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Abstract

Ferroptosis is a type of regulated cell death characterized by the accumulation of lipid peroxides that damage cell membranes specifically. Mitochondrial swelling and dysfunction are hallmarks of ferroptosis; however, what causes mitochondrial swelling and the consequences of mitochondrial swelling in ferroptotic signal transduction remain poorly understood. Our study found that mitochondrial permeability transition pore (mPTP) opening is essential for mitochondrial swelling and ferroptosis activation. During ferroptosis, oxidized mitochondrial DNAs (mtDNAs) are released through the mPTP. These oxidized mtDNAs activate the cyclic GMP-AMP synthase (cGAS)—stimulator of interferon genes (STING) pathway, promoting ferroptosis through activating ferrotinophagy. Consistently, inhibition of mtDNA-repair enhances cellular sensitivity to ferroptosis and therefore synergizes with ferroptosis inducer in suppressing tumorigenesis in mouse xenograft tumor models. This study provides a fundamental understanding of how mPTP engages in ferroptosis by releasing mitochondrial DNAs as crucial messengers to activate ferroptotic signaling.