Mitochondrial and Nuclear Genes of Mitochondrial Components in Cancer

Curr Genomics. 2009 June; 10(4): 281–293. doi: 10.2174/138920209788488517.

E Kirches*

Department of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany

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3. OTHER NUCLEAR-ENCODED MITOCHONDRIAL PROTEINS DISCUSSED IN CANCER
3.1. Does Frataxin Play an Inhibiting Role in ROS-Mediated Tumorigenesis ?
Friedreich’s ataxia is a severe neurodegenerative disease of adulthood, often accompanied by cardial hypertrophy and usually leading to the patient’s death within 15 years. It is inherited as a recessive autosomal trait, caused by an intronic GAA trinucleotid expansion in the frataxin gene, which switches off transcription of the affected allele [55]. Frataxin is a mitochondrial protein, which is suggested to be involved in iron homeostasis in the mitochondria, since a reduced amount of the protein in patients with the intragenic trinucleotide expansion leads to intramitochondrial iron deposits. Although the details of frataxin function are currently a matter of debate, these deposits may indicate an insufficient transport of iron to the sites of iron-sulfur cluster biogenesis by frataxin [56-59], which in turn may hamper the incorporation of correctly iron-loaded Fe/S-clusters into various mitochondrial proteins, such as the Fe/S-containing ETC complexes. In cell cultures, frataxin inactivation was shown to result in ETC inhibition, as demonstrated by a diminished mitochondrial membrane potential, decreased O2-consumption and decreased oxidative ATP synthesis. Frataxin dysfunction may lead to an inhibition of mitochondrial energy metabolism. On the other hand, a dysfunction of ETC complexes, as well as deposits of free iron (by Fenton reaction) can cause enhanced generation of ROS in the mitochondrial matrix and in the intermembrane space. Oxidative stress is thought to further damage ETC complexes and other redox-sensitive proteins, such as the Krebs cycle enzyme aconitase. This oxidative stress component may further inhibit intermediary metabolism and oxidative ATP synthesis.

Ristow and colleagues analyzed for the first time a potential tumor suppressing function of frataxin in cell culture and animal models, although patients suffering from Friedreich’s ataxia are in no way prone to a higher tumor burden. The idea behind this work was a potential connection between the antioxidative properties of frataxin and ROS-mediated tumorigenesis. The authors analyzed this topic initially in murine 3T3L1 cells, which had been transfected with either a vector expressing human frataxin or a control construct [60]. Both cell clones were exposed to culture conditions with artificially enhanced ROS production. The cells overexpressing frataxin exhibited a significantly lower number of anchorage-independent foci in the culture dishes and the rate of colony formation in soft agar assays was significantly lower, indicating that frataxin protected the cells from ROS-induced transformation into a tumor phenotype. This was further supported by the observation that only cells from the anchorage-independent foci were able to induce tumor growth when xenografted to nude mice.

While oxidative stress in frataxin-deficient patients with Friedreich’s ataxia may be due to the disturbed synthesis of Fe/S-clusters and mitochondrial iron deposits, it is less obvious as to how enforced overexpression of frataxin in normal cells may protect them against ROS. The authors explained the protective effect by the observed increase in glutathione peroxidase (GPx) activity and in reduced thiols. GPx and the reduced form of glutathione play an important role in the detoxification of H2O2, which is built as a product of the SOD- (superoxide dismutase) reaction. Superoxide dismutase 2 (SOD2) is a mitochondrial enzyme, which detoxifies superoxide radicals, released mainly from ETC complexes I and III into the mitochondrial matrix.

In a next step, the authors investigated the potential tumor suppressing effect of enforced frataxin expression in the colon cancer lines MIP101, DLD2 and HT29, which lack endogenous expression of the protein. Mitochondrial oxidative metabolism was enhanced in the transfected cells, as could be shown by an increase of mitochondrial membrane potential, cellular respiration and ATP content, as well as aconitase activity. Increased aconitase activity may be explained in part by decreased oxidative stress. Again, the frataxin cells exhibited a lower colony formation rate in soft agar essays and a lower rate of tumor growth after xenotransplantation to nude mice [61]. The most direct evidence for a role of frataxin in carcinogenesis was reported by the same group using targeted hepatic disruption of frataxin expression in mice. The animals had reduced life spans and developed multiple hepatic tumors, in which high apoptotic and mitotic (Ki-67) indices were observed [62]. The liver specimen showed elevated levels of thiobarbituric-acid reactive substances (TBARS), a marker of lipid peroxidation, and elevated levels of oxidized glutathione, a classical oxidative stress marker. Activities of those mitochondrial enzymes, which contain Fe/S-moieties, i.e. aconitase and ETC complexes I, II, III, were reduced. In accordance with an inhibited oxidative metabolism, the ATP content of livers from knock-out animals was decreased.

The authors did not develop a detailed hypothesis regarding the mechanism of liver tumorigenesis, but speculated that an observed reduction in p38-MAP-kinase phosphorylation may play a role, since activation of this type of mitogen activated protein kinase had been discussed earlier as a factor suppressing the formation of hepatic tumors [63, 64]. Although the authors did not discuss this issue, it might be speculated, whether the observed inhibition of SDH (complex II) may participate in tumorigenesis.
 
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Coenzyme Q10 and Neurological Diseases

Pharmaceuticals 2009, 2, 134-149; doi:10.3390/ph203134

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Michelangelo Mancuso *, Daniele Orsucci, Valeria Calsolaro, Anna Choub and Gabriele Siciliano
Department of Neuroscience, Neurological Clinic, University of Pisa, Tuscany, Italy

Abstract: Coenzyme Q10 (CoQ10, or ubiquinone) is a small electron carrier of the mitochondrial respiratory chain with antioxidant properties. CoQ10 supplementation has been widely used for mitochondrial disorders. The rationale for using CoQ10 is very powerful when this compound is primary decreased because of defective synthesis. Primary CoQ10 deficiency is a treatable condition, so heightened “clinical awareness” about this diagnosis is essential. CoQ10 and its analogue, idebenone, have also been widely used in the treatment of other neurodegenerative disorders. These compounds could potentially play a therapeutic role in Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Friedreich’s ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological diseases, from primary CoQ10 deficiency to neurodegenerative disorders.
Keywords: coenzyme Q10;  idebenone;  mitochondria; mitochondrial diseases; neurodegeneration