AKIP1 expression modulates mitochondrial function in rat neonatal cardiomyocytes

PLoS One. 2013 Nov 13;8(11):e80815. doi: 10.1371/journal.pone.0080815. eCollection 2013.


A kinase interacting protein 1 (AKIP1) is a molecular regulator of protein kinase A and nuclear factor kappa B signalling. Recent evidence suggests AKIP1 is increased in response to cardiac stress, modulates acute ischemic stress response, and is localized to mitochondria in cardiomyocytes. The mitochondrial function of AKIP1 is, however, still elusive. Here, we investigated the mitochondrial function of AKIP1 in a neonatal cardiomyocyte model of phenylephrine (PE)-induced hypertrophy. Using a seahorse flux analyzer we show that PE stimulated the mitochondrial oxygen consumption rate (OCR) in cardiomyocytes. This was partially dependent on PE mediated AKIP1 induction, since silencing of AKIP1 attenuated the increase in OCR. Interestingly, AKIP1 overexpression alone was sufficient to stimulate mitochondrial OCR and in particular ATP-linked OCR. This was also true when pyruvate was used as a substrate, indicating that it was independent of glycolytic flux. The increase in OCR was independent of mitochondrial biogenesis, changes in ETC density or altered mitochondrial membrane potential. In fact, the respiratory flux was elevated per amount of ETC, possibly through enhanced ETC coupling. Furthermore, overexpression of AKIP1 reduced and silencing of AKIP1 increased mitochondrial superoxide production, suggesting that AKIP1 modulates the efficiency of electron flux through the ETC. Together, this suggests that AKIP1 overexpression improves mitochondrial function to enhance respiration without excess superoxide generation, thereby implicating a role for AKIP1 in mitochondrial stress adaptation. Upregulation of AKIP1 during different forms of cardiac stress may therefore be an adaptive mechanism to protect the heart.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Animals, Newborn
  • Gene Expression*
  • Gene Silencing
  • Mitochondria / genetics*
  • Mitochondria / metabolism*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Oxygen Consumption / drug effects
  • Oxygen Consumption / genetics
  • Phenylephrine / metabolism
  • Phenylephrine / pharmacology
  • Rats
  • Superoxides / metabolism


  • AKIP1 protein, rat
  • Adaptor Proteins, Signal Transducing
  • Superoxides
  • Phenylephrine

Grant support

HY received a fellowship of the Graduate School for Drug Exploration (GUIDE) from the University of Groningen. This work was partially supported by the Netherlands Heart Foundation (grant 2012T066 to BDW). The Seahorse flux analyzer was obtained via a NWOZonMw Medium Investment Grant (project nr: 91112010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.