Department of Internal Medicine, Cardiovascular Medicine, University of California, Davis, CA, USA.
Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.
Sci Rep. 2018 Nov 1;8(1):16213. doi: 10.1038/s41598-018-34451-2.
Heart failure (HF) is characterized by abnormal mitochondrial calcium (Ca) handling, energy failure and impaired mitophagy resulting in contractile dysfunction and myocyte death. We have previously shown that the 18-kDa mitochondrial translocator protein of the outer mitochondrial membrane (TSPO) can modulate mitochondrial Ca uptake. Experiments were designed to test the role of the TSPO in a murine pressure-overload model of HF induced by transverse aortic constriction (TAC). Conditional, cardiac-specific TSPO knockout (KO) mice were generated using the Cre-loxP system. TSPO-KO and wild-type (WT) mice underwent TAC for 8 weeks. TAC-induced HF significantly increased TSPO expression in WT mice, associated with a marked reduction in systolic function, mitochondrial Ca uptake, complex I activity and energetics. In contrast, TSPO-KO mice undergoing TAC had preserved ejection fraction, and exhibited fewer clinical signs of HF and fibrosis. Mitochondrial Ca uptake and energetics were restored in TSPO KO mice, associated with decreased ROS, improved complex I activity and preserved mitophagy. Thus, HF increases TSPO expression, while preventing this increase limits the progression of HF, preserves ATP production and decreases oxidative stress, thereby preventing metabolic failure. These findings suggest that pharmacological interventions directed at TSPO may provide novel therapeutics to prevent or treat HF.
心力衰竭（HF）的特征是线粒体钙（Ca）处理异常、能量衰竭和受损的自噬，导致收缩功能障碍和心肌细胞死亡。我们之前已经表明，外线粒体膜的 18kDa 线粒体转位蛋白（TSPO）可以调节线粒体 Ca 摄取。设计实验来测试 TSPO 在由横主动脉缩窄（TAC）引起的 HF 的鼠压力超负荷模型中的作用。使用 Cre-loxP 系统生成条件性、心脏特异性 TSPO 敲除（KO）小鼠。TSPO-KO 和野生型（WT）小鼠接受 TAC 治疗 8 周。TAC 诱导的 HF 显著增加了 WT 小鼠的 TSPO 表达，同时伴有收缩功能、线粒体 Ca 摄取、复合物 I 活性和能量显著降低。相比之下，接受 TAC 的 TSPO-KO 小鼠保留了射血分数，并且表现出较少的 HF 和纤维化的临床迹象。TSPO KO 小鼠的线粒体 Ca 摄取和能量得到恢复，同时 ROS 减少，复合物 I 活性提高，自噬得到保留。因此，HF 增加 TSPO 的表达，而防止这种增加可限制 HF 的进展，维持 ATP 产生并减少氧化应激，从而防止代谢衰竭。这些发现表明，针对 TSPO 的药物干预可能为预防或治疗 HF 提供新的治疗方法。
