Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening

Jyotsna Mishra; Ariea J. Davani; Gayathri K. Natarajan; Wai-Meng Kwok; David F. Stowe; Amadou K.S. Camara

doi:10.3390/cells8091052

journal article Open Access Sep 07, 2019

Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening

Jyotsna Mishra Ariea J. Davani Gayathri K. Natarajan Wai-Meng Kwok David F. Stowe Amadou K.S. Camara

Cells Vol. 8 No. 9 pp. 1052 · MDPI AG

View at Publisher Save 10.3390/cells8091052

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 (pHm), and mitochondrial membrane potential (ΔΨm). Notably, we found that in PO43− (Pi)-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 Pi just before pore opening in the Pi-depleted condition reinstated the Ca2+ buffering system and rescued mitochondria from mPTP opening. This study shows that CsA promotes Pi-dependent mitochondrial Ca2+ sequestration to delay mPTP opening and, concomitantly, maintains mitochondrial function.

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Details

Published: Sep 07, 2019
Vol/Issue: 8(9)
Pages: 1052
License: View

Authors

J

Jyotsna Mishra

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA

A

Ariea J. Davani

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA

G

Gayathri K. Natarajan

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA

W

Wai-Meng Kwok

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA

D

David F. Stowe

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Research Service, Zablocki VA Medical Center, Milwaukee, WI 53295, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA

A

Amadou K.S. Camara

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA

Funding

Veterans Administration Award: BX-002539-01

Cite This Article

Jyotsna Mishra, Ariea J. Davani, Gayathri K. Natarajan, et al. (2019). Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening. Cells, 8(9), 1052. https://doi.org/10.3390/cells8091052

Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening

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