Defective mitochondrial cardiolipin remodeling dampens HIF-1α expression in hypoxia
Summary - Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs, integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin remodeling, upon loss of the cardiolipin acyl transferase tafazzin, decreases HIF-1α signaling i...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
October 16, 2018
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| In: |
Cell reports
Year: 2018, Volume: 25, Issue: 3, Pages: 561-570, e1-e6 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2018.09.057 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1016/j.celrep.2018.09.057 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S221112471831502X 
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| Author Notes: | Arpita Chowdhury, Abhishek Aich, Gaurav Jain, Katharina Wozny, Christian Lüchtenborg, Magnus Hartmann, Olaf Bernhard, Martina Balleiniger, Ezzaldin Ahmed Alfar, Anke Zieseniss, Karl Toischer, Kaomei Guan, Silvio O. Rizzoli, Britta Brügger, Andrè Fischer, Dörthe M. Katschinski, Peter Rehling, and Jan Dudek |
| Summary: | Summary - Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs, integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin remodeling, upon loss of the cardiolipin acyl transferase tafazzin, decreases HIF-1α signaling in hypoxia. Tafazzin deficiency does not affect posttranslational HIF-1α regulation but rather HIF-1α gene expression, a dysfunction recapitulated in iPSC-derived cardiomyocytes from Barth syndrome patients with tafazzin deficiency. RNA-seq analyses confirmed drastically altered signaling in tafazzin mutant cells. In hypoxia, tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-κB activation and concomitantly HIF-1α gene expression. Tafazzin-deficient mice hearts display reduced HIF-1α levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin remodeling dampens HIF-1α signaling due to a lack of NF-κB activation through reduced mitochondrial ROS production, decreasing HIF-1α transcription. |
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| Item Description: | Gesehen am 07.05.2019 |
| Physical Description: | Online Resource |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2018.09.057 |