(11) PHB Regulates Mitochondrial Integrity via the Modulation of JAK2-mediated Histone Modifications in the Meiosis of Spermatocytes

Abstract Authors: PHB Regulates Mitochondrial Integrity via the Modulation of JAK2-mediated Histone Modifications in the Meiosis of Spermatocytes

Hong Chen¹; Jie Zhang¹; Wen-Jing Tan-Tai¹; Ling-Fei Zhang¹; Mo-Fang Liu²; Hui-Juan Shi³; Patricia A. Martin-DeLeon⁴; Wai-Sum O⁵

1. Department of Anatomy, Histology & Embryology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China

2. State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences-University of Chinese Academy of Sciences, Shanghai 200031, P. R. China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, P. R. China

3. Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, P. R. 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, P. R. China

Abstract Text:

Previously, we have shown that human sperm Prohibitin (PHB) play important roles in both the maintenance of mitochondrial ROS and membrane potential levels and the regulation of sperm motility. Further studies show that during spermatogenesis, PHB is expressed higher in spermatocytes, and regulate meiotic homologous recombination by the modulation of JAK2-mediated histone modifications. However, the possible role of PHB in mitochondrial integrity during meiosis has not been investigated. The goal of the present study therefore was to determine if PHB is expressed in the mitochondria of spermatocytes during meiosis and its potential role in the process.

In this study, we have investigated PHB expression in the mitochondria of spermatocytes, and determined PHB’s functional role in the mitochondrial integrity during meiosis, with the use of spermatocyte-specific Phb-cKO mice generated first time.

Our results demonstrate that PHB is expressed higher in the mitochondria of spermatocytes during mouse spermatogenesis. Loss of PHB in spermatocytes results in not only defects in meiotic DSB repair and homologous recombination but also an impairment of mitochondrial morphology and metabolic function. Importantly, mitochondria-mediated apoptotic pathway is activated in Phb^-/- spermatocytes, with a decrease in MMP level. Our further mechanistic studies show that PHB in spermatocytes is involved in both the maintenance of chromatin organization and DNA methylation levels and the regulation of mitochondrial cAMP and P53 pathways, particularly, the mitochondrial respiratory complex subunits expression, via the modulation of histone modifications. The findings in this study demonstrate that PHB regulates mitochondrial morphology and function integrity via modulating mitochondrial cAMP and P53 pathways and respiratory complex subunits expression in spermatocytes during meiosis.