The heart is the body's busiest engine, rhythmically contracting and relaxing every minute to continuously pump blood throughout the body. What powers this engine are the mitochondria densely packed in cardiomyocytes, acting like fuel factories thatcontinuously supply energy to the heart. Besides oxygen and nutrients, the heart requires one critical element for efficient operation: iron. Iron is essential for mitochondrial energy metabolism—too little weakens cardiac power, while excess causes myocardial damage via reactive oxygen species.

Both iron deficiency and excess affect heart health

(Image Source: (Generated by author using AI)

Recently, Professor Zhou Bing’s team at the Faculty of Synthetic Biology, Shenzhen University of Advanced Technology, published inCirculation Research a study uncovering a novel cardiac regulatory mechanism:a protein called ZIP13 acts like a delivery courier, precisely transporting iron into mitochondria to fuel the heart’s energy factory.Once ZIP13 is missing or dysregulated, cardiomyocytes fall into power shortage, leading to severe contractile dysfunction.This discovery not only offers new insights into the pathogenesis of heart failure but also inspires future therapies targeting iron metabolism imbalance in cardiac diseases.

ZIP13: more than just a zinc courier

Part.1

ZIP13 is mainly located in the endoplasmic reticulum and Golgi apparatus of cells and was previously considered a zinc transporter. It first gained attention due to its association with the rare genetic disorder Spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS). Recent studies show ZIP13’s primary physiological role is not zinc transport. In 2024, the same group published inNature Communications the first evidence that mammalian ZIP13 functions as an iron transporter, regulating iron distribution from cytosol to organelles including ER, Golgi, mitochondria, and lysosomes.

Why is this discovery so important? Because the proper distribution of iron across different regions is crucial for maintaining normal physiological functions. Mitochondria particularly rely on iron; they are not only the main site for heme and iron-sulfur cluster synthesis but also the core of the cellular respiratory chain and ATP production. If mitochondria do not get enough iron, energy production is hindered, and cell function declines; conversely, if iron accumulates in the cytosol, excessive free iron triggers oxidative stress, causing cellular damage.

In this study, the team used knockout mouse models to confirm ZIP13 as a master regulator of iron. ZIP13-deficient cardiomyocytes exhibited classic iron misdistribution: cytosolic iron overload with severe mitochondrial iron deficiency.This asymmetric iron distribution became the trigger for mitochondrial dysfunction and laid the groundwork for cardiac pathology.

Notably, ZIP13 does not directly reside in mitochondria but achieves indirect iron transport through close inter-organelle contacts, particularly between the endoplasmic reticulum/Golgi and mitochondria. This cross-organelle cooperation mechanism opens a new window into understanding intracellular metal ion transport and positions ZIP13 as an unexpected key player in the iron metabolism network.

Heart Failure: Is the “Iron Railway” Inside Your Body Broken?

Part.2

To test whether ZIP13 truly directs intracellular iron trafficking, the team generated three mouse models: cardiomyocyte-specific Zip13 knockout (Zip13-CKO), adult-inducible knockout (Zip13-iKO), and global knockout (Zip13-KO). The results were striking: ZIP13-deficient mice quickly showed signs of heart failure, with drastically shortened lifespans and significantly reduced cardiac pumping capacity. Echocardiography revealed impaired left ventricular systolic function, thinned ventricular walls, and a heart resembling a deflated balloon, struggling to complete each powerful beat.

Deeper tissue sections and molecular experiments showed that mitochondria in these cardiomyocytes became loose or even fragmented, with reduced respiratory chain complex activity and severely insufficient energy supply. The key issue triggering all this: the "Iron railway" was broken—iron couldn't be transported in, leaving mitochondria starved.Iron quantification revealed cytosolic iron accumulation and severe mitochondrial iron deficiency upon ZIP13 loss. Furthermore, iron–sulfur cluster proteins (e.g., subunits of complexes I and II) critical for mitochondrial function were dramatically reduced, crippling the entire energy system.

So, can this all be reversed? The researchers conducted two rescue experiments. First, supplementing iron to cells using absorbable iron salts like ferric ammonium citrate treated ZIP13-deficient cells, resulting in restored mitochondrial iron levels, recovered respiratory chain activity, and significantly increased ATP production. A second approach involved targeted overexpression of the mitochondrial iron importerMFRN1 (Mitoferrin-1). This was akin to airdropping iron supplies to mitochondria when the " Iron railway" was severed. The results not only restored iron levels but also significantly improved mitochondrial membrane potential and cardiomyocyte contraction frequency.

The study also constructed a double-knockout model of ZIP13 and another iron exporter FPN1, finding that although both caused cytosolic iron accumulation, their mechanisms affecting mitochondrial iron differed. FPN1 deficiency mainly caused cellular iron overload and "poisoning," while ZIP13 deficiency manifested as mitochondrial iron deficiency and "starvation." Simultaneous deficiency of both led to more severe cardiac failure, indicating that "where iron goes" and "how it gets there" are equally important in cells.

This series of experiments proved that ZIP13 is indeed a critical link in the mitochondrial iron supply system. Without it, cardiomyocytes are like a power center failure—energy factories paralyzed, unable to use iron even when it's right beside them.

Summary

Part.3

In summary, ZIP13—previously regarded as a zinc transporter—emerges in this study as a pivotal regulator of cellular iron allocation.It does not directly enter mitochondria but precisely delivers iron to this most-needed location in cardiomyocytes through a collaborative network between the endoplasmic reticulum/Golgi and mitochondria.

The study shows that once ZIP13 is absent, iron cannot enter mitochondria, leading to mitochondrial dysfunction, interrupted energy supply, and ultimately cardiac contractile disorders or even heart failure. This mechanism may not be limited to the heart. The team speculates that ZIP13 may also regulate mitochondrial iron supply in other high-energy-demand organs like the brain, skeletal muscle, and liver, offering new insights into the mechanisms of mitochondrial diseases, metabolic disorders, and even certain neurodegenerative diseases.

We often say "the spirit is willing but the flesh is weak"—at the cellular level, this "weakness" is sometimes not due to lack of raw materials but a problem with the delivery system. ZIP13 is like an unsung delivery courier; once it fails in its duty, the heart—this high-speed engine—falls into crisis. In the future, we may be able to provide stable and precise energy support for the heart by modulating ZIP13 function.

References：

[1] Li, Huihui, et al."SLC39A13 Regulates Heart Function via Mitochondrial Iron Homeostasis Maintenance." Circulation Research (2025).

doi: 10.1161/CIRCRESAHA.125.326201.

[2] Li, Huihui, et al. "Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments." Nature Communications 15.1 (2024): 10838.

doi: 10.1038/s41467-024-55149-2.