Proteomic Signatures of Sperm Mitochondria in Varicocele: Clinical Use as Biomarkers of Varicocele Associated Infertility

Samanta L 1 , Agarwal A 2 , Swain N 1 , Sharma R 3 , Gopalan B 4 , Esteves SC 5 Show all authors , Durairajanayagam D 6 , Sabanegh E 7

Affiliations 

  • 1 American Center for Reproductive Medicine, Department of Urology, Cleveland Clinic Foundation, Cleveland, Ohio; Redox Biology Laboratory, Department of Zoology, School of Life Sciences, Ravenshaw University, Odisha, India
  • 2 American Center for Reproductive Medicine, Department of Urology, Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address: agarwaa@ccf.org
  • 3 American Center for Reproductive Medicine, Department of Urology, Cleveland Clinic Foundation, Cleveland, Ohio
  • 4 Yorg Corp., Plano, Texas
  • 5 ANDROFERT, Andrology and Human Reproduction Clinic, Referral Center for Male Reproduction, Campinas, Brazil
  • 6 Discipline of Physiology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Malaysia
  • 7 Department of Urology, Cleveland Clinic Foundation, Cleveland, Ohio
J Urol, 2018 08;200(2):414-422.
PMID: 29530785 DOI: 10.1016/j.juro.2018.03.009

Abstract

PURPOSE: Varicocele may disrupt testicular microcirculation and induce hypoxia-ischemia related degenerative changes in testicular cells and spermatozoa. Superoxide production at low oxygen concentration exacerbates oxidative stress in men with varicocele. Therefore, the current study was designed to study the role of mitochondrial redox regulation and its possible involvement in sperm dysfunction in varicocele associated infertility.

MATERIALS AND METHODS: We identified differentially expressed mitochondrial proteins in 50 infertile men with varicocele and in 10 fertile controls by secondary liquid chromatography-tandem mass spectroscopy data driven in silico analysis. Identified proteins were validated by Western blot and immunofluorescence. Seminal oxidation-reduction potential was measured.

RESULTS: We identified 22 differentially expressed proteins related to mitochondrial structure (LETM1, EFHC, MIC60, PGAM5, ISOC2 and import TOM22) and function (NDFSU1, UQCRC2 and COX5B, and the core enzymes of carbohydrate and lipid metabolism). Cluster analysis and 3-dimensional principal component analysis revealed a significant difference between the groups. All proteins studied were under expressed in infertile men with varicocele. Liquid chromatography-tandem mass spectroscopy data were corroborated by Western blot and immunofluorescence. Impaired mitochondrial function was associated with decreased expression of the proteins (ATPase1A4, HSPA2, SPA17 and APOA1) responsible for proper sperm function, concomitant with elevated seminal oxidation-reduction potential in the semen of infertile patients with varicocele.

CONCLUSIONS: Impaired mitochondrial structure and function in varicocele may lead to oxidative stress, reduced ATP synthesis and sperm dysfunction. Mitochondrial differentially expressed proteins should be explored for the development of biomarkers as a predictor of infertility in patients with varicocele. Antioxidant therapy targeting sperm mitochondria may help improve the fertility status of these patients.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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