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Remarkably high activities of testicular cytochrome c in destroying reactive oxygen species and in triggering apoptosis.

Institute of Biomedical Informatics, School of Medicine, Tsinghua University, Beijing 100084, China.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 07/2006; 103(24):8965-70. DOI: 10.1073/pnas.0603327103
Source: PubMed

ABSTRACT Hydrogen peroxide (H(2)O(2)) is the major reactive oxygen species (ROS) produced in sperm. High concentrations of H(2)O(2) in sperm induce nuclear DNA fragmentation and lipid peroxidation and result in cell death. The respiratory chain of the mitochondrion is one of the most productive ROS generating systems in sperm, and thus the destruction of ROS in mitochondria is critical for the cell. It was recently reported that H(2)O(2) generated by the respiratory chain of the mitochondrion can be efficiently destroyed by the cytochrome c-mediated electron-leak pathway where the electron of ferrocytochrome c migrates directly to H(2)O(2) instead of to cytochrome c oxidase. In our studies, we found that mouse testis-specific cytochrome c (T-Cc) can catalyze the reduction of H(2)O(2) three times faster than its counterpart in somatic cells (S-Cc) and that the T-Cc heme has the greater resistance to being degraded by H(2)O(2). Together, these findings strongly imply that T-Cc can protect sperm from the damages caused by H(2)O(2). Moreover, the apoptotic activity of T-Cc is three to five times greater than that of S-Cc in a well established apoptosis measurement system using Xenopus egg extract. The dramatically stronger apoptotic activity of T-Cc might be important for the suicide of male germ cells, considered a physiological mechanism that regulates the number of sperm produced and eliminates those with damaged DNA. Thus, it is very likely that T-Cc has evolved to guarantee the biological integrity of sperm produced in mammalian testis.

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    • "The slight differences in amino acid composition between the isoforms affect its function. In comparison with the somatic isoform, testes Cytc shows a threefold increased activity to reduce hydrogen peroxide ; however, it also shows a fourfold increased ability to trigger apoptosis (Liu et al. 2006 ) . For COX, six subunit isoforms have been identi fi ed in mammals to date. "
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    ABSTRACT: The mitochondrial oxidative phosphorylation (OxPhos) system not only generates the vast majority of cellular energy, but is also involved in the generation of reactive oxygen species (ROS), and apoptosis. Cytochrome c (Cytc) and cytochrome c oxidase (COX) represent the terminal step of the electron transport chain (ETC), the proposed rate-limiting reaction in mammals. Cytc and COX show unique regulatory features including allosteric regulation, isoform expression, and regulation through cell signaling pathways. This chapter focuses on the latter and discusses all mapped phosphorylation sites based on the crystal structures of COX and Cytc. Several signaling pathways have been identified that target COX including protein kinase A and C, receptor tyrosine kinase, and inflammatory signaling. In addition, four phosphorylation sites have been mapped on Cytc with potentially large implications due to its multiple functions including apoptosis, a pathway that is overactive in stressed cells but inactive in cancer. The role of COX and Cytc phosphorylation is reviewed in a human disease context, including cancer, inflammation, sepsis, asthma, and ischemia/reperfusion injury as seen in myocardial infarction and ischemic stroke.
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    • "As spermatogenesis proceeds, T-Cytc expression increases, becoming the predominant form in mature sperm (Goldberg et al., 1977; Hess et al., 1993; Liu et al., 2006). T-Cytc operates with a three-fold increased H 2 O 2 reduction activity; however, at the same time its apoptotic activity is also significantly increased (about fourfold compared to S-Cytc) (Liu et al., 2006). The authors concluded that these effects help prevent radical damage of sperm and serve as a selective agent by initiating cellular death of dysfunctional or damaged sperm. "
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    • "A certain proportion of peroxides is absorbed from the intestine and exerts its damaging effect in the organism, too (Oarada et al., 1988a). The testicular tissue is especially susceptible to the effect of reactive oxygen species (Liu et al., 2006). A PV above 20 to 30 is a reliable indicator of harmful oxidative processes, while an AN of 40 to 50 (or higher) is also a sign of faulty performance (Várnagy, 1979). "
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