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Abstract

Volume 22, Issue 6 (November 2020) 22, 583–589; 10.4103/aja.aja_46_20

Prohibitin (PHB) interacts with AKT in mitochondria to coordinately modulate sperm motility

Xiao-Hui Li1, Ran-Ran Chai1,2, Guo-Wu Chen2, Ling-Fei Zhang1, Wen-Jing Tan-Tai1, Hui-Juan Shi3, Patricia A Martin-DeLeon4, O Wai-Sum5, Hong Chen1

1 Department of Anatomy, Histology and Embryology, Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention of Shanghai, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
2 Shanghai Ji'Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China
3 Key Lab of Reproduction Regulation of NPFPC-Shanghai Institute of Planned Parenthood Research, Fudan University Reproduction and Development Institution, Shanghai 200032, China
4 Department of Biological Sciences, University of Delaware, Newark, DE 19716-2590, USA
5 School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China

Correspondence: Dr. H Chen (hchen30@hotmail.com)

Date of Submission 12-Feb-2020 Date of Acceptance 11-Jun-2020 Date of Web Publication 25-Aug-2020

Abstract

Prohibitin (PHB), an evolutionarily conserved mitochondrial inner membrane protein, is highly expressed in cells that require strong mitochondrial function. Recently, we demonstrated that the deletion of Phb in spermatocytes results in impaired mitochondrial function. In addition, PHB expression in the mitochondrial sheath of human sperm has a significantly negative correlation with mitochondrial reactive oxygen species levels, but a positive one with mitochondrial membrane potential and sperm motility. These results suggest that mitochondrial PHB expression plays a role in sperm motility. However, the mechanism of PHB-mediated regulation of sperm motility remains unknown. Here, we demonstrate for the first time that PHB interacts with protein kinase B (AKT) and exists in a complex with phospho-PHB (pT258) and phospho-AKT in the mitochondrial sheath of murine sperm, as determined using colocalization and coimmunoprecipitation assays. After blocking AKT activity using wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), murine sperm have significantly ( P < 0.05) decreased levels of phospho-PHB (pT258) and the total and progressive motility. Furthermore, significantly ( P < 0.05) lower levels of phospho-PI3K P85 subunit α+γ (pY199 and pY467) and phospho-AKT (pS473; pT308) are found in sperm from infertile asthenospermic and oligoasthenospermic men compared with normospermic subjects, which suggest a reduced activity of the PI3K/AKT pathway in these infertile subjects. Importantly, these sperm from infertile subjects also have a significantly ( P < 0.05) lower level of phospho-PHB (pT258). Collectively, our findings suggest that the interaction of PHB with AKT in the mitochondrial sheath is critical for sperm motility, where PHB phosphorylation (pT258) level and PI3K/AKT activity are key regulatory factors.

Keywords: male infertility; prohibitin (PHB); protein kinase B (AKT); sperm motility

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