A phenotypic perspective on Mammalian oxygen sensor candidates

Area of Science:

• Physiology
• Genetics
• Molecular Biology

Background:

• Chronic hypoxia induces mammalian phenotypic changes like polycythemia and pulmonary hypertension.
• These alterations are crucial for investigating oxygen sensing mechanisms.
• Carotid body (CB) enlargement is a key response to sustained low oxygen levels.

Purpose of the Study:

• To evaluate phenotypic evidence for commonly considered oxygen sensor candidates.
• To determine which genes' mutations align with oxygen sensing roles.
• To identify a robust oxygen sensor candidate based on physiological responses.

Main Methods:

• Analysis of phenotypic consequences resulting from germline mutations in various genes (NADPH oxidase, mitochondrial complexes, heme oxygenase 2, VHL, HIF1 prolyl hydroxylase 2, SDH).
• Assessment of polycythemia and carotid body (CB) enlargement phenotypes.
• Evaluation of evidence linking gene mutations to environmental hypoxia responses and altitude influences.

Main Results:

• Mutations in NADPH oxidase, mitochondrial complexes I, III, IV, and heme oxygenase 2 genes indicate distinct physiological roles, not oxygen sensing.
• VHL and HIF1 prolyl hydroxylase 2 mutations cause polycythemia, but their response to environmental oxygen variations is unclear.
• Germline mutations in succinate dehydrogenase (SDH) are linked to CB paragangliomas, with potential altitude-influenced severity, supporting its role as an oxygen sensor.

Conclusions:

• Succinate dehydrogenase (SDH) emerges as a well-supported oxygen sensor candidate based on phenotypic evidence.
• Genes like NADPH oxidase and mitochondrial complexes show distinct functions beyond oxygen sensing.
• A universal oxygen sensor requires validation across multiple biological complexity layers.