The Opening Mechanism Of Mitochondrial Permeability Transition Pore Regulated By Ca²⁺ And Reactive Oxygen Species

Mitochondria can not only provide energy for cell survival,but also regulate cell death.These are intimately linked to calcium ions(Ca²⁺)and reactive oxygen species?ROS?.Under physiological conditions,the entering of an appropriate amount of Ca²⁺ into the mitochondria activates the tricarboxylic acid cycle to produce energy,and meanwhile a small amount of ROS,causing mitochondrial permeability transition pore?PTP?to open in a low-conductance and transient mode,which are necessary for cell survival.While under pathological conditions,the entering of excessive Ca²⁺ into the mitochondria induces the production of a large amount of ROS,causing the PTP to open in a high-conductance and sustained mode,thereby leading to cell death.From the point of view of dynamics,these two states of the PTP correspond to the oscillatory state and the high steady state,respectively.Many biological studies suggest that there exist four feedback loops in the Ca²⁺-ROS-PTP system.During ATP production,ROS production depends on Ca²⁺,which,in turn,exerts a positive feedback on Ca²⁺ influx to the mitochondria?abbreviated as F1?.ROS can induce further ROS generation,constituting a second positive feedback loop?abbreviated as F2?.Although Ca²⁺ and ROS cooperate to promote the opening of PTP,which results in the efflux of Ca²⁺ and ROS from the mitochondria and reduces their amount,thus forming two negative feedback loops,abbreviated as F3 and F4,respectively.These intricate relationships make it difficult to understand how the system works.In this study,a set of differential equations was used to quantitatively characterize the dynamic mechanism of PTP opening regulated by Ca²⁺ and ROS.By robustness analysis,we clarified that although negative feedback loop,F3 or F4,is prerequisite for generating the oscillatory behavior of PTP,positive feedback loop,F1 or F2,is critical for maintaining robustness of the oscillations.The negative feedback loop F3 plays a more prominent role than F4,and the positive feedback loop F1 has a more dominant role than F2.By bifurcation analysis,we revealed that F1 and F2 have positive influences on the oscillatory amplitude,while F3 and F4 have negative influences on it.Furthermore,we manifested that the decrease in F1 and F2 facilitates the transition of the PTP from a high steady state into an oscillatory state,whereas the increase in F3 and F4 has the same effect.While the PTP in an oscillatory state is beneficial for cell survial,the PTP in a high steady state results in cell death.Abnormal opening of the PTP in brain cells often leads to neurodegenerative diseases such as Alzheimer's disease,so this study may provide new insights into the treatment of such diseases.