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Abstract 331: Impact of Acetylated Cyclophilin D on the Mitochondrial Permeability Transition Pore


 Background:
 The mitochondrial matrix protein cyclophilin D (CypD) is a key regulator of mitochondrial function. CypD controls electron transport chain activity and ATP synthesis by regulating the permeability transition pore (PTP). The activity of CypD is regulated by several post-translational modifications including acetylation of lysine 166 in the mouse.
 
 
 Objective:
 To investigate how acetylation at lysine 166 of CypD specifically in the heart modifies its ability to regulate the PTP and the ATP synthase.
 
 
 Results:
 We generated a conditional cardiac knock-in mouse model where lysine 166 has been mutated into glutamine (CypD
 K166Q
 ) to mimic permanent acetylation of CypD. The mice were either +/+, +/- or -/- for the expression of native CypD. Results show that mitochondrial oxygen consumption was not affected by the expression of CypD
 K166Q
 . The calcium retention capacity (CRC) was measured with Arsenazo III and decreased significantly when CypD
 K166Q
 was expressed. The CypD inhibitor cyclosporine A significantly increased the CRC in WT mice. However, cyclosporine A was did not inhibit CypD in the hearts of mice expressing only CypD
 K166Q
 or in addition to wild-type CypD. The ability of the ATP synthase to create dimers or oligomers was assessed by western blotting and the hydrolysis of ATP in in-gel assays and shows that expression of CypD
 K166Q
 decreased the assembly of the ATP synthase into dimers or oligomers.
 
 
 Conclusions:
 Our data show that the expression of CypD
 K166Q
 increases the sensitivity of PTP opening to calcium and limits the assembly of ATP synthase into oligomers.
