Item

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-1 alpha signaling in hypoxia. Tafazzin deficiency does not affect posttranslational HIF-1 alpha regulation but rather HIF-1 alpha 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-kappa B activation and concomitantly HIF-1 alpha gene expression. Tafazzin-deficient mice hearts display reduced HIF-1 alpha levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondria! cardiolipin remodeling dampens HIF-1 alpha signaling due to a lack of NF-kappa B activation through reduced mitochondrial ROS production, decreasing HIF-1 alpha transcription.