PT  - JOURNAL ARTICLE
AU  - Jasiel O. Strubbe-Rivera
AU  - Jason R. Schrad
AU  - Evgeny V. Pavlov
AU  - James F. Conway
AU  - Kristin N. Parent
AU  - Jason N. Bazil
TI  - The Mitochondrial Permeability Transition Phenomenon Elucidated by Cryo-EM Reveals the Genuine Impact of Calcium Overload on Mitochondrial Structure and Function
AID  - 10.1101/2020.03.13.991349
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.13.991349
4099  - http://biorxiv.org/content/early/2020/03/18/2020.03.13.991349.short
4100  - http://biorxiv.org/content/early/2020/03/18/2020.03.13.991349.full
AB  - 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 inner membrane architecture 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.