ArticleeLife2023
Mitochondrial defects caused by PARL deficiency lead to arrested spermatogenesis and ferroptosis.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 32 citations in OpenAlex.
- The role of iron in normal and impaired testicular function.Andrology · 2026Review
- Diverse infections transcriptionally reprogram the intestinal epithelium and epithelial-immune cell interactions.Nature immunology · 2026Article
- Early-life colonization withScience (New York, N.Y.) · 2026Article
- Docosahexaenoic acid alleviates Ornidazole toxicity related to spermatogenic dysfunction by modulating PPARγ-dependent ER-mitochondrial uncoupling.Science China. Life sciences · 2026Article
- Regulation of mitochondrial function during spermatogenesis and sperm maturation.Cellular & molecular biology letters · 2026Review
- Techniques to study chimerism at the tissue level in humanized mice.Veterinary pathology · 2026Article
- The role of integrins in T cell-mediated resistance tobioRxiv : the preprint server for biology · 2026Article
- FBXO39 knockdown promotes spermatogenesis impairment by inducing mitochondrial dysfunction and ferroptosis via inhibiting KDM5A ubiquitination and regulating H3K4me3 demethylation.Cell biology and toxicology · 2026Article
- hnRNPU Safeguards Oocyte Development and Female Fertility via Regulation of Alternative Splicing.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.Cell death & disease · 2025Article
- The transcriptional regulation of NUPR1 expression by MYC is implicated in the regulation of ferroptosis in human spermatogonial stem cells.Cellular and molecular life sciences : CMLS · 2025Article
- Holding Out for a Model: Rhomboid Superfamily in Vertebrate Development and Disease.Journal of cellular physiology · 2025Review
- Single-cell RNA sequencing uncovers dynamic roadmap during chicken spermatogenesis.BMC genomics · 2025Article
- Sodium butyrate promotes synthesis of testosterone and meiosis of hyperuricemic male mice.Scientific reports · 2025Article
- A lack of commensal microbiota influences the male reproductive tract intergenerationally in mice.Reproduction (Cambridge, England) · 2025Article
- CellGAT: A GAT-Based Method for Constructing a Cell Communication Network Integrating Multiomics Information.Biomolecules · 2025Article
- Rhomboid proteases: key players at the cell surface within haloarchaea.Frontiers in microbiology · 2025Article
- Iron regulatory protein 1-deficient mice exhibit hypospermatogenesis.The Journal of biological chemistry · 2025Article
- Iron-fueled ferroptosis: a new axis for immunomodulation to overcome cancer drug resistance-from immune microenvironment crosstalk to therapeutic translation.Frontiers in immunology · 2025Review
- 4-Oxo-β-lactams as Covalent Inhibitors of the Mitochondrial Intramembrane Protease PARL.ACS medicinal chemistry letters · 2024Article
Corrections and comments
- Erratum issued
Authors and funding
10 authors at 4 institutions in 4 countries.
Funding
Abstract
Impaired spermatogenesis and male infertility are common manifestations associated with mitochondrial diseases, yet the underlying mechanisms linking these conditions remain elusive. 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 - three major substrates of PARL with important roles in mitochondrial homeostasis - 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 - 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 - 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.
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