ABHD11-mediated mtDNA transcription restored mitochondrial function to attenuate cardiomyocyte ferroptosis after myocardial infarction

To elucidate the underlying mechanisms, we conducted transcriptomics, non-targeted lipidomics, site-specific mutagenesis, molecular docking, Co-IP, native gel electrophoresis, and proximity ligation assay. RESULTS: We found that cardiac ferroptosis peaked at day 7 post-MI and was enriched in peri-infarct CMs. Mitochondrial dysfunction was a key driver of CM ferroptosis post-MI and the lipid enzyme ABHD11 (αβ-hydrolase domain-containing protein 11) was identified as a potential regulator of both processes.

ABHD11 expression was consistently reduced in mouse and human MI hearts. Functionally, cardiac-specific overexpression of ABHD11 markedly alleviated CM ferroptosis and improved cardiac function after MI. Conversely, loss of ABHD11 in adult mice exacerbated pathological cardiac remodeling and heart failure.

Independent of its canonical enzymatic activities, ABHD11 enhanced the TEFM-POLRMT interaction, thereby promoting mtDNA transcription, restoring mitochondrial function, and thus inhibiting ROS/PUFA-PLs-driven lipid peroxidation and 4-HNE generation. The reduction in 4-HNE stabilized the transcription factor YY1, which subsequently downregulated key ferroptosis drivers and upregulated the nuclear-encoded ETC and FAO genes, thereby establishing a mitochondrial-nuclear crosstalk.

CONCLUSIONS: This study revealed that ABHD11-mediated mtDNA transcription attenuated CM ferroptosis post-MI by orchestrating a mitochondrial-nuclear crosstalk, offering a novel therapeutic strategy for ischemic myocardial injury.