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Aims: We aimed to investigate the independent associations between growth differentiation factor 15 (GDF‐15) level at admission and cardiovascular (CV) death, thrombotic events, heart failure (HF), and bleeding outcomes in patients with coronary artery disease (CAD). Methods and results: We measured the plasma concentrations of GDF‐15 centrally in patients from the BIomarker‐based Prognostic Assessment for patients with Stable angina and acute coronary Syndrome (BIPass) registry, which consecutively enrolled patients with CAD from November 2017 to September 2019 at five tertiary hospitals in China. The outcomes included CV death, thrombotic events [myocardial infarction (MI) and ischaemic stroke], HF events [acute HF during hospitalization and hospitalization for HF post‐discharge (A/H HF) and cardiogenic shock], and bleeding outcomes [non‐coronary artery bypass grafting‐related major bleeding and clinically significant bleeding (CSB)] during the 12 month follow‐up period after hospitalization. Among 6322 patients with CAD {65.4% male, median age 63.7 [inter‐quartile range (IQR)] 56.0–70.1 years}, the median concentration of plasma GDF‐15 at admission was 1091 (IQR 790.5–1635.0) ng/L. Higher concentrations of GDF‐15 were associated with an increased risk of CV death [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.35–2.88, P < 0.001], A/H HF (HR 2.69, 95% CI 1.92–3.77, P < 0.001), cardiogenic shock (HR 1.46, 95% CI 1.04–2.05, P = 0.029), and CSB (HR 1.48, 95% CI 1.22–1.79, P < 0.001), but not for MI or stroke, after adjusting for clinical risk factors and prognostic biomarkers. Adding GDF‐15 to the model with risk factors and biomarkers improved the net reclassification for CV death, A/H HF, cardiogenic shock, and CSB. Conclusions: In patients with CAD, admission levels of GDF‐15 were associated with an increased 1 year risk of CV death, HF, and bleeding outcomes, but not with thrombotic events. GDF‐15 may be a prognostic biomarker for CV death, HF, and bleeding outcomes and could be used to refine the risk assessment of these specific clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT04044066 [ABSTRACT FROM AUTHOR]

Magnetic sense, or termed magnetoreception, has evolved in a broad range of taxa within the animal kingdom to facilitate orientation and navigation. MagRs, highly conserved A-type iron-sulfur proteins, are widely distributed across all phyla and play essential roles in both magnetoreception and iron-sulfur cluster biogenesis. However, the evolutionary origins and functional diversification of MagRs from their prokaryotic ancestor remain unclear. In this study, MagR sequences from 131 species, ranging from bacteria to humans, were selected for analysis, with 23 representative sequences covering species from prokaryotes to Mollusca, Arthropoda, Osteichthyes, Reptilia, Aves, and mammals chosen for protein expression and purification. Biochemical studies revealed a gradual increase in total iron content in MagRs during evolution. Three types of MagRs were identified, each with distinct iron and/or iron-sulfur cluster binding capacity and protein stability, indicating continuous expansion of the functional roles of MagRs during speciation and evolution. This evolutionary biochemical study provides valuable insights into how evolution shapes the physical and chemical properties of biological molecules such as MagRs and how these properties influence the evolutionary trajectories of MagRs.

Iron-sulfur clusters are essential cofactors for proteins involved in various biological processes, such as electron transport, biosynthetic reactions, DNA repair, and gene expression regulation. Iron-sulfur cluster assembly protein IscA1 (or MagR) is found within the mitochondria of most eukaryotes. Magnetoreceptor (MagR) is a highly conserved A-type iron and iron-sulfur cluster-binding protein, characterized by two distinct types of iron-sulfur clusters, [2Fe-2S] and [3Fe-4S], each conferring unique magnetic properties. MagR forms a rod-like polymer structure in complex with photoreceptive cryptochrome (Cry) and serves as a putative magnetoreceptor for retrieving geomagnetic information in animal navigation. Although the N-terminal sequences of MagR vary among species, their specific function remains unknown. In the present study, we found that the N-terminal sequences of pigeon MagR, previously thought to serve as a mitochondrial targeting signal (MTS), were not cleaved following mitochondrial entry but instead modulated the efficiency with which iron-sulfur clusters and irons are bound. Moreover, the N-terminal region of MagR was required for the formation of a stable MagR/Cry complex. Thus, the N-terminal sequences in pigeon MagR fulfil more important functional roles than just mitochondrial targeting. These results further extend our understanding of the function of MagR and provide new insights into the origin of magnetoreception from an evolutionary perspective.

Birds exhibit extraordinary mobility and remarkable navigational skills, obtaining guidance cues from the Earth's magnetic field for orientation and long-distance movement. Bird species also show tremendous diversity in navigation strategies, with considerable differences even within the same taxa and among individuals from the same population. The highly conserved iron and iron-sulfur cluster binding magnetoreceptor (MagR) protein is suggested to enable animals, including birds, to detect the geomagnetic field and navigate accordingly. Notably, MagR is also implicated in other functions, such as electron transfer and biogenesis of iron-sulfur clusters, raising the question of whether variability exists in its biochemical and biophysical features among species, particularly birds. In the current study, we conducted a comparative analysis of MagR from two different bird species, including the migratory European robin and the homing pigeon. Sequence alignment revealed an extremely high degree of similarity between the MagRs of these species, with only three sequence variations. Nevertheless, two of these variations underpinned significant differences in metal binding capacity, oligomeric state, and magnetic properties. These findings offer compelling evidence for the marked differences in MagR between the two avian species, potentially explaining how a highly conserved protein can mediate such diverse functions.

The ability to navigate long distances is essential for many animals to locate shelter, food, and breeding grounds. Magnetic sense has evolved in various migratory and homing species to orient them based on the geomagnetic field. A highly conserved iron-sulfur cluster assembly protein IscA is proposed as an animal magnetoreceptor (MagR). Iron-sulfur cluster binding is also suggested to play an essential role in MagR magnetism and is thus critical in animal magnetoreception. In the current study, we provide evidence for distinct iron binding and iron-sulfur cluster binding in MagR in pigeons, an avian species that relies on the geomagnetic field for navigation and homing. Pigeon MagR showed significantly higher total iron content from both iron- and iron-sulfur binding. Y65 in pigeon MagR was shown to directly mediate mononuclear iron binding, and its mutation abolished iron-binding capacity of the protein. Surprisingly, both iron binding and iron-sulfur binding demonstrated synergistic effects, and thus appear to be integral and indispensable to pigeon MagR magnetism. These results not only extend our current understanding of the origin and complexity of MagR magnetism, but also imply a possible molecular explanation for the huge diversity in animal magnetoreception.