Leydig cell steroidogenesis unexpectedly escapes mitochondrial dysfunction in prematurely aging mice
Irina G Shabalina1, Luise Landreh1, Daniel Edgar1
1*Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
Mitochondrial dysfunction in Leydig cells did not lower testosterone levels in mice. A unique rescue pathway involving the pentose phosphate pathway compensates for damage, suggesting new therapeutic avenues for aging and mitochondrial diseases.
Area of Science:
- Cell Biology
- Mitochondrial Biology
- Reproductive Biology
Background:
- Mitochondrial DNA (mtDNA) mutations and deletions accumulate with age and cause mitochondrial diseases.
- Testosterone synthesis relies on mitochondria within Leydig cells.
- Mitochondrial dysfunction is expected to impair testosterone production.
Purpose of the Study:
- To investigate the effect of experimentally induced mitochondrial dysfunction on testosterone levels in Leydig cells.
- To identify potential compensatory mechanisms in Leydig cells despite mitochondrial damage.
Main Methods:
- Utilized mtDNA mutator mice with impaired mtDNA polymerase γ to induce mitochondrial dysfunction.
- Assessed testicular weight, sperm count, testosterone levels, and mitochondrial function markers (Complex I, IV, ROS, membrane potential) in mice.
- Investigated potential compensatory pathways involving the pentose phosphate pathway and cytochrome b5.
Main Results:
- mtDNA mutator mice exhibited reduced testicular weight and sperm count but maintained normal testosterone levels.
- Leydig cells showed significant mitochondrial damage (Complex I/IV reduction) and increased reactive oxygen species (ROS).
- Despite cellular damage, mitochondrial membrane potential and testosterone production remained high, indicating a compensatory mechanism.
Conclusions:
- Leydig cells possess a unique rescue pathway that compensates for mitochondrial dysfunction, maintaining testosterone production.
- This pathway bypasses respiratory chain defects and involves electron transfer from the pentose phosphate pathway via cytochrome b5.
- The findings offer potential therapeutic strategies for mitochondrial diseases and aging.
