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Aging Results in Increased Autophagy of Mitochondria and Protein Nitration in Rat Hepatocytes Following Heat Stress

Terry D. Oberley, Jamie M. Swanlund, Hannah J. Zhang and Kevin C. Kregel

Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin (TDO); Department of Pathology and Laboratory Medicine, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (TDO,JMS); and Department of Integrative Physiology and Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa (HJZ,KCK)

Correspondence to: Dr. Terry D. Oberley, MD, PhD, Department of Pathology and Laboratory Medicine, William S. Middleton Memorial Veterans Hospital, Room A-35, 2500 Overlook Terrace, Madison, WI 53705. E-mail: toberley{at}wisc.edu. Co-corresponding author: Dr. Kevin C. Kregel. E-mail: kevin-kregel{at}uiowa.edu

The natural breakdown of cells, tissues, and organ systems is a significant consequence of aging and is at least partially caused by a decreased ability to tolerate environmental stressors. Based on quantitative ultrastructural analysis using transmission electron microscopy and computer imaging, we show significant differences in hepatocyte morphology between young and old rats during a 48-hr recovery period following a 2-day heat stress protocol. Mitochondrial injury was greater overall in old compared with young rats. Autophagy was observed in both young and old rats, with autophagy greater overall in old compared with young hepatocytes. Lipid peroxidation and protein nitration were evaluated by localization and quantification of 4-hydroxy-2-nonenal (4-HNE)–modified protein adducts and 3-nitrotyrosine (3-NT) levels, respectively. Levels of 3-NT but not 4-HNE-protein adducts were significantly elevated in hepatocytes of old rats in comparison with young at 90 min after heat stress, suggesting a major role for reactive nitrogen species in the pathology observed at this time point. These results show a differential response of hepatocyte mitochondria to heat stress with aging, as well as greater levels of both autophagic and nitrative damage in old vs young hepatocytes. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 56:615–627, 2008)

Key Words: mitochondria • 3-nitrotyrosine • autophagy • heat stress • oxidative stress

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