Defective mitochondrial cardiolipin remodeling dampens HIF-1a expression in hypoxia. Defective mitochondrial cardiolipin remodeling dampens HIF-1a expression in hypoxia

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, mutes HIF-1a signaling in hypoxia. Tafazzin-deficiency does not affect posttranslational HIF-1a regulation but rather HIF-1a 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-kB activation and concomitantly HIF-1a gene-expression. In agreement, Tafazzin-deficient mice hearts display reduced HIF-1a levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin-remodeling dampens HIF-1a signaling through inactivation of a non-canonical signaling pathway: Lack of NF-kB activation through reduced mitochondrial ROS production diminishes HIF-1a transcription. Overall design: Cells lacking tafazzin were subjected to hypoxia and compared to the ones at normoxia or isogenic WT cells either at hypoxia or nomoxia

线粒体（Mitochondria）是细胞内关键的代谢执行者，同时也是重要的细胞信号枢纽，可将自身代谢状态整合至细胞微环境中。本研究证实，当心磷脂酰转移酶（cardiolipin acyl transferase）Tafazzin缺失时，存在功能缺陷的心磷脂重塑（cardiolipin-remodeling）会抑制缺氧环境下的HIF-1α（HIF-1a）信号通路。Tafazzin缺失并不会影响HIF-1α的翻译后调控过程，而是会干扰其基因表达；这一功能缺陷在携带Tafazzin缺失突变的巴尔特综合征（Barth Syndrome）患者的诱导多能干细胞（induced pluripotent stem cells, iPSCs）分化心肌细胞中得到了重现。RNA测序（RNAseq）分析结果显示，Tafazzin突变细胞的信号通路发生了显著改变。在缺氧条件下，Tafazzin缺失细胞的活性氧（reactive oxygen species, ROS）生成量降低，这会干扰核因子κB（NF-kB）的激活，并随之影响HIF-1α的基因表达。与此一致，Tafazzin缺失小鼠的心脏组织中HIF-1α水平显著降低，且在受到压力超负荷刺激时会出现适应性不良的心肌肥厚，并最终引发心力衰竭。综上，本研究认为线粒体心磷脂重塑缺陷可通过失活一条非经典信号通路（non-canonical signaling pathway）抑制HIF-1α信号通路：线粒体活性氧生成减少导致核因子κB无法激活，进而削弱HIF-1α的转录过程。实验设计：将缺失Tafazzin的细胞置于缺氧环境中培养，并分别与常氧环境下的同批缺失细胞、以及常氧或缺氧环境下的同基因野生型（wild type, WT）细胞进行对照比较。