Our significant findings in this study were (i) Ubc9 overexpression reduces cardiac damage and preserves cardiac function after acute MI, (ii) enhancement of autophagic flux from activation to degradation mediates the protective role of Ubc9, and (iii) promoting the formation of PI3K-III complexes and autophagy-positioning by Ubc9 overexpression may facilitate this autophagy regulation. Here, UBE2I is linked to myocardial infarction.