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A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Mitochondrial sORF-Encoded Peptide MODICA Protects the Heart From Doxorubicin-Induced Cardiac Injury by Suppressing
Jialing Wu1,2, Kang Li1,2, Youchen Yan1,2
1Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine (J.W., K.L., Y.Y., X.X., T.X., H.X., H.Z., T.D., Y.L., C.L., X.L., Y.D., J.-S.O., Y.C., Z.-P.H.), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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 and is significantly downregulated by DOX (1.00±0.08 versus 0.42±0.09; P<0.001). Cardiac-specific overexpression of MODICA via adeno-associated viruses significantly attenuated DOX-induced cardiac injury in both males and females (fractional shortening: males 38.86% versus 51.54%, P<0.001; females 39.81% versus 51.39%, P<0.001, DOX-CTRL versus DOX-MODICA) and was supported by bulk RNA-seq analysis. Conversely, MODICA deficiency exacerbated DOX-induced injury, resulting in reduced fractional shortening (40.37% versus 31.85%, P<0.001; DOX-WT versus DOX-heterozygous) and increased cardiac fibrosis (P=0.009). Proteomic analyses revealed that MODICA interacts with apoptosis-related voltage-dependent anion channel proteins, inhibiting their DOX-induced oligomerization (P<0.001) on the outer mitochondrial membrane, thereby reducing mitochondrial permeability, decreasing cardiomyocyte apoptosis and improving calcium handling.
Conclusions:
Our study shows that the mitochondrial short open reading frame-encoded peptide MODICA alleviates DOX-induced cardiac dysfunction and may represent a therapeutic target against DOX cardiotoxicity.
Insights
The mitochondrial peptide MODICA protects against doxorubicin (DOX)-induced heart damage by preventing mitochondrial dysfunction and apoptosis. MODICA deficiency worsens DOX cardiotoxicity, highlighting its therapeutic potential.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Doxorubicin (DOX) chemotherapy causes cardiotoxicity, primarily through mitochondrial damage, increasing cardiovascular risk in cancer patients.
- The precise mechanisms of DOX-induced cardiotoxicity and the role of mitochondrial short open reading frame-encoded peptides are not fully understood.
Purpose of the Study:
- To investigate the potential of mitochondrial short open reading frame-encoded peptides, specifically MODICA, in mitigating DOX-induced cardiotoxicity.
- To elucidate the molecular mechanisms by which MODICA exerts its protective effects against DOX-induced cardiac injury.
Main Methods:
- Screening of adeno-associated viruses expressing mitochondrial short open reading frame-encoded peptides in a DOX-induced cardiotoxicity mouse model.
- Assessment of cardiac function using echocardiography and molecular/histological analyses in male and female mice with MODICA overexpression or deficiency.
- Proteomic analysis to identify MODICA's interaction partners and molecular targets.
Main Results:
- The mitochondrial short open reading frame-encoded peptide MODICA was identified and found to be downregulated by DOX.
- Cardiac-specific overexpression of MODICA significantly attenuated DOX-induced cardiac injury and fibrosis in both sexes.
- MODICA deficiency exacerbated DOX-induced cardiotoxicity, and proteomic analysis revealed MODICA inhibits voltage-dependent anion channel oligomerization, reducing mitochondrial permeability and apoptosis.
Conclusions:
- The mitochondrial short open reading frame-encoded peptide MODICA effectively alleviates doxorubicin-induced cardiac dysfunction.
- MODICA's protective mechanism involves inhibiting apoptosis-related voltage-dependent anion channel proteins at the outer mitochondrial membrane.
- MODICA represents a promising therapeutic target for preventing or treating doxorubicin cardiotoxicity.
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