Autophagy is a major mechanism of degradation of damaged mitochondria. Without elimination of damaged mitochondria, depolarized mitochondria and reactive oxygen species (ROS) rapidly affect healthy mitochondria, leading to wide-spread mitochondrial dysfunction and cell death. Understanding how damaged mitochondria are removed will provide a key to achieving healthier mitochondria in cardiomyocytes (CMs) and developing novel treatments for heart failure. Although it is believed that damaged mitochondria are degraded primarily by Pink1-Parkin-mediated mitophagy, we have discovered that CMs degrade mitochondria through an Atg7-independent and Ulk1-dependent form of autophagy that is homologous to the ?alternative? autophagy previously reported by Nishida, and that this form of autophagy plays a significant role in the elimination of damaged mitochondria in response to starvation. However, neither the molecular mechanism nor the functional significance of mitophagy mediated through alternative autophagy has been clearly established in CMs yet. Thus, the goal of this project is to demonstrate the functional significance of alternative autophagy in eliminating damaged mitochondria in the heart in response to relevant stresses and to elucidate the underlying molecular mechanisms. Hypothesis 1: In response to myocardial ischemia, the heart activates Atg7- independent/Ulk1-dependent alternative autophagy, which plays an essential role in mediating the clearance of damaged mitochondria and protects the heart from myocardial ischemia. Hypothesis 2: Ulk1 phosphorylated at Ser555 acts as a scaffold to induce Rab9 interaction for autophagosome formation and phosphorylation of Drp1 at Ser616 for mitochondrial fission, both of which are important in mediating mitochondrial autophagy in response to myocardial ischemia. We will:
Aim 1 : Demonstrate that the atg7-independent and ulk1-dependent alternative autophagy is activated by myocardial ischemia. Evaluate whether alternative autophagy protects the heart during myocardial ischemia. To this end, we will use cardiac-specific atg7- and ulk1-knockout mice, electron microscopy, specific reporters of alternative autophagy and mitochondrial autophagy, and functional analyses of mitochondria. We will show that damaged mitochondria are degraded primarily through alternative autophagy during myocardial ischemia.
Aim 2 : Evaluate whether phosphorylation of Ulk1 at Ser555 plays an essential role in mediating alternative autophagy and cardioprotection during myocardial ischemia by stimulating interaction with Rab9 and Ser616-phosphorylated Drp1. To this end, we will use loss-of-function and knock-in mouse models and unique and reliable reporters for alternative autophagy and lysosomal degradation of mitochondria. The knowledge obtained from this aim should lead to development of specific interventions to modulate mitophagy during myocardial ischemia. In summary, our study will demonstrate that alternative autophagy is a novel and predominant mechanism of mitochondrial degradation, which is essential for the maintenance of mitochondrial quality in the heart during ischemia.

Public Health Relevance

Summary Narrative Injury to and dysfunction of the heart in patients are often accompanied by dysfunction of mitochondria, important intracellular organelles involved in energy production, in heart cells. Here, we will test our hypothesis that mitochondria in heart cells are protected against cardiac stress through previously uncharacterized mechanisms to eliminate damaged mitochondria. The knowledge obtained from this study should lead to the development of novel strategies to protect heart cells against stress and treat patients with ischemic heart disease and heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Wong, Renee P
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Rutgers University
Anatomy/Cell Biology
Schools of Medicine
United States
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Ikeda, Shohei; Mizushima, Wataru; Sciarretta, Sebastiano et al. (2018) Hippo Deficiency Leads to Cardiac Dysfunction Accompanied by Cardiomyocyte De-Differentiation During Pressure Overload. Circ Res :
Madrigal-Matute, Julio; Scorrano, Luca; Sadoshima, Junichi (2018) Leducq Network: Modulating Autophagy to Treat Cardiovascular Disease. Circ Res 123:323-325