Work

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

Year: 2025

Type: article

Abstract: Mitochondrial damage determines cell fate, leading to mitochondrial autophagy or cellular apoptosis in health and disease. The molecular mechanisms and role of the acto-myosin cytoskeleton regulating mitochondrial clearance and membrane remodeling are critical in neurodegenerative disease progression including Alzheimer, but remain unclear. To investigate the potential link between full-length Myosin VI (FL-Myo6) recruitment and exposure of the mitochondria-specific lipid cardiolipin (CL), here we adapted a combination of molecular biology, biochemical, high-resolution fluorescence and interferometric light-scattering techniques. We developed analysis tools to reveal the structural Myo6–CL interaction sites, Myo6-oligomerization interfaces and mechanical properties. We found that CL activates backfolded FL-Myo6 and induces Myo6-oligomerization. Myo6 bound to CL cargo-vesicles in vitro mediates processive runs over >500 nm at >90 nm s −1 . We propose a model how CL-interaction regulates backfolded Myo6 activation into a highly processive cargo-bound motor.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.2501022122