Cyclophilin D regulates mitochondrial flashes and metabolism in cardiac myocytes

Wei Shang, Han Gao, Fujian Lu, Qi Ma, Huaqiang Fang, Tao Sun, Jiejia Xu, Yi Ding, Yuan Lin, Yanru Wang, Xianhua Wang, Heping Cheng, Ming Zheng

Research output: Contribution to journalArticlepeer-review

Abstract

Cyclophilin D (CyP-D) is the mitochondrial-specific member of the evolutionally conserved cyclophilin family, and plays an important role in the regulation of mitochondrial permeability transition (MPT) under stress. Recently we have demonstrated that respiratory mitochondria undergo mitochondrial flash ("mitoflash") activity which is coupled with transient MPT under physiological conditions. However, whether and how CyP-D regulates mitoflashes remain incompletely understood. By using both loss- and gain-of-function approaches in isolated cardiomyocytes, beating hearts, and skeletal muscles in living mice, we revisited the role of CyP-D in the regulation of mitoflashes. Overexpression of CyP-D increased, and knockout of it halved, cardiac mitoflash frequency, while mitoflash amplitude and kinetics remained unaffected. However, CyP-D ablation did not alter mitoflash frequency, with mitoflash amplitude increased, in gastrocnemius muscles. This disparity was accompanied by 4-fold higher CyP-D expression in mouse cardiac than skeletal muscles. The mitochondrial maximal respiration rate and reserved capacity were reduced in CyP-D-null cardiomyocytes. These data indicate that CyP-D is a significant regulator of mitoflash ignition and mitochondrial metabolism in heart. In addition, tissue-specific CyP-D expression may partly explain the differential regulation of mitoflashes in the two types of striated muscles.

Original languageEnglish (US)
Pages (from-to)63-71
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume91
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Keywords

  • Cyclophilin D
  • Heart
  • Metabolism
  • Mitochondrial flash
  • Skeletal muscle

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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