Creating conditions similar to those that occur during exposure of cells to microgravity induces apoptosis in human lymphocytes by 5-lipoxygenase-mediated mitochondrial uncoupling and cytochrome c release

Mauro Maccarrone, Natalia Battista, Mariantonia Meloni, Monica Bari, Grazia Galleri, Proto Pippia, Augusto Cogoli, Alessandro Finazzi-Agrò

Research output: Contribution to journalArticlepeer-review

Abstract

Creating conditions similar to those that occur during exposure of cells to microgravity induced a sixfold increase of apoptotic bodies and DNA fragments in human lymphocytes, paralleled by an early (within 2 h) fourfold increase in 5-lipoxygenase (5-LOX) activity and a fivefold decrease in mitochondrial membrane potential and increase in cytochrome c release (within 4 and 8 h, respectively). Similar membrane potential and cytochrome c release were observed in isolated mitochondria treated with physiological amounts of 5-LOX and were enhanced by creating conditions similar to those that occur during exposure of cells to microgravity. 5-LOX inhibitors, 5,8,11,14-eicosatetraynoic acid and caffeic acid, completely prevented apoptosis, whereas the phospholipase A2 inhibitor methyl-arachidonoyl fluorophosphonate and the 5-LOX activating protein inhibitor MK886 reduced it to 65-70%. The intracellular calcium chelator EGTA-acetoxymethylester reduced 5-LOX activity and apoptosis to 30-40% of controls, whereas the p38 mitogen-activated protein kinase inhibitor SB203580 was ineffective. The caspase-3 and caspase-9 inhibitors Z-Asp(OCH 3)-Glu(OCH3)-Val-Asp(OCH3)-fluoromethylketone (FMK) and Z-Leu-Glu(OCH3)-His-Asp(OCH3)-FMK reduced apoptotic bodies to 25-30% of the control cells. Finally, creating conditions similar to those that occur during exposure of cells to microgravity did not induce apoptosis in human lymphoma U937 cells, which did not express an active 5-LOX.

Original languageEnglish
Pages (from-to)472-481
Number of pages10
JournalJournal of Leukocyte Biology
Volume73
Issue number4
DOIs
Publication statusPublished - Apr 2003

Keywords

  • Arachidonate cascade
  • Calcium
  • Caspase
  • Cyclooxygenase
  • Mitochondrial membrane potential

ASJC Scopus subject areas

  • Cell Biology

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