ρ0 cells perform anaerobic glycolysis for sufficient energy supply. Furthermore, a remarka-ble de-ubiquitination was observed, especially of proteins involved in the cytoskele-ton, cytosolic ribosomal proteins and solute carrier (SLC) amino acid transporters. Signaling pathways were significantly up-regulated on the proteome level, which was further supported by a dephosphorylation of proteins involved in GTPase signal-ing and the cytoskeleton organization. Perturbation of the mitochondrial energy me-tabolism could cause an activation of the mitochondrial retrograde response, as ob-served by proteome data and phosphorylation patterns of GTPase signaling pathways in ρ0 cells. In conclusion, the integrated omics approach revealed possible regulato-ry mechanisms and features of mitochondrial diseases in order to adapt to the changed energy metabolism.
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 Creators:
Aretz, Ina1, 2, Author              
Affiliations:
1Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              
2Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin, ou_persistent22              

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Language(s): eng - English
 Dates: 2016-06-07
 Publication Status: Accepted / In Press
 Pages: xiv, 145
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 Rev. Method: -
 Identifiers: URN: urn:nbn:de:kobv:188-fudissthesis000000102467-6
 Degree: PhD

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