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. 2024 Oct 29;23(1):e12602.
doi: 10.1002/rmb2.12602. eCollection 2024 Jan-Dec.

Ectopic expression of the mitochondrial protein COXFA4L3 in human sperm acrosome and its potential application in the selection of male infertility treatments

Yusuke Fujisawa  1 , Sayaka Kikuchi  2 , Fujino Kuba  1 , Kosei Oishi  1 , Soushi Murayama  1 , Tomoya Sugiyama  1 , Reiji Tokito  1 , Hiroe Ueno  3 , Shin-Ichi Kashiwabara  4 , Yasushi Yumura  3 , Yasuyuki Kurihara  5
Affiliations

Ectopic expression of the mitochondrial protein COXFA4L3 in human sperm acrosome and its potential application in the selection of male infertility treatments

Yusuke Fujisawa et al. Reprod Med Biol. .

Abstract

Purpose: Spermatogenesis requires a large amount of energy, which is primarily produced by the mitochondrial electron transfer chain. Mitochondrial dysfunction affects male infertility, suggesting a relationship between the electron transfer chain and male infertility. COXFA4L3 (C15ORF48) is an emerging subunit protein of cytochrome oxidase specifically expressed in germ cells during spermatogenesis, and it may be involved in male infertility. Therefore, to investigate whether COXFA4L3 could be a marker of mitochondrial dysfunction in the sperm, this study examined the protein expression and localization profile of COXFA4L3 in the sperm of male patients with infertility.

Methods: Twenty-seven semen samples from a male infertility clinic at the Reproductive Center of Yokohama City University Medical Center were used to analyze sperm quality parameters and the expression and localization of energy production-related proteins. These data were compared with the outcomes of infertility treatment.

Results: The expression levels of COXFA4L3 varied significantly between samples. Furthermore, COXFA4L3 was ectopically localized to the acrosome.

Conclusions: Ectopic expression of COXFA4L3 and PNA-stained acrosomes may be useful parameters for fertility treatment selection. Assessing the acrosomal localization of COXFA4L3 will expedite pregnancy treatment planning.

Keywords: cytochrome c oxidase; electron transport chain; male infertility; mitochondria; sperm.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Confirmation of specificities of mAbs used in this study. (A) Western blot of exogenously expressed Coxfa4 isoforms in HeLa cells using anti‐Coxfa4l3 mAb. (B) Protein expression analysis using Western blot in human cell lines (HEK293T and HeLa) and human sperm. (C) Localization of Coxfa4l3 in mouse sperm. Nuclei were stained with DAPI and apical parts with PNA‐Alexa Fluor 488, and Coxfa4l3 was visualized using corresponding mAbs labeled with Alexa Fluor 546.
FIGURE 2
FIGURE 2
Expression of COXFA4L3 and GAPDS in human sperm from infertile patients. (A) GAPDS and COXFA4L3 protein expression in male infertile human sperm samples (YN‐1 to YN‐6). Glycolytic GAPDS proteins were used to normalize their protein levels. (B) Relative expression of COXFA4L3 and GAPDS proteins in human sperm samples (based on YN1 ratio).
FIGURE 3
FIGURE 3
COXFA4L3 and GAPDS localization in human sperm. (A) Nuclei were stained with DAPI and acrosome with PNA‐Alexa Fluor 488. GAPDS and COXFA4L3 were visualized using the corresponding mAbs labeled with Alexa Fluor 546. (B) The proportion of spermatozoa with COXFA4L3 localized in the acrosome (N = 21).
FIGURE 4
FIGURE 4
COX4I1 localization in human sperm. Nuclei were stained with DAPI and acrosome with PNA‐Alexa Fluor 488. COX4I1 was visualized using corresponding monoclonal antibodies labeled with Alexa Fluor 546.
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