Shedding of a Rat Epididymal Sperm Protein Associated with Infertility Induced by Ornidazole and α-Chlorohydrin1

Wagenfeld, Andrea; Yeung, Ching‐Hei; Strupat, Kerstin; Cooper, Trevor G.

doi:10.1095/biolreprod58.5.1257

Cited by 60 publications

(52 citation statements)

References 28 publications

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“…In the fly, mitochondrial mutants are often infertile because germ cell maturation requires both energy and mitochondrial morphological changes (27). Similarly, DJ-1 protein levels correlate with infertility in pharmacologically treated male rats that leads to reduced glycolytic enzyme activities in the sperm (28)(29)(30)(31). Third, DKO flies showed agedependent declines in both climbing activity and ATP level.…”

Section: Discussionmentioning

confidence: 99%

DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function

Hao

Giasson

Bonini

2010

Proc. Natl. Acad. Sci. U.S.A.

249

217

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Mutations or deletions in PARKIN/PARK2, PINK1/PARK6, and DJ-1/ PARK7 lead to autosomal recessive parkinsonism. In Drosophila, deletions in parkin and pink1 result in swollen and dysfunctional mitochondria in energy-demanding tissues. The relationship between DJ-1 and mitochondria, however, remains unclear. We now report that Drosophila and mouse mutants in DJ-1 show compromised mitochondrial function with age. Flies deleted for DJ-1 manifest similar defects as pink1 and parkin mutants: male sterility, shortened lifespan, and reduced climbing ability. We further found poorly coupled mitochondria in vitro and reduced ATP levels in fly and mouse DJ-1 mutants. Surprisingly, up-regulation of DJ-1 can ameliorate pink1, but not parkin, mutants in Drosophila; cysteine C104 (analogous to C106 in human) is critical for this rescue, implicating the oxidative functions of DJ-1 in this property. These results suggest that DJ-1 is important for proper mitochondrial function and acts downstream of, or in parallel to, pink1. These findings link DJ-1, pink1, and parkin to mitochondrial integrity and provide the foundation for therapeutics that link bioenergetics and parkinsonism.parkin | Parkinson's disease | oxidative stress | Drosophila P arkinson's disease (PD) is the most common movement disorder and the second most common neurodegenerative disease. Clinically, it is characterized by resting tremor, rigidity, bradykinesia, gait abnormality, and slow movement (1, 2). PD patients show severe dopaminergic neuron loss, resulting in a decrease of striatal dopamine levels responsible for the motor features (3, 4). Age is the most potent risk factor for PD, but other contributing factors include exposure to environmental toxins like paraquat and rotenone. Although predominantly idiopathic, genetic mutations account for ≈10% of cases (5). Studies of genes responsible for familial parkinsonism/PD are yielding critical insight into mechanisms shared by sporadic and familial disease.Mutations in DJ-1/PARK7, PINK1/PARK6, and PARKIN/PARK2 lead to autosomal recessive parkinsonism. Properties of DJ-1 suggest that it may be at a compelling intersection for several risk factors in PD, including genetics, oxidative stress, environmental factors, and age. First, DJ-1 gene mutations lead to early-onset autosomal recessive parkinsonism (6). Second, the DJ-1 protein is sensitive to oxidative stress and may act as a redox-responsive molecular chaperone that can prevent protein misfolding (7). Third, tolerance toward paraquat in animals is mediated, in part, through modifications of DJ-1 protein (8). Finally, age induces the same modifications of the DJ-1 protein as environmental toxins (8). Mice mutant for DJ-1 show dopamine reuptake dysfunction (9) and have increased sensitivity to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) (10). Two DJ-1 orthologs (DJ-1a and DJ-1b) exist in Drosophila, and when deleted, flies have decreased climbing ability (11) and increased sensitivity to H 2 O 2 , paraquat, and rotenone (12). Taken to...

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Section: Discussionmentioning

confidence: 99%

DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function

Hao

Giasson

Bonini

2010

Proc. Natl. Acad. Sci. U.S.A.

