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.

Why translation counts for mitochondria – retrograde signalling links mitochondrial protein synthesis to mitochondrial biogenesis and cell proliferation

“…In some cases, these proliferation defects were attributed to dysfunctional mitochondrial respiration (Escobar-Alvarez et al, 2010;Skrtić et al, 2011). However, this interpretation is at odds with data from a vast scientific literature that demonstrate that glycolysis fuels the metabolic demands of cellular proliferation (reviewed by Hanahan and Weinberg, 2011).…”

“…The proliferation of cultured mammalian cells can be impaired following disruption of mitochondrial function Escobar-Alvarez et al, 2010;Richter et al, 2010;Richter et al, 2013;Rorbach et al, 2008;Skrtić et al, 2011;Soleimanpour-Lichaei et al, 2007;Uchiumi et al, 2010). In some cases, these proliferation defects were attributed to dysfunctional mitochondrial respiration (Escobar-Alvarez et al, 2010;Skrtić et al, 2011).…”

“…It has been shown previously that disrupting mitochondrial translation in cultured mammalian cells, either genetically or with antibiotics, can impair cell proliferation Escobar-Alvarez et al, 2010;Richter et al, 2010;Rorbach et al, 2008;Skrtić et al, 2011;Soleimanpour-Lichaei et al, 2007;Uchiumi et al, 2010); notably these proliferation defects occur when the cells are cultured in glucose. Typically, cultured cells from patients with mitochondrial disorders are not reported to have proliferation defects when they are grown in glucose medium and the patients themselves do not manifest symptoms that are compatible with proliferation defects, such as dysmorphy or abnormal development (Ylikallio and Suomalainen, 2012).…”

Interplay Between N-Terminal Methionine Excision and FtsH Protease Is Essential for Normal Chloroplast Development and Function in Arabidopsis

“…Genetic and pharmacological studies revealed that inhibition of NME activity in vivo leads to the destabilization of several central proteins of either plastid or mitochondrial proteomes Bouzaidi-Tiali et al, 2007;Moon et al, 2008;Escobar-Alvarez et al, 2010). Moreover, organellar NME inhibition induces a cascade of events that impair the biogenesis of the entire compartment as well as the development of the whole organism.…”

Identification of Potent Inhibitors against Human Peptide Deformylase as Anticancer Agents

“…12 The PDF inhibitors may induce a tumor-specific mitochondrial membrane depolarization and ATP depletion, which promote cell death or arrest proliferation in a wide variety of cancer cell lines. [5][6][7] However, the exact mechanism of anticancer effect of PDF inhibitors is still unclear.…”