Oxidative stress pathogenically remodels the cardiac myocyte cytoskeleton via structural alterations to the microtubule lattice

Goldblum, Rebecca R.; McClellan, Mark; White, Kyle; Gonzalez, Samuel J.; Thompson, Brian R.; Vang, Hluechy X.; Cohen, Houda; Higgins, Lee Ann; Markowski, Todd W.; Yang, Tzu Yi; Metzger, Joseph M.; Gardner, Melissa K.

doi:10.1016/j.devcel.2021.07.004

Cited by 39 publications

(31 citation statements)

References 95 publications

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“…Our finding that harmful ROS is a key trigger of MT curling aligns with reports that actin as well as MTs are modified or even damaged by ROS (Goldblum et al, 2021;Wilson et al, 2016;Wioland et al, 2021) and that oxidative stress induces axon swellings in models of Parkinson's disease, multiple sclerosis or ALS (Czaniecki et al, 2019;Nikić et al, 2011;Song et al, 2013). Unfortunately, a more generalised statement cannot be made because axonal MTs have rarely been analysed in oxidative stress experiments (De Vos et al, 2007;Debattisti et al, 2017;Fischer et al, 2012;Saccon et al, 2013;Song et al, 2013).…”

Section: Mitochondria Regulate Ros Homeostasis Required For Mt Bundle Maintenancesupporting

confidence: 86%

New cell biological explanations for kinesin-linked axon degeneration

Liew

Voelzmann

Pinho-Correia

et al. 2021

Preprint

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Axons are the slender, up to meter-long projections of neurons that form the biological cables wiring our bodies. Most of these delicate structures must survive for an organism's lifetime, meaning up to a century in humans. Axon maintenance requires life-sustaining motor protein-driven transport distributing materials and organelles from the distant cell body. It seems logic that impairing this transport causes systemic deprivation linking to axon degeneration. But the key steps underlying these pathological processes are little understood. To investigate mechanisms triggered by motor protein aberrations, we studied more than 40 loss- and gain-of-function conditions of motor proteins, cargo linkers or further genes involved in related processes of cellular physiology. We used one standardised Drosophila primary neuron system and focussed on the organisation of axonal microtubule bundles as an easy to assess readout reflecting axon integrity. We found that bundle disintegration into curled microtubules is caused by the losses of Dynein heavy chain and the Kif1 and Kif5 homologues Unc-104 and Kinesin heavy chain (Khc). Using point mutations of Khc and functional loss of its linker proteins, we studied which of Khc's sub-functions might link to microtubule curling. One cause was emergence of harmful reactive oxygen species through loss of Milton/Miro-mediated mitochondrial transport. In contrast, loss of the Kinesin light chain linker caused microtubule curling through an entirely different mechanism appearing to involve increased mechanical challenge to microtubule bundles through de-inhibition of Khc. The wider implications of our findings for the understanding of axon maintenance and pathology are discussed.

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Section: Mitochondria Regulate Ros Homeostasis Required For Mt Bundle Maintenancesupporting

confidence: 86%

New cell biological explanations for kinesin-linked axon degeneration

Liew

Voelzmann

Pinho-Correia

et al. 2021

Preprint

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“…53 The incorporation of stabilizing GTP-tubulin into these damaged lattice regions leads to an increased frequency of rescue events (the transition from shortening to growth) and thus stabilized microtubules. 53 It has long been recognized that adenosine (a metabolite of ATP) exerts cardioprotective effects in the ischemic preconditioning response, 54,55 which may function through its capacity against oxidative stress-induced damage. Adenosine can regulate microtubule stability, and decreased adenosine availability has been shown to lead to increased microtubule stability.…”

Section: Microtubule Dynamics and Stabilitymentioning

confidence: 99%

Targeting Microtubules for the Treatment of Heart Disease

Warner

2022

Circulation Research

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Heart disease remains the leading cause of morbidity and mortality worldwide. With the advancement of modern technology, the role(s) of microtubules in the pathogenesis of heart disease has become increasingly apparent, though currently there are limited treatments targeting microtubule-relevant mechanisms. Here, we review the functions of microtubules in the cardiovascular system and their specific adaptive and pathological phenotypes in cardiac disorders. We further explore the use of microtubule-targeting drugs and highlight promising druggable therapeutic targets for the future treatment of heart diseases.

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“…Z-stacks were acquired across the volume of these cells. Then, maximum Z-projections were created, followed by analysis of the area of the microtubules divided by the area of the cell, which was performed with a custom MATLAB script (Goldblum et al, 2021). Finally, this normalized value was obtained for multiple cells across each condition from three separate biological replicates and compared using a One-Way ANOVA.…”

Section: Llc-pk1 Microtubule Density Analysismentioning

confidence: 99%

Rapid binding to protofilament edge sites facilitates tip tracking of EB1 at growing microtubule plus-ends

Gonzalez

Goldblum

et al. 2022

Preprint

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EB1 is a key cellular protein that delivers critical regulatory molecules throughout the cell via the tip-tracking of growing microtubule plus-ends. Thus, it is important to understand the mechanism for how EB1 efficiently tracks growing microtubule plus-ends. It is widely accepted that EB1 binds with higher affinity to GTP-tubulin subunits at the growing microtubule tip, relative to GDP-tubulin along the microtubule length. However, it is unclear whether this difference in affinity alone is sufficient to explain the tip-tracking of EB1 at growing microtubule tips. Previously, we found that EB1 binds to exposed microtubule protofilament-edge sites at a ∼70-fold faster rate than to closed-lattice sites, due to diffusional steric hindrance to binding. Thus, we asked whether rapid protofilament-edge binding could contribute to efficient EB1 tip tracking. A computational simulation with differential EB1 on-rates based on closed-lattice or protofilament-edge binding, and with EB1 off-rates that were dependent on tubulin hydrolysis state, recapitulated experimental EB1 tip tracking. To test this model, we used cell-free biophysical assays, as well as live-cell imaging, in combination with the chemotherapy drug Eribulin. We found that Eribulin blocked EB1 protofilament-edge binding, which led to a dramatic decrease in EB1 tip tracking on dynamic microtubules. We conclude that rapid EB1 binding to microtubule protofilament-edge sites increases the efficiency of EB1 tip tracking at the growing microtubule plus end.

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Oxidative stress pathogenically remodels the cardiac myocyte cytoskeleton via structural alterations to the microtubule lattice

Cited by 39 publications

References 95 publications

New cell biological explanations for kinesin-linked axon degeneration

New cell biological explanations for kinesin-linked axon degeneration

Targeting Microtubules for the Treatment of Heart Disease

Rapid binding to protofilament edge sites facilitates tip tracking of EB1 at growing microtubule plus-ends

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