A lactate-induced response to hypoxia.

Area of Science:

• Cellular Biology
• Molecular Biology
• Physiology

Background:

• Organisms require responses to low oxygen (hypoxia) for homeostasis and in disease.
• Hypoxia-inducible factor (HIF) is a known regulator, but HIF-independent pathways also exist.

Purpose of the Study:

• To elucidate a novel lactate-dependent mechanism for hypoxia signaling.
• To identify the role of NDRG3 protein in this pathway.

Main Methods:

• Investigated the interaction between lactate and NDRG3 protein under varying oxygen conditions.
• Utilized PHD2/VHL-dependent degradation assays.
• Examined the activation of the Raf-ERK pathway and downstream effects like angiogenesis and cell growth.
• Assessed the impact of inhibiting cellular lactate production.

Main Results:

• NDRG3 protein is degraded in normoxia but stabilized by lactate accumulation in hypoxia.
• Stabilized NDRG3 binds c-Raf, activating the Raf-ERK pathway.
• This pathway promotes angiogenesis and cell growth.
• Inhibition of lactate production abrogates NDRG3-mediated hypoxia responses.

Conclusions:

• Lactate accumulation directly drives a HIF-independent hypoxia response by stabilizing NDRG3.
• The NDRG3-lactate-Raf-ERK axis is a key mediator of hypoxia-induced angiogenesis and cell growth.
• This pathway presents a potential therapeutic target for hypoxia-related diseases.