Universität zu Köln

Hofer, Annette, Noe, Natalie, Tischner, Christin, Kladt, Nikolay, Lellek, Veronika, Schauss, Astrid and Wenz, Tina (2014). Defining the action spectrum of potential PGC-1 activators on a mitochondrial and cellular level in vivo. Hum. Mol. Genet., 23 (9). S. 2400 - 2416. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Previous studies have demonstrated a therapeutic benefit of pharmaceutical PGC-1 activation in cellular and murine model of disorders linked to mitochondrial dysfunction. While in some cases, this effect seems to be clearly associated with boosting of mitochondrial function, additional alterations as well as tissue- and cell-type-specific effects might play an important role. We initiated a comprehensive analysis of the effects of potential PGC-1-activating drugs and pharmaceutically targeted the PPAR (bezafibrate, rosiglitazone), AMPK (AICAR, metformin) and Sirt1 (resveratrol) pathways in HeLa cells, neuronal cells and PGC-1-deficient MEFs to get insight into cell type specificity and PGC-1 dependence of their working action. We used bezafibrate as a model drug to assess the effect on a tissue-specific level in a murine model. Not all analyzed drugs activate the PGC pathway or alter mitochondrial protein levels. However, they all affect supramolecular assembly of OXPHOS complexes and OXPHOS protein stability. In addition, a clear drug- and cell-type-specific influence on several cellular stress pathways as well as on post-translational modifications could be demonstrated, which might be relevant to fully understand the action of the analyzed drugs in the disease state. Importantly, the effect on the activation of mitochondrial biogenesis and stress response program upon drug treatment is PGC-1 dependent in MEFs demonstrating not only the pleiotropic effects of this molecule but points also to the working mechanism of the analyzed drugs. The definition of the action spectrum of the different drugs forms the basis for a defect-specific compensation strategy and a future personalized therapeutic approach.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hofer, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Noe, Natalie UNSPECIFIED UNSPECIFIED UNSPECIFIED Tischner, Christin UNSPECIFIED UNSPECIFIED UNSPECIFIED Kladt, Nikolay UNSPECIFIED UNSPECIFIED UNSPECIFIED Lellek, Veronika UNSPECIFIED UNSPECIFIED UNSPECIFIED Schauss, Astrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Wenz, Tina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-440038
DOI:	10.1093/hmg/ddt631
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	23
Number:	9
Page Range:	S. 2400 - 2416
Date:	2014
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BIOGENESIS; PGC-1-ALPHA; EXPRESSION; INTEGRATION; IMPROVES; CELLS; MODEL; METABOLISM; MYOPATHY; DISEASE Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44003