ACETYLATION OF CYCLOPHILIN D INCREASES CALCIUM SENSITIVITY OF THE PERMEABILITY TRANSITION PORE

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ESPR71
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Abstract: :

Background: The mitochondrial matrix protein cyclophilin D (CypD) is key regulator of mitochondrial function. It controls electron transport chain activity and ATP synthesis by regulating the permeability transition pore (PTP). The activity of CypD is tuned by several post-translational modifications including acetylation of lysine 166 in the mouse. Objective:  To investigate how acetylation at lysine 166 modifies the ability of CypD to regulate the PTP and the ATP synthesis. Design/Methods: We generated a knock-in mouse model, were specifically in the heart, lysine 166 has been mutated into glutamine (CypDK166Q) to mimic permanent acetylation of CypD. The mice were either +/+, +/- or -/- for the expression of CypD. Calcium retention capacity (CRC) was measured with Arsenazo III in the absence or presence of cyclosporine A (CsA) or ADP. The ability of the ATP synthase to create dimers or oligomers was accessed western blotting and by the hydrolysis of ATP in an in-gel assay. Results: The CRC decreased significantly in mice when CypDK166Q mutation was expressed, while cyclosporine A or NIM811 increased the CRC. ADP increased the CRC in heart mitochondria from all mice in all experimental groups significantly (p ≤ 0.001). In-gel assays and western blotting after clear native electrophoresis show that in mitochondria from mice expressing CypD K166Q the ATP synthase is less likely to form dimers or oligomers. Conclusions: Our data show that the expression of CypD mutant of CypD increases the sensitivity to calcium and limits the generation of ATP synthase oligomers.

University of Rochester Medical Center
University of Rochester Medical Center

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