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.


Available from: Sheng Ye, Dec 17, 2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The catalytic activity of cytochrome c (cyt c) to peroxidize cardiolipin to its oxidized form is required for the release of pro-apoptotic factors from mitochondria, and for execution of the subsequent apoptotic steps. However, the structural basis for this peroxidation reaction remains unclear. In this paper, we determined the three-dimensional NMR solution structure of yeast cyt c Y67H variant with high peroxidase activity, which is almost similar to that of its native form. The structure reveals that the hydrogen bond between Met80 and residue 67 is disrupted. This change destabilizes the sixth coordination bond between heme Fe3+ ion and Met80 sulfur atom in the Y67H variant, and further makes it more easily be broken at low pH conditions. The steady-state studies indicate that the Y67H variant has the highest peroxidase activities when pH condition is between 4.0 and 5.2. Finally, a mechanism is suggested for the peroxidation of cardiolipin catalyzed by the Y67H variant, where the residue His67 acts as a distal histidine, its protonation facilitates O-O bond cleavage of H2O2 by functioning as an acidic catalyst.
    PLoS ONE 09/2014; 9(9):e107305. DOI:10.1371/journal.pone.0107305 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cytochrome c (Cyt c) is an apoptosis-initiating protein when released into the cytoplasm of eukaryotic cells and therefore a possible cancer drug candidate. Although proteins have been increasingly important as pharmaceutical agents, their chemical and physical instability during production, storage, and delivery remains a problem. Chemical glycosylation has been devised as a method to increase protein stability and thus enhance their long-lasting bioavailability.
    BMC Biochemistry 08/2014; 15(1):16. DOI:10.1186/1471-2091-15-16 · 1.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: NanoUPLC/MSE was used to verify the effects of 8 weeks of low (SHR-LIT = 4) and high (SHR-HIT = 4) intensity training over the left ventricle proteome of hypertensive rats (SHR-C = 4). Training enhanced the aerobic capacity and reduced the systolic blood pressure in all exercised rats. NanoUPLC/MSE identified 250 proteins, with 233 in common to all groups and 16 exclusive to SHR-C, 2 to SHR-LIT, and 2 to the SHR-HIT. Cardiac hypertrophy related proteins appeared only in SHR-C. The SHR-LIT enhanced the abundance of 30 proteins and diminished 6, while SHR-HIT enhanced the abundance of 39 proteins and reduced other 7. The levels of metabolic (β and γ-enolase, adenine phosphoribosultransferase, and cytochrome b-c1), myofibril (myosin light chain 4, tropomyosin α and β-chain), and transporter proteins (hemoglobin, serum albumin, and hemopexin) were increased by both intensities. Transcription regulator and histone variants were enhanced by SHR-LIT and SHR-HIT respectively. SHR-LIT reduced the concentration of myosin binding protein C, while desmin and membrane voltage dependent anion selective channel protein-3 were reduced only by SHR-HIT. In addition, polyubiquitin B and C, and transcription regulators decreased in both intensities. Exercise also increased the concentration of anti-oxidant proteins, peroxiredozin-6 and glutathione peroxidase-1.
    Journal of Proteomics 10/2014; 113. DOI:10.1016/j.jprot.2014.10.010 · 3.93 Impact Factor