AKIP1 expression modulates mitochondrial function in rat neonatal cardiomyocytes

Hongjuan Yu, Wardit Tigchelaar, Debby P. Y. Koonen, Hemal H. Patel, Rudolf A. de Boer, Wiek H. van Gilst, B. Daan Westenbrink, Herman H. W. Sillje*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

16 Citaten (Scopus)
145 Downloads (Pure)

Samenvatting

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.

Originele taal-2English
Artikelnummere80815
Aantal pagina's11
TijdschriftPLoS ONE
Volume8
Nummer van het tijdschrift11
DOI's
StatusPublished - 13-nov-2013

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