Reactive oxygen species (ROS) are well-established suspects in aging, atherosclerosis, and neurodegeneration. However, any therapeutic attempts to interfere with these short-lived molecules—which oxidize proteins, lipids, and nucleic acids in cells—will be well-advised to take into account the role of ROS in normal physiological processes in vivo. A paper in the December 5 issue of Science offers some clues about the manifold roles that ROS play in signaling pathways during embryonic development.

Yukimasa Shibata and others working with Siegfried Hekimi at McGill University in Montreal investigated the C. elegans mutant Clk-1, which fails to produce an enzyme necessary for biosynthesis of the electron carrier ubiquinone (coenzyme Q). Coenzyme Q, in turn, is involved in production for ROS. Added dietary CoQ allows the animal to survive, but the worm develops—and ages—too slowly, with delays in organ development and effects on behavior and reproduction. For example, decreased oxidation of LDL-like lipoproteins threw germline development into disarray.

The researchers found two signaling pathways by which this reduced redox chemistry affected development. One depends on reduced oxidation of an analog of vertebrate low-density lipoprotein (LDL) through Ack-related tyrosine kinase (ARK-1) and inositol trisphosphate signaling. The other is the ras pathway, which is altered via lowered cytoplasmic ROS levels.

"These findings provide a unique model to study the effect of redox signal transduction on the development of whole organisms and suggest a model for the Clk-1 pleiotropy, in which the complexity of the phenotype is due to the multiplicity of signaling roles that are carried out by the oxidative modification of cellular constituents," conclude the authors.

Do the molecular interactions described in this study have relevance to aging and neurodegenerative process? Let us know what you think.—Hakon Heimer

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  1. A fatty diet produces oxidative stress, as seen in diabetics, whose urine contains elevated levels of oxidized DNA base products (8-OHdG)—also seen in cases of breast cancer, which has now been firmly linked to a fatty diet (Bingham et al., 2003).

    How can saturated fats do this? A likely mechanism involves changes in mitochondrial membrane structure (as in other membranes), due to monounsaturate loading and reduced supply of essential fatty acids. Saturated fats are metabolized very slowly compared with the EFAs in dietary oils, nuts, etc., and the excess stearic acid converts to oleic acid via fatty acid synthetase, an enzyme that is normally suppressed by EFAs. Membranes have to take what they can get, and so respond rapidly to dietary fatty acid patterns.

    The mitochondrial dysfunction in Parkinson's disease is often associated with clinically undiagnosed diabetes, which suggests that a fatty diet is being consumed, causing the mitochondrial membrane to change and cause uncoupling and superoxide release (along with reduced ATP). Oxidative stress lowers glutathione levels in neurons, and it is the neuromelanin-containing dopaminergic neurons of the substantia nigra, in specific areas lacking glutathione peroxidase protection, that die in Parkinson's. Reduced ATP supply promotes poor recycling of oxidized proteins and also invites glutamate toxicity.

    To add another twist to the story, a fatty diet in pregnancy produces the typical anxious person who is a prime candidate for Parkinson's in later life. These chronically stressed, obsessional, and vigilant patients presumably suffer from oxidative stress in the womb, induced by the fatty maternal diet. Alternatively, an anxiety state may arise from transplacental passage of maternal cortisol, due to oxidative placental changes that may inactivate the cortisol-busting enzyme 11-β-hydroxy steroid dehydrogenase.

    Roughly half of all anxious people are depressed, and half are not. It is usually fatty diet that adds the depression, which is understandable if an already stressed brain now has to cope with synaptic mitochondrial oxidation and reduced ATP output. The overactive serotonin and noradrenaline turnover in stress presumably begins to falter in such conditions.

    Clinically, a low-fat diet soon reverses such superimposed unipolar depression, so we can deduce that the typical Parkinson's case (who is often depressed before the Parkinson's begins) eats sufficient fat to maintain the depression, to develop the typical glucose intolerance, and to cause mitochondrial uncoupling in the midbrain and elsewhere.

    Finally, vascular oxidative stress induced by cortisol may oxidize folate (and/or impair intracellular B12 metabolism), leading to the elevated homocysteine seen in anxiety, Parkinson's, and diabetes; such homocysteine is toxic (as is cortisol) to the hippocampus, and perhaps other brain regions, like midbrain monoaminergic nuclei and cerebral cortex. Intriguing to see the stressed brain destroy itself by generating neurotoxic cortisol and homocysteine in peripheral tissues!

