Mitochondrial Dysfunction Inhibits Hypoxia-Induced HIF-1α Stabilization and Expression of Its Downstream Targets

Frontiers in Oncology
Marike W van GisbergenPhilippe Lambin

Abstract

mtDNA variations often result in bioenergetic dysfunction inducing a metabolic switch toward glycolysis resulting in an unbalanced pH homeostasis. In hypoxic cells, expression of the tumor-associated carbonic anhydrase IX (CAIX) is enhanced to maintain cellular pH homeostasis. We hypothesized that cells with a dysfunctional oxidative phosphorylation machinery display elevated CAIX expression levels. Increased glycolysis was observed for cytoplasmic 143B mutant hybrid (m.3243A>G, >94.5%) cells (p < 0.05) and 143B mitochondrial DNA (mtDNA) depleted cells (p < 0.05). Upon hypoxia (0.2%, 16 h), genetic or pharmacological oxidative phosphorylation (OXPHOS) inhibition resulted in decreased CAIX (p < 0.05), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1α) expression levels. Reactive oxygen species (ROS) and prolyl-hydroxylase 2 (PHD2) levels could not explain these observations. In vivo, tumor take (>500 mm3) took longer for mutant hybrid xenografts, but growth rates were comparable with control tumors upon establishment. Previously, it has been shown that HIF-1α is responsible for tumor establishment. In agreement, we found that HIF-1α expression levels and the pimonidazole-positive hypoxic frac...Continue Reading

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Citations

May 28, 2021·Frontiers in Oncology·Marike W van GisbergenLudwig J Dubois

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Datasets Mentioned

BETA
US2016160287

Methods Mentioned

BETA
PCR
electrophoresis
flow cytometry
xenograft
Metabolic
xenografts

Software Mentioned

ptTheragnostics
Micromanager
GraphPad Prism

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