SLC39A13 Regulates Heart Function via Mitochondrial Iron Homeostasis Maintenance

Area of Science:

• Cardiovascular Biology
• Cellular Metabolism
• Iron Homeostasis

Background:

• Iron is essential but toxic in excess, requiring delicate intracellular balance.
• Solute carrier family 39 member 13 (SLC39A13)/ZIP13 is an endoplasmic reticulum/Golgi-resident iron transporter impacting tissue iron homeostasis.
• ZIP13 deficiency affects iron balance, necessitating investigation into its cardiac role and injury mechanisms.

Purpose of the Study:

• To investigate the role of ZIP13 in regulating cardiac functions.
• To elucidate the precise mechanism of cardiac injury resulting from ZIP13 deficiency.

Main Methods:

• Utilized cardio-specific knockout (Zip13-CKO), inducible knockout (Zip13-iKO), and systemic knockout mouse models.
• Assessed cardiac systolic function, mitochondrial morphology, iron metabolism, and biogenesis in knockout mice.
• Employed mouse embryonic fibroblasts and primary cardiomyocytes for in vitro validation.
• Generated double-knockout mice (Zip13&Fpn1-CKO) for comparative analysis.

Main Results:

• Zip13-CKO mice exhibited severe cardiac systolic dysfunction with abnormal mitochondrial morphology and function.
• ZIP13 deficiency led to increased cytosolic iron and decreased mitochondrial iron in cardiomyocytes.
• Iron supplementation or MFRN1 overexpression restored mitochondrial function in ZIP13-deficient cardiomyocytes.
• Double knockout mice showed more severe cardiac defects, suggesting aggravated cytosolic iron accumulation.

Conclusions:

• ZIP13 is critical for maintaining mitochondrial iron homeostasis and cardiac function.
• ZIP13 and FPN1 maintain cardiac function through distinct but overlapping mechanisms.
• ZIP13 regulates iron equilibrium between the cytosol and organelles, particularly mitochondria.