Stimulation of oxygen consumption promotes mitochondrial calcium accumulation, a process associated with, and causally linked to, enhanced formation of tert-butylhydroperoxide-induced DNA single-strand breaks

Andrea Guidarelli, Liliana Brambilla, Emilio Clementi, Clara Sciorati, Orazio Cantoni

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27 Citations (Scopus)

Abstract

The NADH-linked substrates pyruvate, L-glutamine, and β- hydroxybutyrate, while enhancing the rate of oxygen consumption, also increased the formation of DNA single-strand breaks induced by tert- butylhydroperoxide in intact U937 cells. A cause-effect relationship between these two parameters was established by showing that: (a) rotenone, an inhibitor of complex I, abolished respiration and prevented the enhancement of the DNA-damaging response under all the above circumstances; (b) the membrane-impermeant, complex I-activating substrate L-malate gave similar results in permeabilized cells; and (c) none of the NADH-linked substrates affected the DNA-damaging response to tert-butylhydroperoxide in respiration- deficient cells. Stimulation of electron transport potentiated the DNA- cleaving ability of tert-butylhydroperoxide via a process involving enforced mitochondrial calcium accumulation in the absence of a discernible elevation in the cytosolic concentration of free Ca2+. Finally, mitochondrial calcium was found to promote the mitochondrial formation of DNA-damaging levels of hydrogen peroxide. In conclusion, the data herein presented define a previously unexpected role of respiratory substrates in the control of the deleterious effects of an organic hydroperoxide at the level of genomic DNA. The enhanced DNA cleavage mediated by NADH-linked substrates in response to tert-butylhydroperoxide would appear to depend on a sequence of events involving stimulation of electron transport, mitochondrial accumulation of Ca2+, and mitochondrial formation of DNA-damaging levels of hydrogen peroxide via a Ca2+-dependent process.

Original languageEnglish
Pages (from-to)176-185
Number of pages10
JournalExperimental Cell Research
Volume237
Issue number1
DOIs
Publication statusPublished - Nov 25 1997

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tert-Butylhydroperoxide
Single-Stranded DNA Breaks
Oxygen Consumption
NAD
Hydrogen Peroxide
Calcium
DNA
Electron Transport
Mitochondrial DNA
Hydroxybutyrates
Cell Respiration
Rotenone
U937 Cells
DNA Cleavage
Glutamine
Pyruvic Acid
Respiration
Membranes

ASJC Scopus subject areas

  • Cell Biology

Cite this

Stimulation of oxygen consumption promotes mitochondrial calcium accumulation, a process associated with, and causally linked to, enhanced formation of tert-butylhydroperoxide-induced DNA single-strand breaks. / Guidarelli, Andrea; Brambilla, Liliana; Clementi, Emilio; Sciorati, Clara; Cantoni, Orazio.

In: Experimental Cell Research, Vol. 237, No. 1, 25.11.1997, p. 176-185.

Research output: Contribution to journalArticle

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