Mitochondrial defects leading to arrested spermatogenesis and ferroptosis in a mouse model of Leigh Syndrome

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 PARL, the mitochondrial rhomboid protease, a recently reported model of Leigh syndrome, develop postpubertal testicular atrophy caused by arrested spermatogenesis and 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 phenotype. PARL deficiency in testis mitochondria leads to severe mitochondrial electron transfer chain defects, alterations in Coenzyme Q biosynthesis and redox status, and abrogates GPX4 expression specifically in spermatocytes leading to massive ferroptosis, an iron-dependent regulated cell death modality characterized by uncontrolled lipid peroxidation. Thus, mitochondrial defects can initiate ferroptosis in vivo in specific cell types by simultaneous effects on GPX4 and Coenzyme Q. These results highlight the importance of ferroptosis and cell-type specific downstream responses to mitochondrial deficits with respect to specific manifestations of mitochondrial diseases.

Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer

“…The mitochondrial energetic metabolism and ferroptosis closely interact with each other 58 . However, there are still some controversies concerning the role of energetic metabolism in ferroptotic process [59][60][61][62] . In this study, we demonstrated that SOX13 boosts NADPH production by upregulating SCAF1 to drive ferroptosisresistance.…”