title: Loss of caspase-2 accelerates age-dependent alterations in mitochondrial production of reactive oxygen species.
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.
authors.affiliation: Department of Cellular and Structural Biology, School of Medicine, Barshop Institute for the Study of Aging and Longevity, University of Texas Health Science Center at San Antonio, STRF MC 8254, 8403 Floyd Curl Drive, San Antonio, TX, 78229-3904, USA. lopezcruzan@uthscsa.edu
authors.forename: Marisa
authors.initials: M
authors.lastname: Lopez-Cruzan
authors.forename: Brian
authors.initials: B
authors.lastname: Herman
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D053143:Caspase 2 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism*; D023421:Models, Animal; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D017382:Reactive Oxygen Species; D000968:Antimycin A; D053143:Caspase 2