Mitochondrial defects leading to arrested spermatogenesis and ferroptosis in the PARL deficient mouse model of Leigh Syndrome
- University of Pennsylvania, United States
- University of Angers, France
- Universidad Pablo de Olavide, Spain
- Centre Hospitalier Universitaire d'Angers, France
Abstract
Impaired spermatogenesis and male infertility are common manifestations of mitochondrial diseases, but the underlying mechanisms are unclear. Here we show that mice deficient for the mitochondrial intra-membrane rhomboid protease PARL, a recently reported model of Leigh syndrome, develop early testicular atrophy caused by a complete arrest of spermatogenesis at meiotic prophase I, followed by germ cell death independently of neurodegeneration. Genetic modifications of PINK1, PGAM5, and TTC19, three major substrates of PARL with important roles in mitochondrial homeostasis, do not reproduce or modify this severe phenotype. PARL deficiency in spermatocytes leads to severe abnormalities in mitochondrial structure associated with prominent electron transfer chain defects, alterations in Coenzyme Q (CoQ) biosynthesis, and metabolic rewiring. These mitochondrial defects are associated with a germ-cell specific decrease in GPX4 expression committing arrested spermatocytes to ferroptosis, a regulated cell death modality characterized by uncontrolled lipid peroxidation. Thus, mitochondrial defects, such as those induced by depletion of PARL, spontaneously initiate ferroptosis in primary spermatocytes in vivo by simultaneous effects on GPX4 and CoQ, the two major ferroptosis-inhibitors. Ferroptosis warrants to be further scrutinized in the pathogenesis of mitochondrial diseases and male infertility.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been included
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Funding
University of Pennsylvania (URF Fall 19-0914)
- Enrico Radaelli
Association Française Myopathies Telethon (23019)
- Marco Spinazzi
Abramson Cancer Center (P30CA016520)
- Enrico Radaelli
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were included in a health-monitoring program developed in accordance with guidelines of the Federation of European Laboratory Animal Science Associations (FELASA). All experiments were approved by the Ethical Committee on Animal Experimenting of the University of Leuven (IACUC protocol #072/2015) and by the French Ministry (DUO-OGM 5769 29/3/2019).
Copyright
© 2023, Radaelli et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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