Mitochondrial sORF-Encoded Peptide MODICA Protects the Heart From Doxorubicin-Induced Cardiac Injury by Suppressing VDAC Oligomerization

作者：Jialing Wu, Kang Li, Youchen Yan, Xingfeng Xu, Ting Xu, Xu He, Huimin Zhou, Tailai Du, Yan Li, Chen Liu, Xinxue Liao, Yugang Dong, Jing‐Song Ou, Yili Chen, Zhan‐Peng Huang · 发表于：Circulation Heart Failure · 年份：2025 · DOI：10.1161/circheartfailure.125.013381 · 被引用次数：4 · 研究领域：Chemotherapy-induced cardiotoxicity and mitigation、GDF15 and Related Biomarkers、Lung Cancer Research Studies

BACKGROUND: Doxorubicin (DOX) cardiotoxicity increases cardiovascular risk in cancer patients, mainly through mitochondrial damage. However, the underlying mechanisms remain unclear, and whether mitochondrial short open reading frame-encoded peptides can mitigate DOX-induced cardiotoxicity is unknown. METHODS: Five adeno-associated viruses expressing mitochondrial short open reading frame-encoded peptides under the cardiac troponin T promoter, including MODICA (mito-SEP protector against DOX-induced cardiac injury), were screened in a DOX-induced cardiotoxicity mouse model (n=3–5 per group). Male and female mice were randomized to adeno-associated virus-CTRL or adeno-associated virus-MODICA, respectively, combined with saline or DOX treatment. Sample sizes were: males—saline-CTRL (n=4), saline-MODICA (n=4), DOX-CTRL (n=11), DOX-MODICA (n=10); females—saline-CTRL (n=8), saline-MODICA (n=10), DOX-CTRL (n=10), DOX-MODICA (n=13). MODICA-heterozygous mice generated by CRISPR/Cas9 were also included: saline-WT (n=7), saline-heterozygous (n=4), DOX-WT (n=11), DOX-heterozygous (n=8). Echocardiography was performed at baseline and after 2 weeks of DOX treatment; myocardial tissue and serum samples were collected for molecular and histological analyses. RESULTS: The mitochondrial short open reading frame-encoded peptide MODICA was identified through biochemical analysis and functional screening in a DOX-induced cardiac injury model. MODICA localizes to the outer mitochondrial membrane ...