Genetic inactivation of mitochondria-targeted redox enzyme p66ShcA preserves neuronal viability and mitochondrial integrity in response to oxidative challenges

Kimmy Su; Bourdette, Dennis; Forte, Michael
July 2012
Frontiers in Physiology;Jul2012, Vol. 3, p1
Academic Journal
Mitochondria are essential to neuronal viability and function due to their roles in ATP production, intracellular calcium regulation, and activation of apoptotic pathways. Accordingly, mitochondrial dysfunction has been indicated in a wide variety of neurodegenerative diseases, including Alzheimer's disease (AD), Huntington's disease, amyotrophic lateral sclerosis, stroke, and multiple sclerosis (MS). Recent evidence points to the permeability transition pore (PTP) as a key player in mitochondrial dysfunction in these diseases, in which pathologic opening leads to mitochondrial swelling, rupture, release of cytochrome c, and neuronal death. Reactive oxygen species (ROS), which are inducers of PTP opening, have been prominently implicated in the progression of many of these neurodegenerative diseases. In this context, inactivation of a mitochondria-targeted redox enzyme p66ShcA (p66) has been recently shown to prevent the neuronal cell death leading to axonal severing in the murine model of MS, experimental autoimmune encephalomyelitis (EAE). To further characterize the response of neurons lacking p66, we assessed their reaction to treatment with stressors implicated in neurodegenerative pathways. Specifically, p66-knockout (p66-KO) and wild-type (WT) neurons were treated with hydrogen peroxide (H2O2) and nitric oxide (NO), and assessed for cell viability and changes in mitochondrial properties, including morphology and ROS production. The results showed that p66-KO neurons had greater survival following treatment with each stressor and generated less ROS when compared to WT neurons. Correspondingly, mitochondria in p66-KO neurons showed diminished morphological changes in response to these challenges. Overall, these findings highlight the importance of developing mitochondria-targeted therapeutics for neurodegenerative disorders, and emphasize p66, mitochondrial ROS, and the PTP as key targets for maintaining mitochondrial and neuronal integrity.


Related Articles

  • Antioxidant activities of dithiol alpha-lipoic acid. Islam, M. T. // Bangladesh Journal of Medical Science;Jun2009, Vol. 8 Issue 3, p6 

    Alpha-lipoic acid, a dithiol compound derived from octanoic acid, which acts as a coenzyme for several redox reactions in almost all the tissue of the body. It retains its protective functions in both oxidized and reduced forms. Alpha-lipoic acid reduces oxidative stress by redox generation of...

  • Homeostasis of redox status derived from glucose metabolic pathway could be the key to understanding the Warburg effect. Shiwu Zhang; Chuanwei Yang; Zhenduo Yang; Dan Zhang; Xiaoping Ma; Mills, Gordon; Zesheng Liu // American Journal of Cancer Research;2015, Vol. 5 Issue 4, p1265 

    Glucose metabolism in mitochondria through oxidative phosphorylation (OXPHOS) for generation of adenosine triphosphate (ATP) is vital for cell function. However, reactive oxygen species (ROS), a by-product from OXPHOS, is a major source of endogenously produced toxic stressors on the genome. In...

  • Motexafin gadolinium induces mitochondriallymediated caspase-dependent apoptosis. Chen, J.; Ramos, J.; Sirisawad, M.; Miller, R.; Naumovski, L. // Apoptosis;Sep2005, Vol. 10 Issue 5, p1131 

    Motexafin gadolinium (MGd, Xcytrin®) is a tumor-localizing redox mediator that catalyzes the oxidation of intracellular reducing molecules including NADPH, ascorbate, protein and non-protein thiols, generating reactive oxygen species (ROS). MGd localizes to tumors and cooperates with...

  • Neopterin inhibits ATP-induced calcium release in alveolar epithelial cells in vitro. Hoffmann, Georg; Gollnick, Frank; Meyer, Rainer // Mediators of Inflammation;Jun2002, Vol. 11 Issue 3, p181 

    Background: Serum neopterin concentrations rise during activation of the cellular immune system. It is suggested that neopterin interacts with cellular redox mechanisms. This induces oxidative stress, which inhibits intracellular Ca[sup 2+] transients in various cell types. In type II alveolar...

  • H±nmdash;ATPases in Oxidative and Photosynthetic Phosphorylation. McCarty, Richard E. // BioScience;Jan1985, Vol. 35 Issue 1, p27 

    The H[sup +]-ATPases of mitochondria, chloroplasts, and bacteria are complex enzymes that couple the synthesis and hydrolysis of adenosine 5'-triphosphate to transmembrane fluxes of protons. In both structure and chemical mechanism, this class of enzymes differs markedly from the...

  • A kinetic-metabolic model based on cell energetic state: study of CHO cell behavior under Na-butyrate stimulation. Ghorbaniaghdam, Atefeh; Henry, Olivier; Jolicoeur, Mario // Bioprocess & Biosystems Engineering;Apr2013, Vol. 36 Issue 4, p469 

    A kinetic-metabolic model approach describing and simulating Chinese hamster ovary (CHO) cell behavior is presented. The model includes glycolysis, pentose phosphate pathway, TCA cycle, respiratory chain, redox state and energetic metabolism. Growth kinetic is defined as a function of the major...

  • Marvelous Mitochondria! Kravitz, Len // IDEA Fitness Journal;May2011, Vol. 8 Issue 5, p21 

    The article offers a brief overview of mitochondria's vital energy function capabilities in the human body. Details related to its discovery, metabolic and genetic self-sufficiency characteristics, Lynn Margulis' endosymbiotic theory of mitochondria development, oxidation, and adenosine...

  • Targeting Mitochondria in Fighting Cancer. Gogvadze, Vladimir // Current Pharmaceutical Design;12/11/2011, Vol. 17 Issue 36, p4034 

    During the last years, there have been a number of reports that prove involvement of mitochondria in the pathogenesis of variety of disorders including cancer and neurodegenerative diseases. Alteration of vital mitochondrial functions - production of ATP, calcium buffering capacity, abnormal...

  • Mitochondrial functions during cell death, a complex (I-V) dilemma. Ricci, J-E; Waterhouse, N; Green, D R // Cell Death & Differentiation;May2003, Vol. 10 Issue 5, p488 

    Cell Death and Differentiation (2003) 10, 488-492. doi:10.1038/sj.cdd.4401225


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics