| First Author | Chowdhury A | Year | 2018 |
| Journal | Cell Rep | Volume | 25 |
| Issue | 3 | Pages | 561-570.e6 |
| PubMed ID | 30332638 | Mgi Jnum | J:270756 |
| Mgi Id | MGI:6278690 | Doi | 10.1016/j.celrep.2018.09.057 |
| Citation | Chowdhury A, et al. (2018) Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1alpha Expression in Hypoxia. Cell Rep 25(3):561-570.e6 |
| abstractText | 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-1alpha signaling in hypoxia. Tafazzin deficiency does not affect posttranslational HIF-1alpha regulation but rather HIF-1alpha 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-kappaB activation and concomitantly HIF-1alpha gene expression. Tafazzin-deficient mice hearts display reduced HIF-1alpha levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin remodeling dampens HIF-1alpha signaling due to a lack of NF-kappaB activation through reduced mitochondrial ROS production, decreasing HIF-1alpha transcription. |
