Coordinated metabolic responses to cyclophilin D deletion in the developing heart
Gisela Beutner,
Jonathan Ryan Burris,
Michael P. Collins,
Chaitanya A. Kulkarni,
Sergiy M. Nadtochiy,
Karen L. de Mesy Bentley,
Ethan D. Cohen,
Paul S. Brookes,
George A. Porter, Jr.
Affiliations
Gisela Beutner
Department of Pediatrics, Division of Cardiology, University of Rochester Medical Center, Rochester, NY 14642, USA
Jonathan Ryan Burris
Department of Pediatrics, Division of Cardiology, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Pediatrics, Division of Neonatology, University of Rochester Medical Center, Rochester, NY 14642, USA
Michael P. Collins
Department of Pediatrics, Division of Cardiology, University of Rochester Medical Center, Rochester, NY 14642, USA
Chaitanya A. Kulkarni
Department of Anesthesiology & Perioperative Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Sergiy M. Nadtochiy
Department of Anesthesiology & Perioperative Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Karen L. de Mesy Bentley
Department of Pathology & Laboratory Medicine and the Electron Microscope Resource, University of Rochester Medical Center, Rochester, NY 14642, USA
Ethan D. Cohen
Department of Pediatrics, Division of Cardiology, University of Rochester Medical Center, Rochester, NY 14642, USA
Paul S. Brookes
Department of Anesthesiology & Perioperative Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
George A. Porter, Jr.
Department of Pediatrics, Division of Cardiology, University of Rochester Medical Center, Rochester, NY 14642, USA; Departments of Medicine (Aab Cardiovascular Research Institute) and Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA; Corresponding author
Summary: In the embryonic heart, the activation of the mitochondrial electron transport chain (ETC) coincides with the closure of the cyclophilin D (CypD) regulated mitochondrial permeability transition pore (mPTP). However, it remains to be established whether the absence of CypD has a regulatory effect on mitochondria during cardiac development. Using a variety of assays to analyze cardiac tissue from wildtype and CypD knockout mice from embryonic day (E)9.5 to adult, we found that mitochondrial structure, function, and metabolism show distinct transitions. Deletion of CypD altered the timing of these transitions as the mPTP was closed at all ages, leading to coupled ETC activity in the early embryo, decreased citrate synthase activity, and an altered metabolome particularly after birth. Our results suggest that manipulating CypD activity may control myocyte proliferation and differentiation and could be a tool to increase ATP production and cardiac function in immature hearts.
