Skip to main content

ORIGINAL RESEARCH article

Front. Reprod. Health
Sec. Andrology
Volume 6 - 2024 | doi: 10.3389/frph.2024.1479568
This article is part of the Research Topic Oxidative Stress and Male Fertility View all 7 articles

Mitochondrial dysfunction signatures in idiopathic primary male infertility: A validated proteomics-based diagnostic approach

Provisionally accepted
Raneen Sawaid Kaiyal Raneen Sawaid Kaiyal 1*Sromona D Mukherjee Sromona D Mukherjee 2Manesh Kumar Panner Selvam Manesh Kumar Panner Selvam 3Aaron W Miller Aaron W Miller 2Sarah C Vij Sarah C Vij 1Scott D Lundy Scott D Lundy 1
  • 1 Urology Department, Glickman Urological and Kidney Institute,, Cleveland Clinic, Cleveland, United States
  • 2 Department of Biological Sciences; Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Foundation,, Clevelnad, United States
  • 3 Department of Urology, Tulane University School of Medicine,, New Orleans, United States

The final, formatted version of the article will be published soon.

    Research Question: Male infertility accounts for almost half of all infertility cases worldwide, with idiopathic male infertility accounting for up to 30% of the cases. Sperm proteomics has revealed critical molecular pathway changes in men with infertility. However, the sperm mitochondrial proteome remains poorly understood. We attempted to answer the following question: Do patients with idiopathic primary male infertility exhibit a proteomic signature associated with mitochondrial dysfunction that could be used as a target for future mechanistic investigations? Design: Patients with idiopathic primary infertility (20-40 years old) referred to the Cleveland Clinic between March 2012 and April 2014 were compared with fertile donor controls. Sperm proteins were analyzed using sodium dodecyl sulphate-polyacrylamide gel electrophoresis page (SDS-PAGE) and liquid chromatography-mass spectrometry (LC-MS), and differentially expressed proteins (DEPs) were identified based on significance test results and fold change thresholds. Protein expression was validated using western blotting.Results: Proteomic analysis of pooled samples from fertile donors (n=5) and patients with idiopathic primary infertility (n=5) identified 1134 proteins, including 344 DEPs.Mitochondrial dysfunction topped the ingenuity toxicity list. Analysis of expression levels of three mitochondrial proteins known to combat oxidative stress revealed that peroxiredoxin-5 (PRDX5) and superoxide dismutase 2 (SOD2), but not glutathione disulphide reductase, were significantly decreased in patient samples compared with those in fertile-donor samples.Conclusions: This study revealed an association of downregulated expression of PRDX5 and SOD2 in sperm samples of patients with idiopathic primary male infertility. Our results support future mechanistic studies and development of advanced diagnostic methods to better identify men with mitochondria-related male infertility.Expression of two mitochondrial proteins known to combat oxidative stress, peroxiredoxin-5 and superoxide dismutase 2, is downregulated in patients with idiopathic primary male infertility compared with that in fertile donors. Rapid assessment of key protein content using ELISA could potentially help diagnose idiopathic primary male infertility.

    Keywords: DEP, differentially expressed protein, GAPDH, glyceraldehyde 3-phosphate dehydrogenase, GSR, glutathione disulphide reductase, ICSI, intracytoplasmic sperm injection, IPA, Ingenuity Pathway Analysis, PRDX5, peroxiredoxin-5, SOD2, superoxide dismutase 2, WHO, World Health Organization

    Received: 12 Aug 2024; Accepted: 18 Nov 2024.

    Copyright: © 2024 Sawaid Kaiyal, Mukherjee, Panner Selvam, Miller, Vij and Lundy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Raneen Sawaid Kaiyal, Urology Department, Glickman Urological and Kidney Institute,, Cleveland Clinic, Cleveland, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.