Defective mitochondrial cardiolipin-remodeling dampens HIF1- transcription Peter Rehling1,8, Arpita Chowdhury1, Abhishek Aich1, Jain Gaurav2, Katharina Wozny3, Christian Lüchtenborg3, Magnus Hartmann1, Olaf Bernhard1, Martina Balleiniger1, Ezzaldin Ahmed Alfar4, Anke Zieseniss5, Kaomei Guan4, Silvio O. Rizzoli6, Britta Brügger3, Andrè Fischer2,7, Dörthe M. Katschinski5, & Jan Dudek1, 1Department of Cellular Biochemistry, University Medical Center Göttingen, GZMB, D-37073 Göttingen, Germany. 2Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany. 3Heidelberg University Biochemistry Center (BZH), 69120 University of Heidelberg, Heidelberg 69120, Germany. 4Institute of Pharmacology and Toxicology, Technische Universität Dresden, Germany. 5Institute of Cardiovascular Physiology, University Medical Center Göttingen, Göttingen, Germany. 6Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany. 7Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany. 8Max Planck Institute for Biophysical Chemistry, D-37077, Göttingen, Germany.
Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs integrating their metabolic status into the cellular context. In case of the heart, mitochondria provide 90% of the energy demand by oxidative phosphorylation. Accordingly, defects in mitochondrial functions are frequently linked to human disorders. Barth Syndrome represents a severe X-linked cardiomyopathy caused by mutations in the TAZ gene, encoding the mitochondrial transacylase Tafazzin. Tafazzin facilitates cardiolipin remodeling, converting monolysocardiolipin to a mature cardiolipin molecule with distinct unsaturated fatty acid side chain composition. Concomitantly, the altered lipid composition affects morphology of the mitochondrial inner membrane as well as activity and organization of the oxidative phosphorylation system. Here, we show that defective cardiolipin-remodeling, upon loss of the cardiolipin acyl transferase Tafazzin, mutes HIF-1 signaling in hypoxia. Tafazzin-deficiency does not affect posttranslational HIF-1 regulation but rather HIF-1 gene-expression, a dysfunction recapitulated in iPSCs-derived cardiomyocytes from Barth Syndrome patients with Tafazzin-deficiency. RNAseq analyses confirmed drastically altered signaling in Tafazzin mutant cells. In hypoxia, Tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-B activation and concomitantly HIF-1 gene-expression. In agreement, Tafazzin-deficient mice hearts display impaired HIF-1 stabilization and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin-remodeling dampens HIF-1 signaling through inactivation of a non-canonical signaling pathway: Lack of NF-B activation through reduced mitochondrial ROS production diminishes HIF-1 transcription.
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