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Fluctuation-driven mechanotransduction regulates mitochondrial-network structure and function

Nature Materials volume 14, pages 1049–1057 (2015)Cite this article

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Abstract

Cells can be exposed to irregular mechanical fluctuations, such as those arising from changes in blood pressure. Here, we report that ATP production, assessed through changes in mitochondrial membrane potential, is downregulated in vascular smooth muscle cells in culture exposed to monotonous stretch cycles when compared with cells exposed to a variable cyclic stretch that incorporates physiological levels of cycle-by-cycle variability in stretch amplitude. Variable stretch enhances ATP production by increasing the expression of ATP synthase’s catalytic domain, cytochrome c oxidase and its tyrosine phosphorylation, mitofusins and PGC-1α. Such a fluctuation-driven mechanotransduction mechanism is mediated by motor proteins and by the enhancement of microtubule-, actin- and mitochondrial-network complexity. We also show that, in aorta rings isolated from rats, monotonous stretch downregulates—whereas variable stretch maintains—physiological vessel-wall contractility through mitochondrial ATP production. Our results have implications for ATP-dependent and mechanosensitive intracellular processes.

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Figure 1: Variability in stretch pattern alters mitochondrial and overall cellular energetics without producing injury.
Figure 2: Contractility of aortae is regulated by the stretch pattern.
Figure 3: Variability in the stretch pattern alters the structural organization of the mitochondrial, microtubule and actin networks.
Figure 4: Effects, on TMRM-labelled cells, of inhibitors that eliminate the differences between US and MS as well as US and VS.
Figure 5: Effects, on TMRM-labelled cells, of inhibitors that eliminate the differences between MS and VS.
Figure 6: Similarities and differences in signalling during monotonous (MS) and variable (VS) stretching.

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Acknowledgements

This study was funded by NIH HL-098976, HL-11174 and HL-122513.

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Author notes

  1. Erzsébet Bartolák-Suki and Jasmin Imsirovic: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA

    Erzsébet Bartolák-Suki, Jasmin Imsirovic, Harikrishnan Parameswaran, Tyler J. Wellman, Nuria Martinez, Philip G. Allen & Béla Suki

  2. University Children’s Hospital Basel, CH-4031 Basel, Switzerland

    Urs Frey

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Contributions

E.B.-S. contributed conceptually, carried out cell studies, biochemical assays, histology, analysed data and wrote the manuscript; J.I. contributed conceptually and carried out the aorta physiology experiments; H.P. contributed conceptually and analysed images; N.M. made measurements; P.G.A. carried out confocal imaging; T.J.W. analysed images; U.F. contributed conceptually as well as with the human data; B.S. contributed conceptually, made measurements, analysed data and wrote the manuscript.

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Correspondence to Erzsébet Bartolák-Suki or Béla Suki.

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The authors declare no competing financial interests.

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Bartolák-Suki, E., Imsirovic, J., Parameswaran, H. et al. Fluctuation-driven mechanotransduction regulates mitochondrial-network structure and function. Nature Mater 14, 1049–1057 (2015). https://doi.org/10.1038/nmat4358

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