Krstic Anna Maria, Power Amelia S, Ward Marie-Louise
Department of Physiology Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand.
Life (Basel). 2023 Feb 15;13(2):540. doi: 10.3390/life13020540.
Pulmonary artery hypertension causes right ventricular hypertrophy which rapidly progresses to heart failure with underlying cardiac mitochondrial dysfunction. Prior to failure, there are alterations in cytosolic Ca handling that might impact mitochondrial function in the compensatory phase of RV hypertrophy. Our aims, therefore, were (i) to measure beat-to-beat mitochondrial Ca fluxes, and (ii) to determine mitochondrial abundance and function in non-failing, hypertrophic cardiomyocytes. Male Wistar rats were injected with either saline (CON) or monocrotaline (MCT) to induce pulmonary artery hypertension and RV hypertrophy after four weeks. Cytosolic Ca ([Ca]) transients were obtained in isolated right ventricular (RV) cardiomyocytes, and mitochondrial Ca ([Ca]) was recorded in separate RV cardiomyocytes. The distribution and abundance of key proteins was determined using confocal and stimulated emission depletion (STED) microscopy. The RV mitochondrial function was also assessed in RV homogenates using oxygraphy. The MCT cardiomyocytes had increased area, larger [Ca] transients, increased Ca store content, and faster trans-sarcolemmal Ca extrusion relative to CON. The MCT cardiomyocytes also had larger [Ca] transients. STED images detected increased mitochondrial protein abundance (TOM20 clusters per μm) in MCT, yet no difference was found when comparing mitochondrial respiration and membrane potential between the groups. We suggest that the larger [Ca] transients compensate to match ATP supply to the increased energy demands of hypertrophic cardiomyocytes.
肺动脉高压会导致右心室肥大，进而迅速发展为心力衰竭，并伴有潜在的心脏线粒体功能障碍。在发生心力衰竭之前，细胞质钙处理会发生改变，这可能会在右心室肥大的代偿期影响线粒体功能。因此，我们的目标是：（i）测量逐搏线粒体钙通量，以及（ii）确定未发生衰竭的肥厚型心肌细胞中线粒体的丰度和功能。给雄性Wistar大鼠注射生理盐水（CON）或野百合碱（MCT），四周后诱导肺动脉高压和右心室肥大。在分离的右心室（RV）心肌细胞中获取细胞质钙（[Ca]）瞬变，并在单独的RV心肌细胞中记录线粒体钙（[Ca]）。使用共聚焦显微镜和受激发射损耗（STED）显微镜确定关键蛋白的分布和丰度。还使用氧电极法在RV匀浆中评估RV线粒体功能。与CON相比，MCT心肌细胞的面积增大、[Ca]瞬变更大、钙储存含量增加，且跨肌膜钙外排更快。MCT心肌细胞的[Ca]瞬变也更大。STED图像检测到MCT中线粒体蛋白丰度增加（每微米TOM20簇），但比较两组之间的线粒体呼吸和膜电位时未发现差异。我们认为，更大的[Ca]瞬变起到了代偿作用，以使ATP供应与肥厚型心肌细胞增加的能量需求相匹配。
