HERV-K (HML-2) Envelope Protein Induces Mitochondrial Depolarization and Neurotoxicity via Endolysosome Iron...

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration and is linked to human endogenous retroviruses (HERVs).
• The HERV-K subtype HML-2 envelope protein (HERV-K Env) is found in ALS patients and contributes to neurodegeneration via CD98 receptor interactions.
• Oxidative stress, driven by ferrous iron (Fe²⁺) and reactive oxygen species (ROS), is a key factor in ALS pathogenesis, with endolysosomes playing a critical role in iron regulation.

Purpose of the Study:

• To investigate the effect of HERV-K Env on endolysosome pH and iron levels.
• To determine if HERV-K Env-induced neurotoxicity is mediated by iron release from endolysosomes.
• To elucidate the mechanism by which HERV-K Env contributes to ALS pathogenesis.

Main Methods:

• Utilized SH-SY5Y neuroblastoma cells and primary human cortical neurons (HCNs).
• Examined HERV-K Env endocytosis via CD98 receptors.
• Assessed endolysosome pH, Fe²⁺ concentrations (endolysosomal, cytosolic, mitochondrial), ROS levels, and mitochondrial membrane potential.
• Investigated the impact of anti-CD98 receptor antibody and deferoxamine (an iron chelator) on these processes.
• Monitored cell viability and death.

Main Results:

• HERV-K Env was endocytosed through CD98 receptors and concentration-dependently deacidified endolysosomes.
• Endolysosome Fe²⁺ levels decreased, while cytosolic and mitochondrial Fe²⁺ and ROS levels increased.
• Mitochondrial membrane potential was depolarized, leading to cell death.
• These effects were abrogated by the anti-CD98 receptor antibody and deferoxamine.

Conclusions:

• HERV-K Env endocytosis triggers endolysosome deacidification and subsequent Fe²⁺ efflux into the cytoplasm.
• Increased cytosolic and mitochondrial Fe²⁺ and ROS levels, driven by HERV-K Env, mechanistically cause neurotoxicity and cell death in ALS.
• Targeting HERV-K Env interactions with CD98 or managing iron dysregulation presents potential therapeutic strategies for ALS.