Inhibition of Human Peptide Deformylase Disrupts Mitochondrial Function

Abstract

Deformylases are metalloproteases in bacteria, plants, and humans that remove the N-formyl-methionine off peptides in vitro. The human homolog of peptide deformylase (HsPDF) resides in the mitochondria, along with its putative formylated substrates; however, the cellular function of HsPDF remains elusive. Here we report on the function of HsPDF in mitochondrial translation and oxidative phosphorylation complex biogenesis. Functional HsPDF appears to be necessary for the accumulation of mitochondrial DNA-encoded proteins and assembly of new respiratory complexes containing these proteins. Consequently, inhibition of HsPDF reduces respiratory function and cellular ATP levels, causing dependence on aerobic glycolysis for cell survival. A series of structurally different HsPDF inhibitors and control peptidase inhibitors confirmed that inhibition of HsPDF decreases mtDNA-encoded protein accumulation. Therefore, HsPDF appears to have a role in maintenance of mitochondrial respiratory function, and this function is analogous to that of chloroplast PDF.

This work was supported by NIH grant CA 55349, the Cancer Research and Treatment Foundation, and by the Experimental Therapeutics Center and the Geoffrey Beene Cancer Research Center at Memorial Sloan-Kettering Cancer Center.

We thank Nikola Pavletich and Charles Sawyers for their comments and input during the preparation of the manuscript. We thank Anissa Igoudjil, Rebeca Acín-Pérez, Christopher Antczak, and Hakim Djaballah for their useful advice. Thanks go to David Krige of Chroma Therapeutics for providing CHR-2863 and Hediye Erdjument-Bromage for MS sample analysis.