Figure 5.

Mechanisms of mitochondrial calcium homeostasis and ROS-mediated mitochondrial oxidative stress injury and mitochondrial dysfunction in ICM. Impact of ROS overproduction-activated oxidative stress injury in ICM on mitochondrial homeostasis. Intrinsic and extrinsic stress signals, such as hypoxia, ischemia, reperfusion, and inflammation, can mediate overproduction of ROS and can lead to mitochondrial oxidative stress damage. When mitochondria are damaged excessively, mitochondrial outer membrane permeabilization (OMM) is dysfunctional, and mitochondrial permeability transition pore (mPTP) is abnormally opened. On the other hand, mPTP opening induces necrosis or necroptosis, accompanied by oxidative phosphorylation dysfunction and dysregulation of the tricarboxylic acid cycle. A range of dysfunctions also induces abnormal calcium signaling, excess ROS production and mitochondrial respiratory chain dysfunction and related protein gene expression changes. Disruption of the mitochondrial calcium cycle has important linkages with mitochondrial uniporter complexes (consisting of MCU, EMRE, MICU1, MICU2, MICU3, MCUB and MCUR1), NCLX, LETM1. And calcium transport in mitochondria is also closely related to ryanodine receptors and mitochondrial permeability transition pore. The normal operation of the above mechanisms(mitochondrial calcium homeostasis and oxidative stress injury) directly or indirectly affects the normal operation of mitochondrial respiratory chain function and mitochondrial energy metabolism function.