Our previous studies have shown that STX12 deficiency is neonatally lethal and affects the recycling of TFR receptors,[19] that STX12 is necessary for maintaining mitochondrial function, and that STX12 depletion results in pulmonary mtDNA release activating mtDNA‐dependent innate immunity.[21] In this study, we investigated the role of STX12 in the cardiovascular system and found that STX12 deficiency led to heart failure in both zebrafish and mice, indicating an evolutionarily conserved role in cardiovascular physiology. This evidence concerns the gene STX12 and heart failure.