The mitochondrial permeability transition phenomenon elucidated by cryo-EM reveals the genuine impact of calcium overload on mitochondrial structure and function

Jasiel O Strubbe-Rivera,Kristin N Parent,Jason N Bazil,James F Conway,Jason R Schrad,Evgeny V Pavlov

doi:10.1038/s41598-020-80398-8

Abstract

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.

Highlights

Mitochondria have a remarkable ability to uptake and store massive amounts of calcium
cyclosporin A (CsA) can bind to cyclophilin D (CypD) and sequester it so that its interaction with its target is p revented[39]
While the calcium phosphate granules may induce changes in morphology by mechanically disrupting membranes, it is plausible that free calcium interacts with proteins regulating inner membrane and cristae maintenance or additional regulators of this system

Summary

Introduction

Mitochondria have a remarkable ability to uptake and store massive amounts of calcium. 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 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. The MPT phenomenon was first observed nearly seven decades ago when early studies in the mid1950s to early 1960s demonstrated massive mitochondrial swelling under certain conditions[17,18,19,20,21] These conditions involved calcium overload, high inorganic phosphate concentrations, fatty acids, oxidative stress, and Scientific Reports | (2021) 11:1037. Our new data add exciting therapeutic targets for mitochondrialprotective therapies

Methods

Results

Conclusion