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

Antonino F. Montanarella; Nikolas Hundt; Dominik Keim; Aron Venczel; Felix Zierhut; Simon Langnickel; Andreas Graw; Markus Kröss; Johannes Dietrich; Dario Saczko-Brack; Claudia Veigel

doi:10.1073/pnas.2501022122

Proceedings of the National Academy of Sciences

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

A Antonino F. Montanarella (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München) N Nikolas Hundt (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München) D Dominik Keim (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München) A Aron Venczel (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München) F Felix Zierhut (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München) S Simon Langnickel (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München) A Andreas Graw (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München) M Markus Kröss (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München) J Johannes Dietrich (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München) D Dario Saczko-Brack (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München) C Claudia Veigel (Department of Cellular Physiology, Biomedical Centre, Ludwig-Maximilians-Universität München)

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.

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Article Details

Journal Proceedings of the National Academy of Sciences

Volume / Issue Vol. 122, Issue 22

Published June 03, 2025

DOI 10.1073/pnas.2501022122

ISSN 0027-8424

Publisher National Academy of Sciences

Journal Info

Proceedings of the National Academy of Sciences

National Academy of Sciences

ISSN: 0027-8424 Life Sciences