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Cardiolipin membranes drive Myosin VI activation, oligomerization, and processive cargo transport

Antonino F Montanarella1,2, Nikolas Hundt1,2, Dominik Keim1,2

  • 1Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München, Planegg-Martinsried 82152, Germany.

Proceedings of the National Academy of Sciences of the United States of America
|May 28, 2025
PubMed

Insights

Cardiolipin activates Myosin VI, promoting its oligomerization and processive movement. This mechanism is crucial for mitochondrial clearance and cell fate in neurodegenerative diseases.

Area of Science:

  • Cell Biology
  • Molecular Mechanisms
  • Neuroscience

Background:

  • Mitochondrial damage impacts cell fate, influencing autophagy and apoptosis.
  • The acto-myosin cytoskeleton's role in mitochondrial clearance is vital for neurodegenerative diseases like Alzheimer's but is not fully understood.

Purpose of the Study:

  • To investigate the link between full-length Myosin VI (FL-Myo6) and cardiolipin (CL) exposure.
  • To elucidate the molecular mechanisms of Myo6-CL interaction and its role in mitochondrial dynamics.

Main Methods:

  • Combination of molecular biology, biochemistry, and high-resolution fluorescence techniques.
  • Interferometric light-scattering assays to determine mechanical properties.
  • Development of analysis tools for structural interaction and oligomerization studies.

Main Results:

  • Cardiolipin (CL) activates backfolded FL-Myo6 and induces its oligomerization.
  • Myo6 bound to CL cargo-vesicles exhibits processive movement over >500 nm at >90 nm s⁻¹.
  • Structural analysis revealed specific Myo6-CL interaction sites and Myo6-oligomerization interfaces.

Conclusions:

  • CL binding triggers the activation of backfolded FL-Myo6 into a processive motor.
  • This mechanism is proposed to regulate mitochondrial clearance and cell fate.
  • Findings offer insights into the molecular basis of neurodegenerative disease progression.
Keywords:
cardiolipincytoskeletoniSCATmembranesmotility

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