Effects of altered cellular ultrastructure on energy metabolism in diabetic cardiomyopathy - an in-silico study
Effects of altered cellular ultrastructure on energy metabolism in diabetic cardiomyopathy - an in-silico study
复制标题
细胞超微结构改变对糖尿病心肌病能量代谢的影响——一项计算机研究
DOI：
10.1101/2022.05.22.492785
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Ghosh S
中科院分区：
文献类型：
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作者：
Ghosh S
糖尿病性心肌病是糖尿病心力衰竭的主要原因。在细胞水平，糖尿病心肌病导致线粒体能量代谢和心肌细胞超微结构改变。我们结合电子显微镜（EM）和计算建模，以了解糖尿病引起的超微结构变化对心脏生物能量学的影响。我们使用EM收集了多个对照和I型糖尿病大鼠心肌细胞的横向显微照片。显微照片被转换为有限元网格，并使用生物物理模型在其上模拟生物能量学。该模拟还结合了氧化磷酸化（OXPHOS）和肌酸激酶（CK）反应的抑制线粒体能力，以模拟糖尿病诱导的线粒体功能障碍。显微照片分析显示，糖尿病心肌细胞线粒体面积分数下降14%，线粒体和肌原纤维排列不规则。模拟预测，这种不规则的排列，加上线粒体CK酶的活性降低，导致糖尿病心肌细胞的腺苷二磷酸（ADP）/腺苷三磷酸（ATP）的比例分布的大的空间变化。然而，当空间平均化时，心肌细胞的肌原纤维ADP/ATP比率不随糖尿病而改变。相反，无机磷酸盐的平均浓度上升了40%，由于较低的线粒体面积分数和功能障碍的OXPHOS。这些模拟结果表明，一个混乱的细胞超微结构的负面影响代谢物运输在糖尿病cardiomyopathy.This article is part of the theme issue 'The cardiomyocyte：new revelations on the interplay between architecture and function in growth，health，and disease'.
Diabetic cardiomyopathy is a leading cause of heart failure in diabetes. At the cellular level, diabetic cardiomyopathy leads to altered mitochondrial energy metabolism and cardiomyocyte ultrastructure. We combined electron microscopy (EM) and computational modelling to understand the impact of diabetes-induced ultrastructural changes on cardiac bioenergetics. We collected transverse micrographs of multiple control and type I diabetic rat cardiomyocytes using EM. Micrographs were converted to finite-element meshes, and bioenergetics was simulated over them using a biophysical model. The simulations also incorporated depressed mitochondrial capacity for oxidative phosphorylation (OXPHOS) and creatine kinase (CK) reactions to simulate diabetes-induced mitochondrial dysfunction. Analysis of micrographs revealed a 14% decline in mitochondrial area fraction in diabetic cardiomyocytes, and an irregular arrangement of mitochondria and myofibrils. Simulations predicted that this irregular arrangement, coupled with the depressed activity of mitochondrial CK enzymes, leads to large spatial variation in adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio profile of diabetic cardiomyocytes. However, when spatially averaged, myofibrillar ADP/ATP ratios of a cardiomyocyte do not change with diabetes. Instead, average concentration of inorganic phosphate rises by 40% owing to lower mitochondrial area fraction and dysfunction in OXPHOS. These simulations indicate that a disorganized cellular ultrastructure negatively impacts metabolite transport in diabetic cardiomyopathy.This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.