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Lysine malonylation regulates human sperm motility.

Yimin Cheng1, Yan Tian2, Houyang Chen3,4

  • 1Center for Translational Medicine, Department of Medicine, Yichun University, Yichun, Jiangxi, China.

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Lysine malonylation (Kmal) in human sperm is elevated in asthenozoospermia, reducing motility. This novel post-translational modification offers potential insights for diagnosing and treating male infertility.

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Area of Science:

  • Biochemistry
  • Reproductive Biology
  • Molecular Biology

Background:

  • Lysine malonylation (Kmal) is a newly identified post-translational modification (PTM) involved in various biological functions.
  • While Kmal has been detected in human sperm, its specific role in sperm physiology and its association with male infertility remain largely unexplored.

Purpose of the Study:

  • To investigate the functional significance of lysine malonylation (Kmal) in human sperm.
  • To explore the relationship between Kmal levels, sperm function, and asthenozoospermia.

Main Methods:

  • Proteomic analysis to identify Kmal-modified sperm proteins.
  • Biochemical assays to determine the source and regulatory enzymes of Kmal in sperm.
  • Comparative analysis of Kmal levels in normozoospermic and asthenozoospermic sperm.
  • Functional assays to assess the impact of induced Kmal on sperm motility and penetration ability.

Main Results:

  • Kmal predominantly modifies human sperm tail proteins (15-250 kDa) and is derived from malonyl-CoA, with P300 and SIRT5 as potential writer and eraser enzymes.
  • Asthenozoospermic sperm exhibit significantly higher Kmal levels, negatively correlating with progressive motility.
  • Elevated Kmal in asthenozoospermia is linked to reduced sperm SIRT5, ATP, and suppressed glycolysis.
  • Experimental induction of Kmal in normozoospermic sperm impairs motility and penetration by decreasing intracellular calcium, ATP, cAMP, and inhibiting glycolysis and PKA activity.

Conclusions:

  • Lysine malonylation plays a regulatory role in human sperm motility.
  • Increased Kmal levels are associated with asthenozoospermia and may contribute to male infertility.
  • Kmal presents a potential biomarker for diagnosing and a therapeutic target for idiopathic male infertility.