Mini Review Mitochondrial protein oxidation and degradation in response to oxidative stress and aging Anne-Laure Bulteau a , Luke I. Szweda b , Bertrand Friguet a, * a Universite ´ Denis Diderot–Paris 7, Laboratoire de Biologie et Biochimie Cellulaire du Vieillissement, EA 3106/IFR 117, case courrier 7128, 2 Place Jussieu, 75251 Paris Cedex 05, France b Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, USA Received 19 December 2005; received in revised form 15 March 2006; accepted 17 March 2006 Available online 4 May 2006 Abstract Mitochondria are a major source of intracellular reactive oxygen species (ROS), the production of which increases with age. These organelles are also targets of oxidative damage. The deleterious effects of ROS may be responsible for impairment of mitochondrial function observed during various pathophysiological states associated with oxidative stress and aging. An important factor for protein maintenance in the presence of oxidative stress is enzymatic reversal of oxidative modifications and/or protein degradation. Failure of these protein maintenance systems is likely a critical component of the aging process. Mitochondrial matrix proteins are sensitive to oxidative inactivation and oxidized proteins are known to accumulate during aging. The ATP-stimulated mitochondrial Lon protease is a highly conserved protease found in prokaryotes and the mitochondrial compartment of eukaryotes and is believed to play an important role in the degradation of oxidized mitochondrial matrix proteins. Age-dependent declines in the activity and regulation of this proteolytic system may underlie accumulation of oxidatively modified and dysfunctional protein and loss in mitochondrial viability. q 2006 Elsevier Inc. All rights reserved. Keywords: Mitochondrial protein degradation; Lon protease; Aging; Oxidative stress; Ischemia–reperfusion 1. Introduction Functional integrity and rapid and appropriate responses to physiological and pathophysiological stimuli are required for mitochondria to meet cellular energy demands. In addition, mitochondria participate in cellular Ca 2C homeostasis, signaling cascades, and under certain conditions, can initiate cell death. Nevertheless, the mitochondrial respiratory chain is one of the main sources of endogenous reactive oxygen species (ROS) and mitochondrial proteins represent targets for oxidative modification and loss in function. Mitochondrial dysfunction has been implicated in the aging process as well as a number of age-associated diseases such as Parkinson’s disease and Alzheimer’s disease associated with increased levels of mitochondrial derived free radicals and oxidative damage. Enzymatic repair of oxidative modification and protein degradation have been recognized as important factors for the maintenance of cellular homeostasis and survival. Failure of protein maintenance systems is considered a critical component of the aging process. In the cytosol, the proteasome constitutes the main proteolytic machinery involved in the elimination of oxidized protein (Shringarpure et al., 2001), however, this proteolytic complex is not present in the mitochondria. Pioneering studies have shown that mitochon- drial matrix from liver and heart contains proteolytic activity that degrades oxidized, dysfunctional, and misfolded protein (Marcillat et al., 1988). More recent work supports a role for the mitochondrial matrix Lon protease in eliminating oxida- tively modified mitochondrial proteins (Bota and Davies, 2002), similar to the role of the proteasome in the cytosol. 2. Oxidized protein degradation by the mitochondrial matrix Lon protease In the mitochondria, the steady state level of oxidatively modified protein is dependent on five major determinants: (1) ROS production, (2) ROS removal, (3) susceptibility of proteins to ROS mediated modification, (4) oxidized protein repair and (5) oxidized protein degradation. Protein degra- dation constitutes the final step by which oxidatively modified proteins can be eliminated. Mammalian mitochondria contain Experimental Gerontology 41 (2006) 653–657 www.elsevier.com/locate/expgero 0531-5565/$ - see front matter q 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2006.03.013 * Corresponding author. Tel./fax: C33 1 44 27 82 34. E-mail address: bfriguet@paris7.jussieu.fr (B. Friguet).