Hypoxia

Activation of HIF1

Cofactors and substrates involved in HIF1 activation:

TODO (succinate, iron, lack of oxygen)

Changes initiated by HIF-1

Highlights

• HIF-1 stops Fe-S clusters assembly by reducing expression of ISCU1/2 and NDUFA4L2 (via miR-201)
• Decreased Fe-S clusters assembly represses mito respiration and ETC, by decreasing Complex I activity
• Import of glucose is increased
• Lactate level increases because of the shift to glycolysis
• mitochondrial-selective autophagy is induced
• All these changes allow to reduce ROS

Several studies have shown that HIF-1 reduces cellular ROS production by switching energy production from oxidative phosphorylation to glycolysis via multiple pathways (6).

For instance, HIF-1 represses mitochondrial respiration and electron transfer chain activity by activating transcription of the microRNA miR-201, which reduces expression of the iron–sulfur cluster assembly proteins ISCU1/2 and NDUFA4L2, thereby decreasing complex I activity (7).

HIF-1 also activates transcription of genes encoding glucose transporters and glycolytic enzymes, which increases flux from glucose to lactate (8). In addition, HIF-1 activates the apoptotic protein BNIP3, which induces mitochondrial-selective autophagy under hypoxia (9). (R2)

GSK3b downregulates HIF-1

TRPA1 activation

Hypoxia activates TRPA1 channels (presumably by generated ROS and products of oxidation):

We hypothesized that TRPA1 channels in endothelial cells are activated by hypoxia-derived reactive oxygen species, leading to cerebral artery dilation and reduced ischemic damage.

Using isolated cerebral arteries expressing a Ca2+ biosensor in endothelial cells, we show that 4-hydroxynonenal and hypoxia increased TRPA1 activity, detected as TRPA1 sparklets. TRPA1 activity during hypoxia was blocked by antioxidants and by TRPA1 antagonism. (R1)

TRPA1 channels activation can be related to OCD and pain sensitivity. See other notes about TPRA1.

Mitochondrial role of HIF-1

Until recently, HIF-1-dependent regulation of mitochondrial function was thought to depend directly or indirectly on HIF-1 nuclear translocation. However, several studies have reported that HIF-1α localizes to the mitochondria after hypoxic exposure or preconditioning.

Mylonis et al. also identified HIF-1α-mortalin-VDAC1-HK-II complex at mitochondrial outer membrane which inhibits hypoxia-induced apoptosis.

Here, we further investigated HIF-1α protein trafficking to mitochondria in more human cancerous and normal cell lines. We found that a small fraction of HIF-1α trafficked to the mitochondria after chemical or hypoxic stabilization in a highly reproducible manner. (R2)

HIF-1 is a heterodimer of HIF-1a and HIF-1b

HIF-1 is a heterodimer of two basic helix loop-helix/PER-SIM-ARNT(PAS) proteins: HIF-1α and the aryl hydrocarbon nuclear trans-locator (ARNT or HIF-1β).

Both HIF-1α and HIF-1β protein subunits are expressed ubiquitously, but the stability of each protein is differentially regulated by oxygen levels. HIF-1α protein is rapidly degraded under normal oxygen conditions, whereas HIF-1β protein levels are constitutively stable. (R4)

Inhibited reacylation of fatty acids in the brain

arachidonic acid uptake by phosphatidylinositols of a crude synaptosomal fraction from ischemic and severe hypoxic rat brain was decreased compared to controls. Arachidonic acid uptake by other phospholipids was also decreased in ischemic, but not in hypoxic, synaptosomes. (R3)

The results suggest that reacylation of fatty acids into brain membrane phospholipids (especially phosphatidylinositol) is hampered during ischemia and hypoxia. Consequently, inhibition of arachidonic acid uptake by membrane phospholipids is at least partially responsible for the accumulation of the free fatty acids in brain caused by the hypoxic and ischemic treatment. (R3)

Two stages of hypoxia and elevated hypoxanthine

It is important to be aware that hypoxia has two stages. In the first stage it is compensated because the cells are able to meet energy demands through anaerobic metabolism and other mechanisms. (We are not dealing with physiologic adaptation to hypoxia.)

In the second stage of hypoxia or uncompensated hypoxia, energy demands are not met and cell injury ensues.

At present there are no techniques for distinguishing between these two stages in clinical medicine, and such a distinction would be useful. Theoretically hypoxanthine should only be elevated in uncompensated hypoxia, while pH and lactate changes occur in compensated hypoxia.

It seems, however, that hypoxanthine is also elevated to some extent in uncompensated hypoxia. (R5)