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

Kathayat RS; Cao Y; Elvira PD; Sandoz PA; Zaballa ME; Springer MZ; Drake LE; Macleod KF; van der Goot FG; Dickinson BC

doi:10.1038/s41467-017-02655-1

Back

Journal article

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

Kathayat RS Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA.
Cao Y Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA.
Elvira PD Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA.
Sandoz PA Global Health Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, CH-1015, Switzerland.
Zaballa ME Global Health Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, CH-1015, Switzerland.
Springer MZ The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 60637, USA.
Drake LE The Committee on Cancer Biology, The University of Chicago, Chicago, IL, 60637, USA.
Macleod KF The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 60637, USA.
van der Goot FG Global Health Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, CH-1015, Switzerland. Gisou.vandergoot@epfl.ch.
Dickinson BC Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA. Dickinson@uchicago.edu.

2018-01-25

Published in:

Nature communications. - 2018

English 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.

Language