Abstract 17276: Cyclophilin D is Required for Mitophagy-Regulating Parkin Translocation to Mitochondria
INTRODUCTION Cyclophilin D (CyD), encoded by the Ppif gene, is a mitochondrial protein that regulates the Mitochondria Permeability Transition Pore (MPTP) and is necessary for the removal of damaged mitochondria via autophagy in cardiac cells. Ppif -/- mice show an increase in the mitochondrial calcium retention capacity and a desensitization of MPTP opening. These features are associated with protection against ischemia/reperfusion injury. However recent finding show that CyD is involved in different physiological pathways important for cell homeostasis.
HYPOTHESIS We tested the hypothesis that the CyD mediates mitochondrial removal by controlling Parkin translocation to the mitochondrial outer membrane.
METHODS Cardiac mitochondria were isolated from wild type and Ppif -/- young (2 months) and old (20 months) mice according to standard protocol using a sucrose based buffer.
RESULTS Western Blot analysis of total heart tissue lysate showed a 1.8 fold increase in the microtubule-associated protein1 light chain 3 (LC3) and a 2.2 fold increase in the total Parkin protein levels in the Ppif -/- young mice compared to age matched wild type mice. Parkin in the mitochondrial fraction was 2.0 fold less in the samples from young and old Ppif -/- mice compared to age-matched wild type mice. The diminished activity in the Parkin-dependent mitophagy results in accumulation of defective mitochondria, leading to metabolic reprogramming followed by pathological hypertrophy. While young Ppif -/- mice show normal phenotype, old mice develop cardiac hypertrophy with elevated HW/BW ratio and ANF compared to age-matched wild type mice.
CONCLUSIONS The decrease in the Parkin-dependent mitophagy machinery activity observed in the Ppif -/- mice describe for the first time the requirement for CyD in the Parkin-dependent mitophagy and give a further explanation for the cardiac hypertrophic phenotype in old Ppif -/- mice.
- © 2011 by American Heart Association, Inc.