Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes

Rahul S. Kathayat, Yang Cao, Pablo D. Elvira, Patrick A. Sandoz, María-Eugenia Zaballa, Maya Z. Springer, Lauren E. Drake, Kay F. Macleod, F. Gisou van der Goot () and Bryan C. Dickinson ()
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Rahul S. Kathayat: The University of Chicago
Yang Cao: The University of Chicago
Pablo D. Elvira: The University of Chicago
Patrick A. Sandoz: Ecole Polytechnique Fédérale de Lausanne
María-Eugenia Zaballa: Ecole Polytechnique Fédérale de Lausanne
Maya Z. Springer: The University of Chicago
Lauren E. Drake: The University of Chicago
Kay F. Macleod: The University of Chicago
F. Gisou van der Goot: Ecole Polytechnique Fédérale de Lausanne
Bryan C. Dickinson: The University of Chicago

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract The reversible modification of cysteine residues by thioester formation with palmitate (S-palmitoylation) is an abundant lipid post-translational modification (PTM) in mammalian systems. S-palmitoylation has been observed on mitochondrial proteins, providing an intriguing potential connection between metabolic lipids and mitochondrial regulation. However, it is unknown whether and/or how mitochondrial S-palmitoylation is regulated. Here we report the development of mitoDPPs, targeted fluorescent probes that measure the activity levels of “erasers” of S-palmitoylation, acyl-protein thioesterases (APTs), within mitochondria of live cells. Using mitoDPPs, we discover active S-depalmitoylation in mitochondria, in part mediated by APT1, an S-depalmitoylase previously thought to reside in the cytosol and on the Golgi apparatus. We also find that perturbation of long-chain acyl-CoA cytoplasm and mitochondrial regulatory proteins, respectively, results in selective responses from cytosolic and mitochondrial S-depalmitoylases. Altogether, this work reveals that mitochondrial S-palmitoylation is actively regulated by “eraser” enzymes that respond to alterations in mitochondrial lipid homeostasis.

Date: 2018
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DOI: 10.1038/s41467-017-02655-1

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