NME3 binds to phosphatidic acid and mediates PLD6-induced mitochondrial tethering

Area of Science:

• Cell Biology
• Mitochondrial Dynamics
• Membrane Biology

Background:

• Mitochondria are essential organelles whose function and quality depend on dynamic fission and fusion processes.
• Phosphatidic acid (PA), generated by PLD6 on the mitochondrial outer membrane, is known to facilitate mitochondrial fusion.
• The precise mechanism by which PA promotes mitochondrial fusion remains largely unknown.

Purpose of the Study:

• To elucidate the role of the mitochondrial outer membrane protein NME3 in PA-mediated mitochondrial fusion.
• To investigate how NME3 interacts with PA and contributes to mitochondrial tethering and fusion.

Main Methods:

• Investigated the role of NME3 in PLD6-induced mitochondrial tethering using cell-based assays.
• Determined the localization and binding characteristics of NME3 at mitochondrial contact sites.
• Analyzed the function of NME3's N-terminal amphipathic helix in PA binding and tethering activity.
• Examined the effect of nutrient starvation on NME3 enrichment and mitochondrial fusion efficiency.

Main Results:

• NME3 is essential for PLD6-induced mitochondrial tethering and clustering.
• NME3 localizes to the interface between closely apposed mitochondria, dependent on PLD6.
• NME3 directly binds to PA-exposed lipid packing defects via its N-terminal amphipathic helix.
• PA binding and hexamerization of NME3 are critical for its mitochondrial tethering activity.
• Nutrient starvation enhances NME3 enrichment at mitochondrial contact sites, increasing fusion efficiency.

Conclusions:

• NME3 acts as a specific tethering protein that promotes fusion between mitochondria remodeled by PLD6.
• The interaction of NME3 with PA is a key mechanism for initiating mitochondrial tethering.
• NME3-mediated tethering contributes to selective mitochondrial fusion, crucial for organelle quality control, particularly under stress conditions like nutrient starvation.