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

          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
          -enoyl-ACP reductase (MECR) rescues respiratory growth and lipoylation defects of a
          Saccharomyces cerevisiae
          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.


DOI: 10.1038/s41467-023-36358-7

Research Groups: Molecular and Cellular Modeling

Publication type: Journal

Journal: Nature Communications

Citation: Nat Commun 14(1),619

Date Published: 1st Dec 2023

Registered Mode: by DOI

Authors: 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

help Submitter
Tanvir Rahman, M., Kristian Koski, M., Panecka-Hofman, J., Schmitz, W., Kastaniotis, A. J., Wade, R. C., Wierenga, R. K., Kalervo Hiltunen, J., & Autio, K. J. (2023). An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration. In Nature Communications (Vol. 14, Issue 1). Springer Science and Business Media LLC.

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Created: 6th Feb 2023 at 09:30

Last updated: 5th Mar 2024 at 21:25

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