Loss of caspase-2 accelerates age-dependent alterations in mitochondrial production of reactive oxygen species

Marisa Lopez-Cruzan, Brian Herman

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Mitochondria are known to be a major source and target of oxidative stress. Oxidative stress increases during aging and is suggested to underlie in part the aging process. We have previously documented an increase in endogenous caspase-2 (casp2) activity in hepatocytes obtained from old (28 months) vs. young mice (5 months). More recently, we have shown that casp2 is activated by oxidative stress and is critical for mitochondrial oxidative stress-induced apoptosis. Since casp2 appears integral to mitochondrial oxidative stress-induced apoptosis, in this study we determined whether loss of casp2 altered the production of mitochondrial reactive oxygen radicals (mROS) as a function of age in intact living hepatocytes. To stimulate mitochondrial metabolic activity, we added a mixture of pyruvate and glutamate to hepatocytes while continuously monitoring endogenous mROS production in the presence or absence of rotenone and/or antimycin A. Our data demonstrate that mROS production and neutralization are compromised in hepatocytes of old mice. Interestingly, casp2 deficient hepatocytes from middle age mice (12 months) had similar mROS neutralization kinetics to those of hepatocytes from old WT mice. Rotenone had no effect on mROS metabolism, whereas antimycin A significantly altered mROS production and metabolism in an age-dependent fashion. Our results indicate that: (1) hepatocytes from young and old mice respond differently to dysfunction of the mitochondrial electron transport chain; (2) age-dependent alterations in mROS metabolism are likely regulated by complex III; and (3) absence of casp2 accelerates age-dependent changes in terms of pyruvate/glutamate-induced mROS metabolism.

Original languageEnglish (US)
Pages (from-to)121-130
Number of pages10
JournalBiogerontology
Volume14
Issue number2
DOIs
StatePublished - Apr 2013

Bibliographical note

Funding Information:
Acknowledgments This work has been supported by NIH 5T32 AG021890 and 2R37 AG007218.

Keywords

  • Aging
  • Caspase-2
  • Hepatocytes
  • Mitochondria
  • Reactive oxygen species

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