We showed that cardiomyocyte STIM1 was an essential regulator of ER/SR and mitochondrial function as STIM1-KO mice had a progressive dilated cardiomyopathy associated with significant ER stress, the presence of abnormally shaped and distributed mitochondria, and changes indicative of increased mitochondrial fission. The gene discussed is STIM1; the disease is dilated cardiomyopathy.