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Impairment of mitochondrial respiratory function as an early biomarker of apoptosis induced by growth factor removal

View ORCID ProfileHélène Lemieux, Patrick Subarsky, Christine Doblander, Martin Wurm, View ORCID ProfileJakob Troppmair, View ORCID ProfileErich Gnaiger
doi: https://doi.org/10.1101/151480
Hélène Lemieux
1Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria;
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  • ORCID record for Hélène Lemieux
  • For correspondence: erich.gnaiger@oroboros.at Helene.lemieux@ualberta.ca
Patrick Subarsky
2Oroboros Instruments, Innsbruck, Austria;
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Christine Doblander
1Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria;
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Martin Wurm
1Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria;
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Jakob Troppmair
1Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria;
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Erich Gnaiger
1Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria;
2Oroboros Instruments, Innsbruck, Austria;
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  • For correspondence: erich.gnaiger@oroboros.at Helene.lemieux@ualberta.ca
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Abstract

Intracellular signaling pathways not only control cell proliferation and survival, but also regulate the provision of cellular energy and building blocks through mitochondrial and non-mitochondrial metabolism. Wild-type and oncogenic RAF kinases have been shown to prevent apoptosis following the removal of interleukin 3 (IL-3) from mouse pro-myeloid 32D cells by reducing mitochondrial reactive oxygen species production. To study primary effects of RAF on mitochondrial energy metabolism, we applied high-resolution respirometry after short-term IL-3 deprivation (8 h), before 32D cells show detectable signs of cell death. Respiration in intact 32D cells was suppressed as an early event following removal of IL-3, but remained more stable in 32D cells expressing the v-RAF oncogene. In permeabilized 32D cells deprived of IL-3, respiratory capacities of the NADH-pathway, the convergent NADH&succinate-pathway, and Complex IV activity were decreased compared to cells grown in the presence of IL-3, whereas succinate-supported respiration remained unchanged, consistent with control by Complex IV. The apparent Complex IV excess capacity was zero above NADH&succinate-pathway capacity reconstituting tricarboxylic acid cycle function. In comparison, electron flow reached only 60% when supported by succinate alone through Complexes II, III and IV, and was therefore relatively insensitive to Complex IV injuries up to a threshold of 40% inhibition. A slight increase in respiration following addition of cytochrome c, a marker of mitochondrial outer membrane leakage, was present after IL-3 depletion, indicating mitochondrial fragility. Our results highlight a novel link between the key mitogenic and survival kinase CRAF and mitochondrial energy homeostasis.

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Posted June 19, 2017.
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Impairment of mitochondrial respiratory function as an early biomarker of apoptosis induced by growth factor removal
Hélène Lemieux, Patrick Subarsky, Christine Doblander, Martin Wurm, Jakob Troppmair, Erich Gnaiger
bioRxiv 151480; doi: https://doi.org/10.1101/151480
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Impairment of mitochondrial respiratory function as an early biomarker of apoptosis induced by growth factor removal
Hélène Lemieux, Patrick Subarsky, Christine Doblander, Martin Wurm, Jakob Troppmair, Erich Gnaiger
bioRxiv 151480; doi: https://doi.org/10.1101/151480

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