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An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration

Author

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  • M. Tanvir Rahman

    (University of Oulu)

  • M. Kristian Koski

    (University of Oulu)

  • Joanna Panecka-Hofman

    (University of Warsaw
    Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS))

  • Werner Schmitz

    (University of Würzburg)

  • Alexander J. Kastaniotis

    (University of Oulu)

  • Rebecca C. Wade

    (Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS)
    Heidelberg University)

  • Rik K. Wierenga

    (University of Oulu)

  • J. Kalervo Hiltunen

    (University of Oulu)

  • Kaija J. Autio

    (University of Oulu)

Abstract

Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory function. MtFAS generates the octanoic acid precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. The structurally well-characterized component of mtFAS, human 2E-enoyl-ACP reductase (MECR) rescues respiratory growth and lipoylation defects of a Saccharomyces cerevisiae Δetr1 strain lacking native mtFAS enoyl reductase. To address the role of longer products of mtFAS, we employed in silico molecular simulations to design a MECR variant with a shortened substrate binding cavity. Our in vitro and in vivo analyses indicate that the MECR G165Q variant allows synthesis of octanoyl groups but not long chain fatty acids, confirming the validity of our computational approach to engineer substrate length specificity. Furthermore, our data imply that restoring lipoylation in mtFAS deficient yeast strains is not sufficient to support respiration and that long chain acyl-ACPs generated by mtFAS are required for mitochondrial function.

Suggested Citation

  • M. Tanvir Rahman & M. Kristian Koski & Joanna Panecka-Hofman & Werner Schmitz & Alexander J. Kastaniotis & Rebecca C. Wade & Rik K. Wierenga & J. Kalervo Hiltunen & Kaija J. Autio, 2023. "An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36358-7
    DOI: 10.1038/s41467-023-36358-7
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    References listed on IDEAS

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    1. Jan Gajewski & Renata Pavlovic & Manuel Fischer & Eckhard Boles & Martin Grininger, 2017. "Engineering fungal de novo fatty acid synthesis for short chain fatty acid production," Nature Communications, Nature, vol. 8(1), pages 1-8, April.
    2. Jonathan C. Greenhalgh & Sarah A. Fahlberg & Brian F. Pfleger & Philip A. Romero, 2021. "Machine learning-guided acyl-ACP reductase engineering for improved in vivo fatty alcohol production," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. Jiapeng Zhu & Kutti R. Vinothkumar & Judy Hirst, 2016. "Structure of mammalian respiratory complex I," Nature, Nature, vol. 536(7616), pages 354-358, August.
    4. Michal T. Boniecki & Sven A. Freibert & Ulrich Mühlenhoff & Roland Lill & Miroslaw Cygler, 2017. "Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    5. Tao Yu & Yongjin J. Zhou & Leonie Wenning & Quanli Liu & Anastasia Krivoruchko & Verena Siewers & Jens Nielsen & Florian David, 2017. "Metabolic engineering of Saccharomyces cerevisiae for production of very long chain fatty acid-derived chemicals," Nature Communications, Nature, vol. 8(1), pages 1-11, August.
    6. Karol Fiedorczuk & James A. Letts & Gianluca Degliesposti & Karol Kaszuba & Mark Skehel & Leonid A. Sazanov, 2016. "Atomic structure of the entire mammalian mitochondrial complex I," Nature, Nature, vol. 538(7625), pages 406-410, October.
    7. Nicholas G. Fox & Xiaodi Yu & Xidong Feng & Henry J. Bailey & Alain Martelli & Joseph F. Nabhan & Claire Strain-Damerell & Christine Bulawa & Wyatt W. Yue & Seungil Han, 2019. "Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
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