Question

A cell is defective in succinate dehydrogenase. Will its HIF-1 be hydroxylated by PH-2 under this condition? Justify.

Answer 1

Hypoxia inhibitory factor or HIF is composed of HIF1 alpha and HIF 1 beta and is involved in low oxygen condition or hypoxia. HIF 1 alpha is degraded in cells under high oxygen concentration. However, when oxygen levels decline, it accumulates in the cell. HIF 1 beta levels are constant.

When oxygen levels are normal (normoxia-20% oxygen), prolyl hydroxylase enzymes react with HIF 1a, and hydroxylates two proline residues in it. These are Pro-402 and Pro-564. This hydroxylation leads to ubiquitination via binding to von Hippel-Lindau (VHL) ubiquitin ligase complex, followed by proteasomal degradation. However, in hypoxia, HIF 1a is stabilized and will interact with co-activators such as CBP/p300. This will induce transcription of target genes.

The prolyl hydroxylase isoform PDH2 enzyme is the major prolyl hydroxylase enzyme in the cell during normoxia conditions. PDH2, thus control HIF 1a levels in normoxia. PDH2 requires iron as a cofactor for activate. It also requires alpha ketoglutarate and oxygen for activity. It hydroxylates HIFα to produce carbon dioxide and succinate. Succinate is a competitive inhibitor of PDH2 enzyme in normoxia conditions. Succinate dehydrogenase is the enzyme that oxidizes succinate to fumarate in the TCA cycle. Hence, if the cell lacks succinate dehydrogenase, then succinate levels will rise in the cell. This succinate will competitively inhibit PDH2, thereby not allowing the degradation of HIF1a in normoxia. Thus, HIF1a is stabilized under normoxia conditions and is capable of activating the downstream signaling pathway by binding to its receptor. Thus, in absence of succinate dehydrogenase, HIF 1 alpha will not be hydroxylated and hence, becomes stable.