Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany.
Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany.
EMBO Mol Med. 2023 Sep 11;15(9):e17399. doi: 10.15252/emmm.202317399. Epub 2023 Aug 3.
Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZ mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid-driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZ . Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.
线粒体是细胞代谢和能量供应的核心。巴特综合征（BTHS）是一种严重的疾病，由于线粒体心磷脂酰基转移酶 tafazzin 的功能障碍。心磷脂重塑的改变会影响线粒体内膜的组织和膜蛋白的功能，如转运蛋白和氧化磷酸化（OXPHOS）系统。在这里，我们描述了一种携带 tafazzin 中 G197V 交换的小鼠模型，该交换对应于 BTHS 患者。TAZ 小鼠重现了包括心脏功能障碍和氧化磷酸化减少在内的特定疾病病理学。我们表明，由于肉毒碱棕榈酰转移酶水平降低，突变线粒体显示出脂肪酸驱动的氧化磷酸化功能缺陷。在小鼠心脏和患者诱导多能干细胞衍生的心肌细胞中，明显出现了从 OXPHOS 到糖酵解的 ATP 产生的代谢转换。糖酵解 ATP 产生的增加使 AMPK 失活，导致 TAZ 中代谢信号的改变。用 AMPK 激活剂处理突变细胞可重建脂肪酸驱动的 OXPHOS，并保护小鼠免受心脏功能障碍。
