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Cell Rep. 2018 Oct 16;25(3):561-570.e6. doi: 10.1016/j.celrep.2018.09.057.

Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1α Expression in Hypoxia.

Author information

1
Department of Cellular Biochemistry, University Medical Center Göttingen, GZMB, 37073 Göttingen, Germany.
2
Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany.
3
Heidelberg University Biochemistry Center (BZH), University of Heidelberg, Heidelberg 69120, Germany.
4
Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany.
5
Institute of Cardiovascular Physiology, University Medical Center Göttingen, Göttingen, Germany.
6
Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), Göttingen, Germany.
7
Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany.
8
Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
9
Department of Cellular Biochemistry, University Medical Center Göttingen, GZMB, 37073 Göttingen, Germany; Max Planck Institute for Biophysical Chemistry, 37073, Göttingen, Germany. Electronic address: peter.rehling@medizin.uni-goettingen.de.

Abstract

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.

KEYWORDS:

Barth syndrome; Hif1 alpha; NF-κB signaling; ROS; cardiolipin; lipid; mitochondria; respiratory chain

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