Poster Presentation 43rd Lorne Genome Conference 2022

Disruption of mitochondrial factor SDHA-2 affects sperm motility and male fertility (#107)

Natalya Frolows 1 , Rachel Woodhouse 1 , Guoqiang Wang 2 , Alyson Ashe 1
  1. University of Sydney, Sydney, NSW, Australia
  2. Rutgers, The State University of New Jersey, New Brunswick, New Jersey, United States of America

Exposure to environmental stress and mitochondrial health are both clinically established to influence male fertility, but their exact roles and the connection between them has not been well defined. SDHA-2 is a component of the succinate dehydrogenase (SDH) complex and plays a critical role in mitochondria in both the citric acid cycle and mitochondrial respiration. We have found that SDHA-2 plays a key role in male fertility and is required for proper sperm activation and localisation. sdha-2 mutants display significantly decreased brood size, hyperfused mitochondria and increased oxidative stress markers. We analysed RNA-seq data from nine environmental stress conditions and found that SDH related genes are significantly differentially expressed after stress exposure. These genes show a specific pattern of downregulation in starvation and upregulation after heat shock. Other genes involved in sperm regulation including the peroxiredoxin genes, sod-2 and alh-6 also displayed this same expression pattern, indicating that these may be part of a linked sperm regulatory pathway. Interestingly icl-1, the gene responsible for the glyoxylate shunt in C. elegans which bypasses SDHA-2 function, showed the opposite pattern of regulation. We observed spontaneous, non-genetic reversions of the fertility defect in around 4% of tested sdha-2 mutant animals and hypothesise that this could be explained by a form of mitohormesis. Heat stress upregulates genes that may allow compensation for the loss of sdha-2 by potentially directly replacing sdha-2 activity, in the case of sdha-1, or increasing the ability to cope with damage caused by sdha-2 loss, in the case of antioxidants such as the peroxiredoxins. In humans, SDH activity is positively correlated with sperm quality, and mutations in SDHA are associated with Leigh Syndrome. This strain may provide a new model of human SDH deficiency-associated infertility and other pathologies, and the reversions indicate that these may be amenable to treatment.