Impaired translocation and activation of mitochondrial Akt1 mitigated mitochondrial oxidative phosphorylation Complex V activity in diabetic myocardium

Jia Ying Yang, Wu Deng, Yumay Chen, Weiwei Fan, Kenneth M. Baldwin, Richard S. Jope, Douglas C. Wallace, Ping H. Wang

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Insulin can translocate Akt to mitochondria in cardiac muscle. The goals of this study were to define sub-mitochondrial localization of the translocated Akt, to dissect the effects of insulin on Akt isoform translocation, and to determine the direct effect of mitochondrial Akt activation on Complex V activity in normal and diabetic myocardium. The translocated Akt sequentially localized to the mitochondrial intermembrane space, inner membrane, and matrix. To confirm Akt translocation, in vitro import assay showed rapid entry of Akt into mitochondria. Akt isoforms were differentially regulated by insulin stimulation, only Akt1 translocated into mitochondria. In the insulin-resistant Type 2 diabetes model, Akt1 translocation was blunted. Mitochondrial activation of Akt1 increased Complex V activity by 24% in normal myocardium in vivo and restored Complex V activity in diabetic myocardium. Basal mitochondrial Complex V activity was lower by 22% in the Akt1-/- myocardium. Insulin-stimulated Complex V activity was not impaired in the Akt1-/- myocardium, due to compensatory translocation of Akt2 to mitochondria. Akt1 is the primary isoform that relayed insulin signaling to mitochondria and modulated mitochondrial Complex V activity. Activation of mitochondrial Akt1 enhanced ATP production and increased phosphocreatine in cardiac muscle cells. Dysregulation of this signal pathway might impair mitochondrial bioenergetics in diabetic myocardium.

Original languageEnglish (US)
Pages (from-to)167-175
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume59
Issue number1
DOIs
StatePublished - Jun 1 2013

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ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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