A Therapeutic Role for the F1FO-ATP Synthase

SLAS Discov. 2019 Oct;24(9):893-903. doi: 10.1177/2472555219860448. Epub 2019 Jul 2.

Abstract

Recently, the F1FO-ATP synthase, due to its dual role of life enzyme as main adenosine triphosphate (ATP) maker and of death enzyme, as ATP dissipator and putative structural component of the mitochondrial permeability transition pore (mPTP), which triggers cell death, has been increasingly considered as a drug target. Accordingly, the enzyme offers new strategies to counteract the increased antibiotic resistance. The challenge is to find or synthesize compounds able to discriminate between prokaryotic and mitochondrial F1FO-ATP synthase, exploiting subtle structural differences to kill pathogens without affecting the host. From this perspective, the eukaryotic enzyme could also be made refractory to macrolide antibiotics by chemically produced posttranslational modifications. Moreover, because the mitochondrial F1FO-ATPase activity stimulated by Ca2+ instead of by the natural modulator Mg2+ is most likely involved in mPTP formation, effectors preferentially targeting the Ca2+-activated enzyme may modulate the mPTP. If the enzyme involvement in the mPTP is confirmed, Ca2+-ATPase inhibitors may counteract conditions featured by an increased mPTP activity, such as neurodegenerative and cardiovascular diseases and physiological aging. Conversely, mPTP opening could be pharmacologically stimulated to selectively kill unwanted cells. On the basis of recent literature and promising lab findings, the action mechanism of F1 and FO inhibitors is considered. These molecules may act as enzyme modifiers and constitute new drugs to kill pathogens, improve compromised enzyme functions, and limit the deathly enzyme role in pathologies. The enzyme offers a wide spectrum of therapeutic strategies to fight at the molecular level diseases whose treatment is still insufficient or merely symptomatic.

Keywords: F1FO-ATP synthase; diseases; drug binding sites; mitochondria; mitochondrial permeability transition pore.

Publication types

  • Review

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Calcium / metabolism
  • Humans
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Permeability Transition Pore
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Protein Processing, Post-Translational / physiology

Substances

  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Adenosine Triphosphate
  • F1F0-ATP synthase
  • Mitochondrial Proton-Translocating ATPases
  • Calcium