Specific cyprinid HIF isoforms contribute to cellular mitochondrial regulation

Area of Science:

• Cellular Biology
• Molecular Biology
• Genomics

Background:

• Hypoxia-inducible factor 1 (HIF-1) is a key regulator of cellular response to low oxygen conditions.
• Euteleosts possess two HIF-1α paralogs (HIF-1αA and HIF-1αB) due to a third round of genome duplication, with cyprinid fish retaining both.
• The specific roles of these paralogs in mitochondrial regulation and hypoxia tolerance remain largely unexplored.

Purpose of the Study:

• To elucidate the divergent functions of the two zebrafish Hif-1a paralogs, Hif-1aa and Hif-1ab.
• To investigate their roles in cellular mitochondrial regulation and biogenesis.
• To understand their contribution to hypoxia tolerance in zebrafish.

Main Methods:

• Cellular assays were employed to analyze the functions of Hif-1aa and Hif-1ab.
• Gene expression analysis was performed for key mitochondrial genes, including Citrate synthase.
• Mitochondrial activity, membrane potential, ROS production, ATP content, and mitochondrial mass were assessed.

Main Results:

• Hif-1aa enhances the tricarboxylic acid cycle via Citrate synthase and mitochondrial complex II activity, boosts mitochondrial membrane potential, and increases ROS production.
• Hif-1ab elevates intracellular ATP levels by up-regulating mitochondrial complexes I, III, and IV and associated gene expression.
• Both paralogs promote mitochondrial mass and mitochondrial DNA (mtDNA) expression, contributing to mitochondrial biogenesis.

Conclusions:

• Zebrafish Hif-1aa and Hif-1ab display divergent functional specialization in cellular mitochondrial regulation.
• These distinct roles contribute to cellular adaptation and potentially hypoxia tolerance.
• The findings reveal the evolutionary significance of retaining HIF-1α paralogs in cyprinid fish.