Oral Presentation ESA-SRB-APEG-NZSE 2022

Chasing their own tail: Malate dehydrogenase 1B is a testis-enriched energy protein required for progressive sperm swimming motion and male fertility.   (#120)

Tianpengcheng (Amy) Luan 1 , Brendan J Houston 1 , Anne E O’Connor 1 , Donna J Merriner 1 , Liina Nagirnaja 2 , Don F Conrad 2 , Richard Burke 3 , Moira K O'Bryan 1
  1. The School of Biosciences, and The Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Parkville, 3502, VIC, Australia
  2. Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, 97006, USA
  3. School of Biological Sciences, Monash University, Clayton, Victoria, 3800, Australia

To reach the site of fertilization, sperm must swim through the viscous fluid of the female tract. This and other processes, such as hyperactivated sperm motility and the acrosome reaction, likely require ATP production. We recently identified a high-confidence loss of function mutation in a previously uncharacterised malate dehydrogenase (MDH1) paralogue, MDH1B. Canonical MDH1 is a cytoplasmic enzyme that translocates electrons generated during glycolysis into the electron transport chain for ATP payoff. To characterise the function of MDH1B, we produced a knockout mouse model. Mdh1b knockout males are sterile but have histologically normal spermatogenesis and produced normal numbers of morphologically normal, motile sperm. MDH1B is localised to the mitochondrial sheath in mouse sperm and Mdh1b knockout sperm exhibit a ‘stiff midpiece’ phenotype that results in beat cycle asymmetry, reduced flagellar amplitude and inefficient power dissipation. Further analysis of free-swimming sperm revealed that in fluids of increasing viscosity, sperm lacking Mdh1b display precocious rolling suppression and swim in circles compared to wildtype. Both the rolling suppression (3D) and circular swimming (2D) can be rescued with the addition of exogenous ATP, suggesting that MDH1B plays a vital role in the supply of ATP to the sperm in situations of physical challenge. Furthermore, following mating, sperm from Mdh1b knockout mice fail to reach the site of fertilisation in the female reproductive tract.  Collectively these data reveal MDH1B as an essential regulator of mouse, and likely human, male fertility and suggest that MDH1B plays a vital role in the supply or production of ATP required for sperm motility through viscous fluid.