Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Wende, AR; O'Neill, BT; Bugger, H; Riehle, C; Tuinei, J; Buchanan, J; Tsushima, K; Wang, L; Caro, P; Guo, A; Sloan, C; Kim, BJ; Wang, X; Pereira, RO; McCrory, MA; Nye, BG; Benavides, GA; Darley-Usmar, VM; Shioi, T; Weimer, BC; Abel, ED.
Enhanced cardiac Akt/protein kinase B signaling contributes to pathological cardiac hypertrophy in part by impairing mitochondrial function via transcriptional repression of mitochondrion-targeted nuclear genes.
Mol Cell Biol. 2015; 35(5): 831-846.
Doi: 10.1128/MCB.01109-14
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- Co-Autor*innen der Med Uni Graz
- Bugger Heiko Matthias
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- Abstract:
- Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor α (PPARα)/PGC-1α and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Adenosine Triphosphate - metabolism
- Animals -
- Cardiomegaly - metabolism
- Cell Nucleus - metabolism
- Fatty Acids - metabolism
- Female -
- Gene Expression Profiling -
- Gene Expression Regulation -
- Glycolysis -
- Heart - physiology
- Hemodynamics -
- Hypertrophy -
- Male -
- Mice -
- Mitochondria - metabolism
- Muscle Cells - cytology
- Oxygen - metabolism
- PPAR alpha - metabolism
- Proteomics -
- Proto-Oncogene Proteins c-akt - metabolism
- Signal Transduction -
- Transcription, Genetic -
- Transgenes -