Mitochondrial defects caused by PARL deficiency lead to arrested spermatogenesis and ferroptosis
Enrico Radaelli1, Charles-Antoine Assenmacher1, Jillian Verrelle1
1Department of Pathobiology, Comparative Pathology Core, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United States.
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.
Insights
Mitochondrial dysfunction in male infertility: PARL deficiency causes testicular atrophy by arresting spermatogenesis and triggering ferroptosis, a cell death pathway. This reveals new insights into mitochondrial diseases and male reproductive health.
Area of Science:
- Mitochondrial Biology
- Reproductive Biology
- Cell Death Pathways
Background:
- Mitochondrial diseases are linked to impaired spermatogenesis and male infertility, but mechanisms are unclear.
- The mitochondrial protease PARL is implicated in mitochondrial homeostasis and disease.
- PARL deficiency in mice models Leigh syndrome, offering a model to study mitochondrial dysfunction in reproduction.
Purpose of the Study:
- To investigate the role of PARL in spermatogenesis and male fertility.
- To elucidate the molecular mechanisms linking PARL deficiency to testicular dysfunction.
- To explore the potential involvement of ferroptosis in PARL-related male infertility.
Main Methods:
- Generation and analysis of PARL-deficient mice.
- Assessment of testicular histology and spermatogenesis progression.
- Mitochondrial function analysis, including electron transport chain activity and CoQ biosynthesis.
- Evaluation of GPX4 expression and lipid peroxidation markers.
- Investigation of ferroptosis markers in spermatocytes.
Main Results:
- PARL deficiency caused early testicular atrophy and complete arrest of spermatogenesis at meiotic prophase I.
- PARL-deficient spermatocytes exhibited mitochondrial ultrastructural abnormalities, electron transfer chain defects, and disrupted CoQ biosynthesis.
- Germ cell-specific decrease in GPX4 expression was observed, leading to ferroptosis in arrested spermatocytes.
- PARL deficiency triggered ferroptosis via simultaneous effects on GPX4 and Coenzyme Q (CoQ).
Conclusions:
- PARL is essential for spermatogenesis and male fertility.
- Mitochondrial defects in PARL-deficient mice initiate ferroptosis in primary spermatocytes.
- This study highlights ferroptosis as a key player in the pathogenesis of mitochondrial diseases and male infertility.
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