Actin-dependent mitochondrial internalization in cardiomyocytes: evidence for rescue of mitochondrial function

Christina A Pacak; Janine M Preble; Hiroshi Kondo; Peter Seibel; Sidney Levitsky; Pedro J Del Nido; Douglas B Cowan; James D McCully

doi:10.1242/bio.201511478

Actin-dependent mitochondrial internalization in cardiomyocytes: evidence for rescue of mitochondrial function

Biol Open. 2015 Apr 10;4(5):622-6. doi: 10.1242/bio.201511478.

Authors

Christina A Pacak¹, Janine M Preble², Hiroshi Kondo², Peter Seibel³, Sidney Levitsky⁴, Pedro J Del Nido⁵, Douglas B Cowan⁶, James D McCully⁷

Affiliations

¹ Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32607, USA.
² Division of Cardiac Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
³ Universitat Leipzig, Molekulare Zelltherapie, Biotechnologisch-Biomedizinisches Zentrum, 04103 Leipzig, Germany.
⁴ Division of Cardiac Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA Harvard Medical School, Boston, MA 02115, USA.
⁵ Harvard Medical School, Boston, MA 02115, USA Division of Cardiac Surgery, Boston Children's Hospital, Boston, MA 02115, USA.
⁶ Harvard Medical School, Boston, MA 02115, USA Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
⁷ Division of Cardiac Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA Harvard Medical School, Boston, MA 02115, USA Division of Cardiac Surgery, Boston Children's Hospital, Boston, MA 02115, USA james_mccully@hms.harvard.edu.

Abstract

Previously, we have demonstrated that the transplantation of viable, structurally intact, respiration competent mitochondria into the ischemic myocardium during early reperfusion significantly enhanced cardioprotection by decreasing myocellular damage and enhancing functional recovery. Our in vitro and in vivo studies established that autologous mitochondria are internalized into cardiomyocytes following transplantation; however, the mechanism(s) modulating internalization of these organelles were unknown. Here, we show that internalization of mitochondria occurs through actin-dependent endocytosis and rescues cell function by increasing ATP content and oxygen consumption rates. We also show that internalized mitochondria replace depleted mitochondrial (mt)DNA. These results describe the mechanism for internalization of mitochondria within host cells and provide a basis for novel therapeutic interventions allowing for the rescue and replacement of damaged or impaired mitochondria.

Keywords: Cardioprotection; Endocytosis; Mitochondria; Mitochondrial DNA; Transplantation.