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Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening.
- Source :
- Cells (2073-4409); Sep2019, Vol. 8 Issue 9, p1052, 1p
- Publication Year :
- 2019
-
Abstract
- Regulation of mitochondrial free Ca<superscript>2+</superscript> is critically important for cellular homeostasis. An increase in mitochondrial matrix free Ca<superscript>2+</superscript> concentration ([Ca<superscript>2+</superscript>]<subscript>m</subscript>) 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 Ca<superscript>2+</superscript>. Cardiac-isolated mitochondria were challenged with repetitive CaCl<subscript>2</subscript> boluses under Na<superscript>+</superscript>-free buffer conditions with and without CsA. CsA significantly delayed mPTP opening primarily by promoting matrix Ca<superscript>2+</superscript> sequestration, leading to sustained basal [Ca<superscript>2+</superscript>]<subscript>m</subscript> levels for an extended period. The preservation of basal [Ca<superscript>2+</superscript>]<subscript>m</subscript> during the CaCl<subscript>2</subscript> pulse challenge was associated with normalized NADH, matrix pH (pH<subscript>m</subscript>), and mitochondrial membrane potential (ΔΨ<subscript>m</subscript>). Notably, we found that in PO<subscript>4</subscript><superscript>3−</superscript> (P<subscript>i</subscript>)-free buffer condition, the CsA-mediated buffering of [Ca<superscript>2+</superscript>]<subscript>m</subscript> was abrogated, and mitochondrial bioenergetics variables were concurrently compromised. In the presence of CsA, addition of P<subscript>i</subscript> just before pore opening in the P<subscript>i</subscript>-depleted condition reinstated the Ca<superscript>2+</superscript> buffering system and rescued mitochondria from mPTP opening. This study shows that CsA promotes P<subscript>i</subscript>-dependent mitochondrial Ca<superscript>2+</superscript> sequestration to delay mPTP opening and, concomitantly, maintains mitochondrial function. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 20734409
- Volume :
- 8
- Issue :
- 9
- Database :
- Complementary Index
- Journal :
- Cells (2073-4409)
- Publication Type :
- Academic Journal
- Accession number :
- 139036873
- Full Text :
- https://doi.org/10.3390/cells8091052