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Varicocele-induced male infertility – a mitochondrial disease

L. Samanta, A. Agarwal, R. Sharma, N. Swain, E.S. Sabanegh
P-533 Wednesday, November 1, 2017
DOI: http://dx.doi.org/10.1016/j.fertnstert.2017.07.915

Objective
Impaired respiratory chain, oxidative phosphorylation, mitochondrial protein import, alterations of the inner mitochondrial membrane composition and defects of mitochondrial dynamics are characteristics of mitochondrial disease. Our recently published proteomic data on comparative proteomic analysis of sperm proteins identified 22 differentially expressed proteins (DEP) of mitochondrial origin. Proteins involved in mitochondrial organization (LETM1, EFHC1 and MIC60), import receptor TOM22, 3 crucial subunits of electron transport chain (ETC) and the core enzymes of carbohydrate and lipid metabolism were under-expressed in the varicocele group. In varicocele, stagnation in the testicular microcirculation inducing hypoxic-ischemic degenerative changes in all cell types in the sperm production site. During hypoxia, superoxide production at low oxygen concentrations results in oxidative stress (OS). With this background, we hypothesize that hypoxia-mediated OS is involved in sperm dysfunction in varicocele due to impaired blood supply to the testis.

Design
Validation of key DEP by Western blot (WB) analysis.

Materials and Methods
Oxidation-reduction potential (ORP) as an index of OS was measured in infertile men with varicocele (n=13) and fertile controls (n=10) using the MiOXSYS analyzer. Expression profile of ETC complexes, cAMP-dependent protein kinase A regulatory subunit α (PKARIA) and DEPs responsible for sperm function were validated by WB and indirect immunofluorescence (IF) (n=5 each; for patients and controls). Relative intensity of each band was calculated using I-image software.

Results
All proteins studied were under expressed in varicocele group together with an increase in ORP. These are shown in Table 1. WB data was supported by IF findings.

Conclusions
Impaired mitochondrial function in infertile men with varicocele leads to OS and sperm dysfunction. Reduction in cAMP level due to declining ATP synthesis results in deregulated protein kinase initiating a vicious cycle by impairing mitochondrial activity. Therefore, along with conventional management, therapy targeted towards mitochondria may improve the treatment outcome in infertile men with varicocele.

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