Pharmacology and Toxicology, Michigan State University, East Lansing, MI, 48824, USA.
Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA.
Sci Rep. 2021 Jan 13;11(1):1037. doi: 10.1038/s41598-020-80398-8.
Mitochondria have a remarkable ability to uptake and store massive amounts of calcium. However, the consequences of massive calcium accumulation remain enigmatic. In the present study, we analyzed a series of time-course experiments to identify the sequence of events that occur in a population of guinea pig cardiac mitochondria exposed to excessive calcium overload that cause mitochondrial permeability transition (MPT). By analyzing coincident structural and functional data, we determined that excessive calcium overload is associated with large calcium phosphate granules and inner membrane fragmentation, which explains the extent of mitochondrial dysfunction. This data also reveals a novel mechanism for cyclosporin A, an inhibitor of MPT, in which it preserves cristae despite the presence of massive calcium phosphate granules in the matrix. Overall, these findings establish a mechanism of calcium-induced mitochondrial dysfunction and the impact of calcium regulation on mitochondrial structure and function.
线粒体具有摄取和储存大量钙的非凡能力。然而，大量钙积累的后果仍然是个谜。在本研究中，我们分析了一系列时程实验，以确定在暴露于过量钙超载的豚鼠心肌线粒体群体中发生的一系列事件的顺序，这种钙超载会导致线粒体通透性转换（MPT）。通过分析同时发生的结构和功能数据，我们确定过量钙超载与大的磷酸钙颗粒和内膜片段化有关，这解释了线粒体功能障碍的程度。该数据还揭示了环孢素 A（一种 MPT 抑制剂）的一种新机制，即在基质中存在大量磷酸钙颗粒的情况下，它能保持嵴的结构。总的来说，这些发现建立了钙诱导的线粒体功能障碍的机制以及钙调节对线粒体结构和功能的影响。
