Faculty Collaboration Database

Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening. Cells 2019 Sep 07;8(9)

Date

09/11/2019

Pubmed ID

31500337

Pubmed Central ID

PMC6770067

DOI

10.3390/cells8091052

Scopus ID

2-s2.0-85082240408 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

Regulation of mitochondrial free Ca²⁺ is critically important for cellular homeostasis. An increase in mitochondrial matrix free Ca²⁺ concentration ([Ca²⁺]_m) predisposes mitochondria to opening of the permeability transition pore (mPTP). Opening of the pore can be delayed by cyclosporin A (CsA), possibly by inhibiting cyclophilin D (Cyp D), a key regulator of mPTP. Here, we report on a novel mechanism by which CsA delays mPTP opening by enhanced sequestration of matrix free Ca²⁺. Cardiac-isolated mitochondria were challenged with repetitive CaCl₂ boluses under Na⁺-free buffer conditions with and without CsA. CsA significantly delayed mPTP opening primarily by promoting matrix Ca²⁺ sequestration, leading to sustained basal [Ca²⁺]_m levels for an extended period. The preservation of basal [Ca²⁺]_m during the CaCl₂ pulse challenge was associated with normalized NADH, matrix pH (pH_m), and mitochondrial membrane potential (ΔΨ_m). Notably, we found that in PO₄^3- (P_i)-free buffer condition, the CsA-mediated buffering of [Ca²⁺]_m was abrogated, and mitochondrial bioenergetics variables were concurrently compromised. In the presence of CsA, addition of P_i just before pore opening in the P_i-depleted condition reinstated the Ca²⁺ buffering system and rescued mitochondria from mPTP opening. This study shows that CsA promotes P_i-dependent mitochondrial Ca²⁺ sequestration to delay mPTP opening and, concomitantly, maintains mitochondrial function.

Author List

Mishra J, Davani AJ, Natarajan GK, Kwok WM, Stowe DF, Camara AKS

Authors

Amadou K. Camara PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Wai-Meng Kwok PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Jyotsna Mishra PHD Research Scientist I in the Anesthesiology department at Medical College of Wisconsin
Gayathri K. Natarajan Research Scientist I in the Anesthesiology department at Medical College of Wisconsin
David F. Stowe MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Buffers
Calcium
Cyclosporine
Energy Metabolism
Female
Guinea Pigs
Heart
Male
Membrane Potential, Mitochondrial
Mitochondria
Mitochondria, Heart
Mitochondrial Membrane Transport Proteins
Mitochondrial Membranes
Myocardium
Reactive Oxygen Species