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PGAM1-dependent VDAC1 oligomerization disrupts mitochondrial quality control to drive doxorubicin cardiotoxicity via
Yukun Li1, Sicheng Zheng2, Haowen Zhuang3
1Department of Cardiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China; Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100012, China.
Objectives:
Doxorubicin (Dox) is a potent chemotherapeutic agent whose clinical use is limited by severe cardiotoxicity. The underlying molecular mechanisms remain incompletely understood. This study aimed to investigate the role of the phosphoglycerate mutase 1 (PGAM1)/voltage-dependent anion channel 1 (VDAC1) axis in early-stage Dox-induced cardiotoxicity, focusing on its impact on mitochondrial quality control (MQC), endoplasmic reticulum (ER) stress, and the subsequent activation of innate immune signaling.
Methods:
We established a short-term cumulative Dox-induced cardiomyopathy model using wild-type and cardiomyocyte-specific PGAM1 knockout (PGAM1-CKO) mice. Cardiac function was assessed by echocardiography. In vitro experiments were performed on neonatal mouse cardiomyocytes (NMCMs) and HL-1 cells. Molecular techniques including Western blotting, immunofluorescence, co-immunoprecipitation, and quantitative PCR were used to dissect the signaling pathway. Key pathway components were validated using specific pharmacological inhibitors and activators.
Results:
Dox treatment significantly upregulated PGAM1 expression in cardiomyocytes. PGAM1-CKO mice were protected from Dox-induced cardiac dysfunction, fibrosis, and inflammation. Mechanistically, Dox-induced PGAM1 promoted the pathological oligomerization of VDAC1. This PGAM1-VDAC1 interaction triggered the collapse of MQC and induced ER stress, leading to the leakage of mitochondrial DNA (mtDNA) into the cytosol. The released cytosolic mtDNA subsequently activated the cGAS-STING innate immune pathway, which we identified as a critical upstream driver of cardiomyocyte ferroptosis. Pharmacological induction of VDAC1 oligomerization or STING activation abolished the cardioprotective effects observed in PGAM1-CKO mice.
Conclusion:
Our findings reveal a novel PGAM1/VDAC1 signaling axis that triggers early Dox-induced cardiotoxicity. This axis disrupts mitochondrial homeostasis, leading to mtDNA release, which activates the cGAS-STING pathway and ultimately culminates in cardiomyocyte ferroptosis. Targeting the PGAM1/VDAC1 interaction presents a promising therapeutic strategy to mitigate Dox-induced cardiac injury.
Insights
This study reveals a new phosphoglycerate mutase 1 (PGAM1)/voltage-dependent anion channel 1 (VDAC1) pathway driving doxorubicin (Dox)-induced cardiotoxicity. Targeting this axis may prevent Dox-related heart damage.
Area of Science:
- Cardiology
- Molecular Biology
- Oncology
Background:
- Doxorubicin (Dox) is a vital chemotherapy drug, but its use is limited by severe cardiotoxicity.
- The precise molecular mechanisms underlying Dox-induced cardiotoxicity are not fully understood.
- Mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and innate immune activation are implicated in cardiac injury.
Purpose of the Study:
- To investigate the role of the phosphoglycerate mutase 1 (PGAM1)/voltage-dependent anion channel 1 (VDAC1) axis in early Dox-induced cardiotoxicity.
- To elucidate the impact of this axis on mitochondrial quality control (MQC), ER stress, and innate immune signaling.
- To identify potential therapeutic targets for mitigating Dox-related cardiac damage.
Main Methods:
- A short-term cumulative Dox-induced cardiomyopathy mouse model was established.
- Cardiomyocyte-specific PGAM1 knockout (PGAM1-CKO) mice were utilized to assess the role of PGAM1.
- In vitro studies on neonatal mouse cardiomyocytes and HL-1 cells were conducted.
- Molecular techniques including Western blotting, immunofluorescence, and qPCR were employed.
- Pharmacological inhibitors and activators were used for pathway validation.
Main Results:
- Dox treatment upregulated PGAM1 expression and promoted VDAC1 oligomerization in cardiomyocytes.
- PGAM1-CKO mice exhibited protection against Dox-induced cardiac dysfunction, fibrosis, and inflammation.
- The PGAM1-VDAC1 interaction disrupted MQC, induced ER stress, and led to mitochondrial DNA (mtDNA) release.
- Released mtDNA activated the cGAS-STING innate immune pathway, driving cardiomyocyte ferroptosis.
- Pharmacological targeting of VDAC1 oligomerization or STING activation reversed cardioprotective effects.
Conclusions:
- A novel PGAM1/VDAC1 signaling axis is identified as a key driver of early Dox-induced cardiotoxicity.
- This axis disrupts mitochondrial homeostasis, leading to mtDNA release and subsequent cGAS-STING activation.
- The pathway culminates in cardiomyocyte ferroptosis, contributing to cardiac injury.
- Targeting the PGAM1/VDAC1 interaction offers a promising therapeutic strategy for Dox-induced cardiotoxicity.
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