TMEM87a Maintains Cardiomyocyte Integrity by Limiting Ferroptosis in Dilated Cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Cellular Mechanisms of Disease
• Molecular Cardiology

Background:

• Dilated cardiomyopathy (DCM) is a leading cause of heart failure, with underlying organelle-level mechanisms poorly understood.
• Transmembrane protein 87a (TMEM87a), a Golgi-associated protein, is involved in organelle homeostasis and ion transport.
• Understanding novel regulators of cardiomyocyte stress response is crucial for DCM pathogenesis.

Purpose of the Study:

• To investigate the role of TMEM87a in regulating cardiomyocyte integrity and DCM.
• To elucidate the molecular pathways linking TMEM87a dysfunction to cardiac remodeling.

Main Methods:

• Generated cardiomyocyte-specific Tmem87a knockout mice.
• Utilized a doxorubicin-induced mouse model of DCM.
• Performed quantitative proteomics to identify affected pathways.
• Assessed cardiac function, histology, and biochemical markers.
• Investigated the effect of ferroptosis inhibition using ferrostatin-1.

Main Results:

• Cardiac TMEM87a expression increased in a doxorubicin-induced DCM model.
• Tmem87a knockout mice spontaneously developed DCM with impaired function, dilation, and fibrosis.
• Proteomics identified ferroptosis as a key pathway disrupted in Tmem87a-null hearts.
• Tmem87a deficiency led to iron dysregulation, oxidative stress, and ferroptosis markers.
• Ferrostatin-1 treatment improved cardiac function and attenuated DCM in knockout mice.

Conclusions:

• TMEM87a is a critical regulator of cardiomyocyte homeostasis.
• TMEM87a deficiency promotes DCM pathogenesis through ferroptosis.
• Targeting ferroptosis may offer a therapeutic strategy for DCM associated with TMEM87a dysfunction.