Wuest 2018 MiP2018b

From Bioblast
Jump to: navigation, search
Wuest Rob
The antibiotic doxycycline impairs cardiac mitochondrial and contractile function.

Link: MiP2018

Wuest RCI, Held NM, Daal M, Baks-te Bulte L, Wiersma M, van Deel ED, Kuster DWD, Brundel BJJM, van Weeghel M, Coolen BF, Strijkers GJ, Houtkooper RH (2018)

Event: MiP2018

COST Action MitoEAGLE

Tetracycline antibiotics act through inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction. We cultured H9C2 cardiomyoblasts and adult rat cardiomyocytes in the presence of doxycycline. Doxycycline reduced protein expression of mitochondrially DNA-encoded cytochrome c oxidase subunit I, while the nuclear DNA-encoded OXPHOS subunit succinate dehydrogenase A was unchanged. This mitonuclear protein imbalance led to lower maximal uncoupled cellular respiration, with complex I respiration being more affected compared to complex II respiration in doxycycline-treated cells. Mitochondria appeared fragmented after doxycycline treatment. Flux measurements using stable isotope tracers showed a clear shift away from OXPHOS towards glycolysis after doxycycline exposure. To establish the functional consequences, we tested cardiac contractility in cultured adult rat cardiomyocytes and in the heart of Drosophila melanogaster. Diastolic calcium concentration increased, and the number of arrhythmias was significantly higher in doxycycline-treated primary cardiomyocytes. A higher arrhythmicity index, and systolic and diastolic dysfunction were observed in Drosophila exposed to doxycycline. We conclude that doxycycline impairs mitochondrial function and causes contractile dysfunction. Whether doxycycline also impairs mitochondrial and cardiac function in mice is under current investigation.


Bioblast editor: Plangger M, Kandolf G O2k-Network Lab: NL Amsterdam Wuest RC


Labels: MiParea: Respiration, mtDNA;mt-genetics, nDNA;cell genetics, Pharmacology;toxicology 


Organism: Rat  Tissue;cell: Heart, Other cell lines 

Enzyme: Complex II;succinate dehydrogenase 

Coupling state: OXPHOS, ET  Pathway: N, S  HRR: Oxygraph-2k 


Affiliations

Wüst RCI(1), Held NM(1), Daal M(3), Baks-te Bulte L(2), Wiersma M(2), van Deel ED(2), Kuster DWD(2), Brundel BJJM(2), van Weeghel M(1), Coolen BF(3), Strijkers GJ(3), Houtkooper RH(1)

  1. Lab Genetic Metabolic Diseases, Academic Medical Center, Amsterdam
  2. Dept Physiology, Amsterdam Cardiovascular Sciences, VU Univ Medical Center
  3. Dept Biomedical Engineering and Physics, Academic Medical Center, Amsterdam; The Netherlands. - r.wust@amc.uva.nl