title: 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.
authors.affiliation: Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Sindy
authors.initials: S
authors.lastname: Escobar-Alvarez
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Gardner
authors.forename: Aneesh
authors.initials: A
authors.lastname: Sheth
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.forename: Guangli
authors.initials: G
authors.lastname: Yang
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.forename: Mark L
authors.initials: ML
authors.lastname: Heaney
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000502:physiology; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects
chemical_list: D004272:DNA, Mitochondrial; D045222:Electron Transport Chain Complex Proteins; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D000255:Adenosine Triphosphate; D000581:Amidohydrolases; C084507:peptide deformylase
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