SETD3 is a mechanosensitive enzyme that methylates actin on His73 to regulate mitochondrial dynamics and function

Area of Science:

• Cell Biology
• Mitochondrial Biology
• Cytoskeletal Dynamics

Background:

• Mitochondria are dynamic organelles essential for cellular energy production and homeostasis.
• Mitochondrial dynamics and function are influenced by the F-actin cytoskeleton, but the underlying mechanisms are not fully understood.

Purpose of the Study:

• To investigate the role of SET domain protein 3 (SETD3) in regulating mitochondrial F-actin polymerization and mitochondrial function.
• To elucidate the mechanism by which SETD3 influences mitochondrial morphology, movement, and oxidative phosphorylation.

Main Methods:

• Biochemical assays to detect actin methylation by SETD3.
• Mitochondrial imaging and live-cell microscopy to assess mitochondrial dynamics and F-actin distribution.
• Functional assays to evaluate oxidative phosphorylation and mitochondrial complex I activity.
• Experiments manipulating SETD3 levels and extracellular matrix (ECM) stiffness.

Main Results:

• SETD3 directly methylates actin at histidine-73, promoting F-actin polymerization on mitochondria.
• SETD3 localizes to the outer mitochondrial membrane and enhances F-actin assembly around mitochondria.
• SETD3 loss of function impairs mitochondrial F-actin, reduces mitochondrial branching and movement, and compromises oxidative phosphorylation.
• SETD3 levels are regulated by ECM stiffness, influencing mitochondrial shape in response to mechanical cues.

Conclusions:

• SETD3 is a key regulator of mitochondrial F-actin polymerization, essential for maintaining mitochondrial morphology, dynamics, and function.
• SETD3 acts as a mechano-sensitive enzyme linking extracellular matrix stiffness to mitochondrial adaptation.
• These findings uncover a novel mechanism for F-actin regulation at the mitochondrial surface, impacting cellular energy metabolism.