A novel fission-independent role of dynaminrelated protein 1 in cardiac mitochondrial respiration

Huiliang Zhang, Pei Wang, Sara Bisetto, Yisang Yoon, Quan Chen, Shey Shing Sheu, Wang Wang

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Aims 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, dynaminrelated protein 1 (DRP1), on mitochondrial respiration regulation in adult cardiomyocytes. Methods and results 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). Conclusion 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.

Original languageEnglish (US)
Pages (from-to)160-170
Number of pages11
JournalCardiovascular Research
Volume113
Issue number2
DOIs
StatePublished - Jan 1 2017

Keywords

  • Adult cardiomyocyte
  • Dynamin related protein 1
  • Mitochondrial morphology
  • Mitochondrial permeability transition pore
  • Mitochondrial respiration

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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