    Vascular disease and cancer are common in Parkinson's, as one would expect when signaling pathways suffer chronic oxidative activation of protein kinases and inhibition of protein phosphatases, not to mention DNA oxidation itself. Correct redox balance will prevent all these diseases, and is easily arranged by instituting a preventive low-fat (but EFA-rich) diet in pregnancy, and ensuring its continuance thereafter. This is the Mitochondria-Friendly Diet!

    References:

    . Are imprecise methods obscuring a relation between fat and breast cancer?. Lancet. 2003 Jul 19;362(9379):212-4. PubMed.

    . Phosphorus metabolism in unsaturated fatty acid-deficient rats. J Biol Chem. 1954 Nov;211(1):103-10. PubMed.

    . Deficiency of essential fatty acids and atherosclerosis, etcetera. Lancet. 1956 Apr 7;270(6919):381-3. PubMed.

  2. Is Redox Regulation of Development in Caenorhabditis elegans a Critical Issue?
    Shibata and colleagues (2003) present compelling evidence of reactive oxygen species (ROS) and oxidation of lipoprotein as important mediators of signal transduction. They explore this issue by examining the mechanisms for the long life of worms with the mutation of clk-1. The authors hypothesized that the phenotypes of clk-1 mutants (C. elegans' delayed development) is due to altered ROS levels (Miyadera et al., 2002). The authors use SOD-1 and lipoprotein mutants together to show a linkage between ROS and development, even though they have not shown the direct evidence that oxidatively modified low-density lipoprotein (LDL) is the critical signal for development. These studies suggest that oxidative stress is bifunctional. One is a physiological signal for development, and another is the cause of aging and diseases.

    These findings may shed new light on the SOD-1 mutations linked to amyotrophic lateral sclerosis, where bifunctionality of oxidative stress suggests a pivotal homeostatic function highly dependent on subtle catalytic distinction. Further, these findings interplay with the role of diet or any antioxidant in health, where oxidative stress plays a homeostatic function (Smith et al., 2000).

    This study highlights an important role for oxidized lipoproteins in mediating regulatory signals necessary for proper maturation of germ cells. Since oxidative stress is inevitable as long as organisms use molecular oxygen, it is not surprising that the same machinery may be provided in other species. Although apolipoprotein (Apo) B and LDL have not been detected in human cerebrospinal fluid, several other lipoproteins such as ApoE may fulfill the requirements in human brain. From the standpoint of research in Alzheimer's disease, of particular interest in association with this study is a recent report suggesting that oxidized LDL receptor 1 (OLR1) gene polymorphisms on chromosome 12 are linked to Alzheimer's disease (AD). Luedecking-Zimmer and colleagues (2002) suggested 3’-UTR +1073 C/T polymorphism modifies the risk of sporadic AD in an ApoE-dependent manner. ApoE4 not only correlates with elevated cholesterol level, but also is associated with amyloid-β peptide to form a stable complex both in vitro and in vivo. Since Aβ is able to bind redox active metals such as copper and iron, it might cause oxidation of lipoproteins. Also, microglia are known to produce ApoE. Because microglia can generate reactive oxygen species, they may contribute to the production of oxidized lipoproteins. Binding of oxidized lipoproteins to receptors such as OLR might propagate a kind of “aging signal” within neurons. Since lipid peroxide levels increase with age, it is not strange that our body recognizes oxidized lipoprotein as a mediator of aging signals.

    References:

    . Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer's disease on chromosome 12. Hum Genet. 2002 Oct;111(4-5):443-51. PubMed.

    . Quinones in long-lived clk-1 mutants of Caenorhabditis elegans. FEBS Lett. 2002 Feb 13;512(1-3):33-7. PubMed.

    . Redox regulation of germline and vulval development in Caenorhabditis elegans. Science. 2003 Dec 5;302(5651):1779-82. PubMed.

    . Oxidative stress in Alzheimer's disease. Neurosci Bull. 2014 Apr;30(2):271-81. Epub 2014 Mar 24 PubMed.

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  1. . Redox regulation of germline and vulval development in Caenorhabditis elegans. Science. 2003 Dec 5;302(5651):1779-82. PubMed.