title: Defective Human Sperm Cells Are Associated with Mitochondrial Dysfunction and Oxidant Production.
abstract: Infertility affects about 15% of couples of reproductive age. The male factor is involved in nearly 50% of infertility cases. Defective human sperm function has been associated with evidence of high levels of reactive oxygen species (ROS) and a resultant loss of fertilizing potential in vivo and in vitro. Analogous to what has been observed in somatic cells, mitochondria are likely the major sources of ROS in sperm cells. In this study, we analyzed mitochondrial function using high-resolution respirometry, ROS production, and footprints of oxidative and nitrative stress processes in intact human sperm cells. We showed that mitochondrial dysfunction (measured through the respiratory control ratio) was correlated with a decrease in human sperm motility. The samples analyzed presented nitro-oxidative modifications of proteins, such as protein 3-nitrotyrosine, that were observed mainly in the mid-piece (where mitochondria are localized) and in the sperm head. Semen samples presenting lower percentage of motile sperm showed higher amounts of nitro-oxidative protein modifications than those with larger quantities of motile sperm. When spermatozoa were exposed to inhibitors of the respiratory mitochondrial function, in the presence of a nitric oxide flux, sperm produced potent nitro-oxidative species (i.e., peroxynitrite). This effect was observed in more than 90% of intact living sperm cells and in sperm mitochondrial fractions. These data suggest that dysfunctional mitochondria in sperm cells produce oxidants that may contribute to male infertility. These data provide the rationale for testing the potential of compounds that improve sperm mitochondrial function to treat male infertility.
authors.affiliation: Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay.
authors.forename: Adriana
authors.initials: A
authors.lastname: Cassina
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay.
authors.forename: Patricia
authors.initials: P
authors.lastname: Silveira
authors.affiliation: Andrology Clinic Fertilab, Montevideo, Uruguay.
authors.forename: Lidia
authors.initials: L
authors.lastname: Cantu
authors.affiliation: Andrology Clinic Fertilab, Montevideo, Uruguay.
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Montes
authors.affiliation: Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay.
authors.forename: Rafael
authors.initials: R
authors.lastname: Radi
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay rsapiro@fmed.edu.uy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Sapiro
mesh_terms: D000293:Adolescent; D000328:Adult; D019069:Cell Respiration; D006801:Humans; D007248:Infertility, Male / Q000209:etiology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D013081:Sperm Motility; D013094:Spermatozoa / Q000378:metabolism*; D055815:Young Adult
chemical_list: D026361:Reactive Nitrogen Species
keywords: male infertility; mitochondria; nitro-oxidative stress; reactive oxygen species; sperm motility and transport