Coenzyme Q deficiency in endothelial mito caused by hypoxia;remodeling of the respiratory chain & sensitivity to anoxia/reoxygenation 2024 Dominiak+

Full title: Coenzyme Q deficiency in endothelial mitochondria caused by hypoxia; remodeling of the respiratory chain and sensitivity to anoxia/reoxygenation

Highlights

• In endothelial cells, hypoxia reduces HMGCR levels via HIF1α, leading to Q deficiency.
  
  
• The hypoxia-induced increased level of mQ reduction promotes the formation of mROS.
  
  
• Mitochondria of endothelial cells cultured in hypoxia cope better with A/R stress.

Abstract

This study examined the effects of hypoxia on coenzyme Q (Q) levels and mitochondrial function in EA. hy926 endothelial cells, shedding light on their responses to changes in oxygen levels. Chronic hypoxia during endothelial cell culture reduced Q synthesis by reducing hydroxy-methylglutaryl-CoA reductase (HMGCR) levels via hypoxia-inducible factor 1α (HIF1α), leading to severe Q deficiency. In endothelial mitochondria, hypoxia led to reorganization of the respiratory chain through upregulation of supercomplexes (I + III2+IV), forming a complete mitochondrial Q (mQ)-mediated electron transfer pathway.

Mitochondria of endothelial cells cultured under hypoxic conditions showed reduced respiratory rates and membrane potential, as well as increased production of mitochondrial reactive oxygen species (mROS) as a result of increased mQ reduction levels (mQH2/mQtot). Anoxia/reoxygenation (A/R) in vitro caused impairment of endothelial mitochondria, manifested by reduced maximal respiration, complex III activity, membrane potential, coupling parameters, and increased mQ reduction and mROS production. Weaker A/R-induced changes compared to control mitochondria indicated better tolerance of A/R stress by the mitochondria of hypoxic cells. Moreover, in endothelial mitochondria, hypoxia-induced increases in uncoupling protein 3 (UCP3) and mitochondrial large-conductance Ca2+-activated potassium channel (mitoBKCa) levels and activities appear to have alleviated reoxygenation injury after A/R.

These results not only highlight hypoxia-induced changes in mQ redox homeostasis and related mitochondrial function, but also indicate that chronic hypoxia during endothelial cell culture leads to mitochondrial adaptations that help mitochondria better withstand subsequent oxygen fluctuations.

Paywall, https://www.sciencedirect.com/science/article/abs/pii/S0891584924000790