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FUNDC1-mediated mitochondrial quality control protects against immune checkpoint inhibitor-associated cardiac injury
Nengfeng Zhang1, Yao Zhou1, Hailing Li1
1Department of Cardiology, The Second People's Hospital of Huai'an/The Affiliated Huai'an Hospital of Xuzhou Medical University, 60# Huaihai South Road, Qingjiangpu District, Huai'an City, 223002, Jiangsu Province, China.
Abstract:
Immune checkpoint inhibitors (ICIs) targeting PD-1 are effective cancer therapies but can cause severe myocarditis. The molecular mechanisms linking PD-1 blockade to cardiomyocyte damage are incompletely understood. We established a murine model of anti-PD-1-associated cardiac injury and used human AC16 cardiomyocytes in co-culture with CD8+ T cells. Global Fundc1 knockout (Fundc1-/-) mice and cardiac-specific Fundc1 reconstitution via AAV9 were employed to investigate the role of this mitophagy receptor. Cardiac function was assessed by echocardiography, and injury was evaluated through serum biomarkers, histology, and molecular analyses. Anti-PD-1 treatment induced cardiac dysfunction, myocardial T-cell infiltration, and reduced myocardial FUNDC1 expression in mice. FUNDC1 deficiency, both in vitro and in vivo, aggravated anti-PD-1-associated cardiomyocyte injury, cardiac dysfunction, inflammation, and fibrosis. Conversely, FUNDC1 overexpression or cardiac-specific Fundc1 restoration attenuated these pathological changes. Mechanistically, FUNDC1 loss was associated with altered mitophagy-related marker profiles, mitochondrial protein accumulation, increased oxidative stress, and mitochondrial functional impairment. FUNDC1-mediated mitochondrial quality control may represent an endogenous protective mechanism against anti-PD-1 antibody-associated cardiac injury.
Insights
Immune checkpoint inhibitors (ICIs) cause myocarditis by damaging heart cells. The protein FUNDC1 protects against this damage, suggesting a new therapeutic target for managing ICI-related cardiac side effects.
Area of Science:
- Cardiology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) targeting PD-1 are vital cancer treatments.
- PD-1 blockade can lead to severe myocarditis, with unclear molecular mechanisms.
- Understanding these mechanisms is crucial for mitigating cardiac toxicity.
Purpose of the Study:
- To investigate the role of FUNDC1 in anti-PD-1 antibody-associated cardiac injury.
- To elucidate the molecular pathways linking PD-1 blockade to cardiomyocyte damage.
- To explore FUNDC1 as a potential therapeutic target for preventing ICI-induced myocarditis.
Main Methods:
- Established a murine model of anti-PD-1-associated cardiac injury.
- Utilized co-culture systems with human cardiomyocytes and CD8+ T cells.
- Employed global Fundc1 knockout mice and cardiac-specific Fundc1 restoration via AAV9.
- Assessed cardiac function, biomarkers, histology, and molecular analyses.
Main Results:
- Anti-PD-1 treatment caused cardiac dysfunction, T-cell infiltration, and reduced FUNDC1 in mice.
- FUNDC1 deficiency exacerbated cardiomyocyte injury, cardiac dysfunction, inflammation, and fibrosis.
- FUNDC1 overexpression or restoration attenuated anti-PD-1-induced pathological changes.
- FUNDC1 loss correlated with impaired mitophagy, increased oxidative stress, and mitochondrial dysfunction.
Conclusions:
- FUNDC1 plays a protective role in mitigating anti-PD-1 antibody-associated cardiac injury.
- FUNDC1-mediated mitochondrial quality control is an endogenous protective mechanism.
- Targeting FUNDC1 may offer a novel strategy to prevent or treat ICI-induced myocarditis.
