title: A novel fission-independent role of dynamin-related protein 1 in cardiac mitochondrial respiration.
abstract: Mitochondria in adult cardiomyocytes exhibit static morphology and infrequent dynamic changes, despite the high abundance of fission and fusion regulatory proteins in the heart. Previous reports have indicated that fusion proteins may bear functions beyond morphology regulation. Here, we investigated the role of fission protein, dynamin-related protein 1 (DRP1), on mitochondrial respiration regulation in adult cardiomyocytes.
  
  
  
  By using genetic or pharmacological approaches, we manipulated the activity or protein level of fission and fusion proteins and found they mildly influenced mitochondrial morphology in adult rodent cardiomyocytes, which is in contrast to their significant effect in H9C2 cardiac myoblasts. Intriguingly, inhibiting endogenous DRP1 by dominant-negative DRP1 mutation (K38A), shRNA, or Mdivi-1 suppressed maximal respiration and respiratory control ratio in isolated mitochondria from adult mouse heart or in adult cardiomyocytes from rat. Meanwhile, basal respiration was increased due to increased proton leak. Facilitating mitofusin-mediated fusion by S3 compound, however, failed to inhibit mitochondrial respiration in adult cardiomyocytes. Mechanistically, DRP1 inhibition did not affect the maximal activity of individual respiratory chain complexes or the assembly of supercomplexes. Knocking out cyclophilin D, a regulator of mitochondrial permeability transition pore (mPTP), abolished the effect of DRP1 inhibition on respiration. Finally, DRP1 inhibition decreased transient mPTP-mediated mitochondrial flashes, delayed laser-induced mPTP opening and suppressed mitochondrial reactive oxygen species (ROS).
  
  
  
  These results uncover a novel non-canonical function of the fission protein, DRP1 in maintaining or positively stimulating mitochondrial respiration, bioenergetics and ROS signalling in adult cardiomyocyte, which is likely independent of morphological changes.
authors: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, 850 Republican Street N121, Seattle, WA 98109, USA.
authors: Huiliang
authors: H
authors: Zhang
authors: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, 850 Republican Street N121, Seattle, WA 98109, USA.
authors: Pei
authors: P
authors: Wang
authors: Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street, Room 543D, Philadelphia, PA 19107, USA.
authors: Sara
authors: S
authors: Bisetto
authors: Department of Physiology, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA 30912, USA.
authors: Yisang
authors: Y
authors: Yoon
authors: Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, China.
authors: Quan
authors: Q
authors: Chen
authors: Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street, Room 543D, Philadelphia, PA 19107, USA.
authors: Shey-Shing
authors: SS
authors: Sheu
authors: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, 850 Republican Street N121, Seattle, WA 98109, USA wangwang@uw.edu.
authors: Wang
authors: W
authors: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D019069:Cell Respiration; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005838:Genotype; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D052999:Quinazolinones / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D000081406:Peptidyl-Prolyl Isomerase F; D045222:Electron Transport Chain Complex Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D052999:Quinazolinones; D017382:Reactive Oxygen Species; C486391:Dnm1l protein, mouse; C519851:Dnm1l protein, rat; D034281:Dynamins; D021983:Cyclophilins
keywords: Adult cardiomyocyte; Dynamin related protein 1; Mitochondrial morphology; Mitochondrial permeability transition pore; Mitochondrial respiration