TY - THES A1 - Kuhlow, Doreen T1 - Mitochondriale Dysfunktion aufgrund Frataxinmangels induziert ernährungsabhängig Symptome des Metabolischen Syndroms in der Maus Y1 - 2007 CY - Potsdam ER - TY - JOUR A1 - Thierbach, René A1 - Drewes, Gunnar A1 - Fusser, Markus A1 - Voigt, Anja A1 - Kuhlow, Doreen A1 - Blume, Urte A1 - Schulz, Tim Julius A1 - Reiche, Carina A1 - Glatt, Hansruedi A1 - Epe, Bernd A1 - Steinberg, Pablo A1 - Ristow, Michael T1 - The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals N2 - DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron-sulfur clusters). The nuclear-encoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte- specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA 104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation. Y1 - 2010 UR - http://www.biochemj.org/bj/toc.htm U6 - https://doi.org/10.1042/Bj20101116 SN - 0264-6021 ER - TY - JOUR A1 - Gohlke, Sabrina A1 - Zagoriy, Vyacheslav A1 - Inostroza, Alvaro Cuadros A1 - Meret, Michael A1 - Mancini, Carola A1 - Japtok, Lukasz A1 - Schumacher, Fabian A1 - Kuhlow, Doreen A1 - Graja, Antonia A1 - Stephanowitz, Heike A1 - Jähnert, Markus A1 - Krause, Eberhard A1 - Wernitz, Andreas A1 - Petzke, Klaus-Juergen A1 - Schürmann, Annette A1 - Kleuser, Burkhard A1 - Schulz, Tim Julius T1 - Identification of functional lipid metabolism biomarkers of brown adipose tissue aging JF - Molecular Metabolism N2 - Objective: Aging is accompanied by loss of brown adipocytes and a decline in their thermogenic potential, which may exacerbate the development of adiposity and other metabolic disorders. Presently, only limited evidence exists describing the molecular alterations leading to impaired brown adipogenesis with aging and the contribution of these processes to changes of systemic energy metabolism. Methods: Samples of young and aged murine brown and white adipose tissue were used to compare age-related changes of brown adipogenic gene expression and thermogenesis-related lipid mobilization. To identify potential markers of brown adipose tissue aging, non-targeted proteomic and metabolomic as well as targeted lipid analyses were conducted on young and aged tissue samples. Subsequently, the effects of several candidate lipid classes on brown adipocyte function were examined. Results: Corroborating previous reports of reduced expression of uncoupling protein-1, we observe impaired signaling required for lipid mobilization in aged brown fat after adrenergic stimulation. Omics analyses additionally confirm the age-related impairment of lipid homeostasis and reveal the accumulation of specific lipid classes, including certain sphingolipids, ceramides, and dolichols in aged brown fat. While ceramides as well as enzymes of dolichol metabolism inhibit brown adipogenesis, inhibition of sphingosine 1-phosphate receptor 2 induces brown adipocyte differentiation. Conclusions: Our functional analyses show that changes in specific lipid species, as observed during aging, may contribute to reduced thermogenic potential. They thus uncover potential biomarkers of aging as well as molecular mechanisms that could contribute to the degradation of brown adipocytes, thereby providing potential treatment strategies of age-related metabolic conditions. KW - Brown adipose tissue KW - Aging KW - Ceramides KW - Sphingolipids KW - Dolichol lipids Y1 - 2019 U6 - https://doi.org/10.1016/j.molmet.2019.03.011 SN - 2212-8778 VL - 24 SP - 1 EP - 17 PB - Elsevier CY - Amsterdam ER -