249

217

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“…At the dosage administered, the drug has no e ect on the testis and the infertility is completely reversible within 7 days after withdrawal. Kinematic measurements of motile spermatozoa using computer-assisted analysis revealed reduction in the straight-line and average path velocities of sperm obtained from the distal epididymal regions; however, the percentages of motile spermatozoa in all the regions of the epididymis in ornidazole-treate d rats were similar to that of controls [35]. The infertility-inducing action of this drug suggests that motility and sperm proteins can be signi®cantly a ected by altered epididymal function and can be a focal point in the regulation of sperm function.…”

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confidence: 86%

“…Sperm maturation is dependent on the changing microenvironment within the various regions of the epididymis [2]. The transport of metabolites, hormones, and nutrients, and the secretion and resorption of luminal¯uid in the e erent ducts of the rete testis and epididymis are essential for the maintenance of a proper milieu for the maturation and capacitation of sperm [35]. An interesting physiological occurrence is the low HCO 3 7 concentration in the epididymis and its high content in the seminal plasma.…”

mentioning

confidence: 99%

“…Moreover, proper motility of pig sperm is highly dependent on an optimal HCO 3 7 concentration in the extracellular milieu and is correlated positively with changes in the concentration of this anion in the male and female reproductive tracts, whereby regulating sperm capacitation possibly by in¯uencing phosphorylatio n of critical sperm proteins [34]. Also, the epididymis is capable of reabsorbing NaCl and water under basal conditions and paradoxicall y secretes NaCl and NaHCO 3 under stimulatory conditions [35].…”

mentioning

confidence: 99%

“…A few compounds (e.g., chlorosugars, a-chlorohydrin) are known to act rapidly and induce infertility in the male by e ecting spermatozoa in the epididymis. The epididymis also seems to be the primary site of action for ornidazole, a nitroimdazole derivative, that induces infertility in male rats within 10±14 days of treatment [35]. At the dosage administered, the drug has no e ect on the testis and the infertility is completely reversible within 7 days after withdrawal.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Influence of Acetazolamide on Aqp1 Gene Expression in Testis and on Sperm Count/Motility in Epididymis of Rats

Sun

Bai

et al. 2002

Archives of Andrology

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Identification and characterization of a novel protein that regulates RNA-protein interaction

et al. 1999

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In a previous study [Nachaliel et al., 1993], we identified an RNA-binding protein (RBP) in FTO-2B rat hepatoma cells whose activity was stimulated upon the dissociation of a protein factor. We report in this article that the RBP is a complex protein of about 400 kDa, composed of RNA-binding subunit(s) (RBS), and regulatory subunit(s) (RS). We purified the RS to near-homogeneity (Mr approximately 25,000) and determined the amino acid sequence of a peptide derived from RS. On the basis of this sequence information, the cDNA for RS was obtained. Recombinant RS protein expressed in Escherichia coli had the capacity to bind RBS and inhibit its RNA-binding activity. The cDNA contains the complete coding sequence because the recombinant protein has the same electrophoretic mobility as that of the native RS in SDS-polyacrylamide gels. Sequence comparison showed that RS is almost identical to DJ-1, a recently discovered protein with an oncogenic potential, and CAP1, a rat sperm protein. However, the protein does not contain any known motifs that can provide a clue as to its exact function. Indirect immunofluorescence analyses showed that in addition to the cytoplasm, where RS is associated with microtubular filaments, the polypeptide is localized to the cell nucleus. The possible role of RS is discussed.

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Shedding of a Rat Epididymal Sperm Protein Associated with Infertility Induced by Ornidazole and α-Chlorohydrin1

Cited by 60 publications

References 28 publications

DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function

DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function

Influence of Acetazolamide on Aqp1 Gene Expression in Testis and on Sperm Count/Motility in Epididymis of Rats

Identification and characterization of a novel protein that regulates RNA-protein interaction

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