Hypertrophy induced KIF5B controls mitochondrial localization and function in neonatal rat cardiomyocytes.
Cardiac hypertrophy is associated with growth and functional changes of cardiomyocytes, including mitochondrial alterations, but the latter are still poorly understood. Here we investigated mitochondrial function and dynamic localization in neonatal rat ventricular cardiomyocytes (NRVCs) stimulated with insulin like growth factor 1 (IGF1) or phenylephrine (PE), mimicking physiological and pathological hypertrophic responses, respectively. A decreased activity of the mitochondrial electron transport chain (ETC) (state 3) was observed in permeabilized NRVCs stimulated with PE, whereas this was improved in IGF1 stimulated NRVCs. In contrast, in intact NRVCs, mitochondrial oxygen consumption rate (OCR) was increased in PE stimulated NRVCs, but remained constant in IGF1 stimulated NRVCs. After stimulation with PE, mitochondria were localized to the periphery of the cell. To study the differences in more detail, we performed gene array studies. IGF1 and PE stimulated NRVCs did not reveal major differences in gene expression of mitochondrial encoding proteins, but we identified a gene encoding a motor protein implicated in mitochondrial localization, kinesin family member 5b (Kif5b), which was clearly elevated in PE stimulated NRVCs but not in IGF1 stimulated NRVCs. We confirmed that Kif5b gene and protein expression were elevated in animal models with pathological cardiac hypertrophy. Silencing of Kif5b reverted the peripheral mitochondrial localization in PE stimulated NRVCs and diminished PE induced increases in mitochondrial OCR, indicating that KIF5B dependent localization affects cellular responses to PE stimulated NRVCs. These results indicate that KIF5B contributes to mitochondrial localization and function in cardiomyocytes and may play a role in pathological hypertrophic responses in vivo.
Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands.
Wardit
W
Tigchelaar
Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands.
Anne Margreet
AM
de Jong
Paediatrics, University Medical Center Groningen, University of Groningen, The Netherlands.
Vincent W
VW
Bloks
Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands.
Wiek H
WH
van Gilst
Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands.
Rudolf A
RA
de Boer
Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands. Electronic address: h.h.w.sillje@umcg.nl.
Herman H W
HH
Silljé
D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism*; D019069:Cell Respiration; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D001678:Organelle Biogenesis; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats
C521566:KIF5B protein, rat; C548904:insulin-like growth factor-1, rat; D010656:Phenylephrine; D007334:Insulin-Like Growth Factor I; D042963:Electron Transport Complex II; D016547:Kinesins; D042967:Electron Transport Complex I
Cardiomyocyte; Heart; Hypertrophy; Kif5b; Mitochondria