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Mitochondrial biogenesis and adequate energy production in various organs of mammals are necessary for postnatal adaptation to extrauterine life in an environment with high oxygen content. Even though transgenic mice are frequently used as experimental models, to date, no combined detailed molecular and morphological analysis on the mitochondrial compartment in different lung cell types has been performed during postnatal mouse lung development. In our study, we revealed a significant upregulation of most mitochondrial respiratory complexes at protein and mRNA levels in the lungs of P15 and adult animals in comparison to newborns. The majority of adult animal samples showed the strongest increase, except for succinate dehydrogenase protein (SDHD). Likewise, an increase in mRNA expression for mtDNA transcription machinery genes (Polrmt, Tfam, Tfb1m, and Tfb2m), mitochondrially encoded RNA (mt-Rnr1 and mt-Rnr2), and the nuclear-encoded mitochondrial DNA polymerase (POLG) was observed. The biochemical and molecular results were corroborated by a parallel increase of mitochondrial number, size, cristae number, and complexity, exhibiting heterogeneous patterns in distinct bronchiolar and alveolar epithelial cells. Taken together, our results suggest a specific adaptation and differential maturation of the mitochondrial compartment according to the metabolic needs of individual cell types during postnatal development of the mouse lung.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and morbidity globally, and its development is mainly associated with tobacco-induced oxidative stress. In the lung, pulmonary epithelia are the first targets of cigarette smoke components overwhelming the antioxidative capacity of the epithelial cells and contributing strongly to COPD pathogenesis. Peroxisomes are single membrane-bound organelles that possess heterogeneous functions and enzyme composition depending on the organ and cell type. Until the beginning of experimental work of this thesis, no information was available so far on the role of peroxisomes in the molecular pathogenesis of COPD. The fact that peroxisomes are abundant in the airway epithelia and that they could be directly affected by CS, as they are located underneath the apical surface of the epithelial cells, made us hypothesize that they could alter the molecular-pathogenesis of COPD. Peroxisomes could protect the pulmonary airway epithelium against ROS and lipotoxicity since they are rich in different antioxidative enzymes, they synthesize plasmalogens (ROS trapping lipids) and play an important role in beta-oxidation of eicosanoids.Therefore, the main goal of the thesis was to analyze the possible alterations of the peroxisomal compartment in lung samples of COPD patients and a mouse COPD model in comparison to control samples, and to study the functional consequences of cigarette smoke extract-treatment on the peroxisomal compartment in human HBE cells and mouse C22 cells in culture. Studying the peroxisomal alterations would clarify whether the impairment in peroxisomal metabolism could affect the molecular pathogenesis of COPD. Moreover, changes in the peroxisomal compartment, antioxidative enzymes and cytokines following Pex13 deletion, RZG treatment, PPARgamma overexpression or knockdown in cigarette smoke-treated cells could be detected.To get a complete overview of the peroxisomal compartment and its alteration in the pathogenesis of COPD, several techniques were used, such as: immunofluorescence with a variety of antibodies against peroxisomal and cell marker proteins, cell and lung tissue homogenization, Western blot analysis, total RNA isolation, qRT-PCR, molecular cloning, transfections, luciferase assays and ELISAsThe results of this thesis indicate that a peroxisomal gene expression (Cat, Pex13, Pex14, Acox1, Acaa1, Agps, Gnpat) and corresponding protein upregulation occurs in human and mouse COPD samples. Moreover, the knock-down of the peroxisomal biogenesis gene Pex13 provoked strong oxidative stress and a release of pro-inflammatory mediators suggesting a protective role of peroxisomes in preventing the chronification of inflammation in the disease pathogenesis. Furthermore, treatment with the PPARgamma agonist Rosiglitazone and PPARgamma overexpression were able to reverse the effects produced by cigarette smoke extract in C22 cells by inducing peroxisome proliferation by PPARgamma activation. These results revealed the important role of PPARgamma and the PPARgamma regulated peroxisomal response for the protection against chronification and aggravation of the inflammation in COPD.