Background: Ischemic heart disease is still a major global public health challenge with poor outcomes. The small GTPase Rab7 governs the vesicular trafficking in endocytosis and autophagy. However, the role of Rab7 in myocardial infarction is incompletely understood. In this study, we aimed to clarify the pathophysiological significance of Rab7 in myocardial infarction and explore the underlying mechanism.

Methods: We first observed the dynamic change of Rab7 in cardiac tissues from ischemic heart failure patients and murine ischemia models via permanent ligation of left anterior descending coronary artery. We then generated and characterized a cardiomyocyte specific Rab7 knockout mouse. Gain of function was achieved by adenovirus harboring Rab7 or a Rab7 activator ML098. The effect of Rab7 in myocardial infarction was further investigated in vitro and in vivo.

Results: Rab7 was dicreased in failing human hearts and in murine hearts after myocardial infarction. Low Rab7 levels in failing hearts were linked to deficient mitophagy, which activated the caspase 8-mediated mitochondrial apoptosis pathway. Constitutive Rab7 deletion in the cardiomyocyte resulted in impaired mitochondrial autophagy, myocardial apoptosis, and sudden death after AMI. Inducible cardiac-specific deletion of Rab7 resulted in defective mitophagy, elevated oxidative stress, and HF after AMI, although Rab7 itself did not exert any myocardial effect in the absence of MI. Mechanistically, Rab7 upregulates non-canonical mitophagy pathway via promoting Tufm translocation to the damaged mitochondria and recruitment of p62/SQSTM1, without affecting PINK1/Parkin pathway. Restoring Rab7 expression after myocardial infarction by either adeno associated virus–mediated Rab7 expression or small molecule activator ML098 activated mitophagy and substantially improved myocardial outcome after AMI.

Conclusions: Rab7 is essential for mitophagy activation and mitochondrial homeostasis via modulating mitophagosome maturation after AMI. Rab7-Tufm complex dysfunction is a potential mechanism for mitophagosome defects in AMI, and restoring Rab7 in the injured heart confers myocardial protection. These results identify the Rab7-Tufm-p62/SQSTM1 as a novel non- canonical mitophagy pathway as a target for therapeutic intervention of ischemic heart failure.

Key words: myocardial infarction; autophagy; mitophagy; mitochondrial dysfunction; Rab7