SMYD1, a striated muscle-specific lysine methyltransferase, was originally shown to play a key role in embryonic cardiac development but more recently we demonstrated that loss of Smyd1 in the murine adult heart leads to cardiac hypertrophy and failure. However, the effects of SMYD1 overexpression in the heart and its molecular function in the cardiomyocyte in response to ischemic stress are unknown. In this study, we show that inducible, cardiomyocyte-specific overexpression of SMYD1a in mice protects the heart from ischemic injury as seen by a > 50% reduction in infarct size and decreased myocyte cell death. We also demonstrate that attenuated pathological remodeling is a result of enhanced mitochondrial respiration efficiency, which is driven by increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae. These morphological changes occur concomitant with increased OPA1 expression, a known driver of cristae morphology and supercomplex formation. Together, these analyses identify OPA1 as a novel downstream target of SMYD1a whereby cardiomyocytes upregulate energy efficiency to dynamically adapt to the energy demands of the cell. In addition, these findings highlight a new epigenetic mechanism by which SMYD1a regulates mitochondrial energetics and functions to protect the heart from ischemic injury.

SMYD1 是一种横纹肌特异性赖氨酸甲基转移酶，最初被证明在胚胎心脏发育中发挥关键作用，但最近我们证明，小鼠成年心脏中 Smyd1 的缺失会导致心脏肥大和衰竭。然而，SMYD1 在心脏中过度表达的影响及其在心肌细胞中响应缺血应激的分子功能尚不清楚。在这项研究中，我们表明，小鼠中 SMYD1a 的诱导型心肌细胞特异性过度表达可以保护心脏免受缺血性损伤，梗塞面积减少 50% 以上，并且心肌细胞死亡减少。我们还证明，病理重塑减弱是线粒体呼吸效率增强的结果，而线粒体呼吸效率增强是由线粒体嵴形成增加和嵴内呼吸链超复合物稳定性驱动的。这些形态变化伴随着 OPA1 表达的增加而发生，OPA1 表达是嵴形态和超复合物形成的已知驱动因素。总之，这些分析将 OPA1 确定为 SMYD1a 的新下游靶标，心肌细胞可通过该靶标上调能量效率以动态适应细胞的能量需求。此外，这些发现强调了一种新的表观遗传机制，SMYD1a 通过该机制调节线粒体能量和功能，以保护心脏免受缺血性损伤。