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In this study, we demonstrate that mice deficient for the mitochondrial intra-membrane rhomboid protease PARL, a recently reported model of the mitochondrial encephalopathy Leigh syndrome, develop early testicular atrophy caused by a complete arrest of spermatogenesis during meiotic prophase I, followed by degeneration and death of arrested spermatocytes. This process is independent of neurodegeneration. Interestingly, genetic modifications of PINK1, PGAM5, and TTC19 \u2013 three major substrates of PARL with important roles in mitochondrial homeostasis \u2013 fail to reproduce or modify this severe phenotype, indicating that the spermatogenic arrest arises from distinct molecular pathways. We further observed severe abnormalities in mitochondrial ultrastructure in PARL-deficient spermatocytes, along with prominent electron transfer chain defects, disrupted coenzyme Q (CoQ) biosynthesis, and metabolic rewiring. These mitochondrial defects are associated with a germ cell-specific decrease in GPX4 expression leading arrested spermatocytes to ferroptosis \u2013 a regulated cell death modality characterized by uncontrolled lipid peroxidation. Our results suggest that mitochondrial defects induced by PARL depletion act as an initiating trigger for ferroptosis in primary spermatocytes through simultaneous effects on GPX4 and CoQ \u2013 two major inhibitors of ferroptosis. These findings shed new light on the potential role of ferroptosis in the pathogenesis of mitochondrial diseases and male infertility warranting further investigation.<\/jats:p>","DOI":"10.7554\/elife.84710","type":"journal-article","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T06:15:12Z","timestamp":1690179312000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.84710","source":"Crossref","is-referenced-by-count":39,"title":["Mitochondrial defects caused by PARL deficiency lead to arrested spermatogenesis and ferroptosis"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2885-0221","authenticated-orcid":true,"given":"Enrico","family":"Radaelli","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathobiology, Comparative Pathology Core, School of Veterinary Medicine, University of Pennsylvania","place":["Philadelphia, United 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