Up-regulation of plasma membrane-associated redox activities in neuronal cells lacking functional mitochondria Dong-Hoon Hyun,* Nicole D. Hunt, Scott S. Emerson,* Joe O. Hernandez,* Mark P. Mattson* and Rafael de Cabo  *Laboratory of Neurosciences and  Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA Abstract Mitochondria-deficient cells (q o cells) survive through en- hanced glycolytic metabolism in the presence of pyruvate and uridine. The plasma membrane redox system (PMRS) con- tains several NAD(P)H-related enzymes and plays a key role in maintaining the levels of NAD + /NADH and reduced coen- zyme Q. In this study, q o cells were used to investigate how the PMRS is regulated under conditions of mitochondrial dysfunction. q o cells exhibited a lower oxygen consumption rate and higher levels of lactate than parental cells, and were more sensitive to glycolysis inhibitors (2-deoxyglucose and iodoacetamide) than control cells. However, they were more resistant to H 2 O 2 , consistent with increased catalase activity and decreased oxidative damage (protein carbonyls and nitrotyrosine). PM-associated redox enzyme activities were enhanced in q o cells compared to those in control cells. Our data suggest that all PMRS enzymes and biomarkers tested are closely related to the ability of the PMs to maintain redox homeostasis. These results illustrate that an up-regulated PM redox activity can protect cells from oxidative stress as a result of an improved antioxidant capacity, and suggest a mechan- ism by which neurons adapt to conditions of impaired mito- chondrial function. Keywords: mitochondrial deficiency, oxidative stress, plas- ma membrane redox system. J. Neurochem. (2007) 100, 1364–1374. Mitochondria are the main source of ATP production required to support cell survival and specialized functions such as synaptic transmission in neurons, although ATP is also produced by cytosolic glycolysis. During mitochondrial oxidative phosphorylation, reactive oxygen species (ROS) are produced; ROS have been associated with damage to DNA, lipids and proteins in aging (Halliwell 1992, 2001). Neurons, which have a very high metabolic demand and must endure relatively high levels of oxidative stress, are particularly vulnerable to mitochondrial dysfunction. Indeed, perturbed mitochondrial function and oxidative stress are believed to play prominent roles in neurodegenerative disorders including Alzheimer’s disease (AD) and Parkin- son’s disease (PD) (Mattson and Kroemer 2003; Reddy and Beal 2005). The plasma membrane (PM) is involved in the response of cells to oxidative stress and can also regulate the physiology of cells by controlling their relationship to the environment. In both cases, the activity of the PM redox system (PMRS) is necessary. PM respond to external oxidative stress by transferring electrons from internal reductants such as NAD(P)H to external oxidants (Alcain et al. 1991; del Castillo-Olivares et al. 2000). A key molecule involved in PMRS activity is coenzyme Q (CoQ) which, in its reduced form, functions as an antioxidant that protects lipids from oxidative damage either directly or by maintaining the active reduced forms of both a-tocopherol and ascorbate (Kagan et al. 1990a,b; Beyer 1994; Gomez-Diaz et al. 1997b; Santos-Ocana et al. Received May 2, 2006; revised manuscript received September 5, 2006; accepted September 5, 2006. Address correspondence and reprint requests to Dr Rafael de Cabo, Experimental Gerontology, National Institute on Aging Intramural Re- search Program, National Institutes of Health, Baltimore, MD 21224, USA. E-mail: decabora@grc.nia.nih.gov Abbreviations used: AD, Alzheimer’s disease; AFR, ascorbate free radical; ARE, antioxidant response element; b5R, NADH-cytochrome b5 reductase; CoQ, Coenzyme Q; ETS, electron transport system; FeCN, ferricyanide; HSP, heat shock protein; KCN, potassium cyanide; MPP + , 1-methyl-4-phenyl-phenyl-pyridinium iodide; NQO1, NAD(P)H-qui- none oxidoreductase 1; Nrf2, NF-E2-related factor-2; n-SMase, neutral sphingomyelinase; PD, Parkinson’s disease; PMRS, plasma membrane redox system; ROS, reactive oxygen species. Journal of Neurochemistry , 2007, 100, 1364–1374 doi:10.1111/j.1471-4159.2006.04411.x 1364 No claim to original US government works Ó 2007 International Society for Neurochemistry, J. Neurochem. (2007) 100, 1364–1374