Mitochondria engage in multiple fundamental processes including biogenesis, fission/fusion, mitophagy, and cell death - in addition to their role as ATP generators in the cell. These processes are complex, and for this reason, have been largely studied in isolation. Yet, it is clear that they overlap substantially at the molecula level, functionally, and with respect to their roles in disease. In this application, we propose experiments that bi-directionally connect Bax, a central mediator of cardiomyocyte death, with Parkin, an important activator of mitophagy in cardiomyocytes. Using genetic manipulations, we have found unexpectedly that endogenous levels of Bax in healthy cells suppress mitophagy. We have observed this in adult cardiomyocytes in vitro and in the heart in vivo. We postulate that this is a physiological mechanism that restrains inappropriate or excessive elimination of mitochondria, a situation that would be deleterious to cardiomyocytes, which are highly dependent on ATP. We will elucidate the mechanism, which may involve an interaction between Bax and Parkin, and test the functional significance in vitro and in vivo. The fact that Bax and Parkin interact raises the reciprocal question: What might Parkin be doing to Bax in the heart? Previous work in non-cardiac systems has shown that Parkin inhibits Bax translocation to mitochondria during cell death, but the mechanism has not been elucidated. Parkin is known to inhibit cardiomyocyte death in vitro, and deletion of Parkin in vivo markedly exacerbates post-infarct remodeling, heart failure, and mortality. These effects have been assumed to be mediated solely through Parkin-stimulated mitophagy. Given the directness of the connection between Bax and cardiomyocyte apoptosis and necrosis, however, we challenge that view and hypothesize that Parkin protects the heart primarily through its inhibition of Bax. We will test ths hypothesis and delineate the molecular mechanism by which Parkin inhibits Bax. Accordingly, the over-arching hypothesis of this project is that Bax and Parkin antagonize each other for the benefit of cardiomyocytes: The binding of Bax, likely in its cell death-inactive conformation, to Parkin inhibits Parkin-mediated mitophagy to prevent mitochondrial depletion. Conversely, the Bax-Parkin interaction inhibits Bax, likely through interfering with its transition to its active conformation, thereby inhibiting cardiomyocyte apoptosis and necrosis. This is an MPI application that brings together the expertise of Richard Kitsis (cardiomyocyte death) and Gerald Dorn (cardiac mitophagy). This research is highly significant as it will stimulate the field to consider and investigate connections between individual mitochondrial processes, such as cell death and mitophagy. In addition, it will lead to a reconsideration of the primary mechanism by which Parkin protects the heart. The work is also highly innovative because most of the concepts and relationships have not been previously considered. Through this research, we will achieve a better understanding of the pathogenesis of acute cardiac injury during ischemia/reperfusion and post-infarct remodeling.
This project connects two fundamental mitochondrial processes in the heart - cell death and mitophagy - through molecular connections and bi-directional antagonism between Bax (a central mediator of cardiomyocyte apoptosis and necrosis) and Parkin (a critical inducer of cardiomyocyte mitophagy). The resulting information will prompt a rethinking of the mechanistic and functional relationships between mitophagy and cell death and a reconsideration of the primary mechanism by which Parkin protects the heart.
| Kushnir, Alexander; Santulli, Gaetano; Reiken, Steven R et al. (2018) Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure. Circulation 138:1144-1154 |
| Rocha, Agostinho G; Franco, Antonietta; Krezel, Andrzej M et al. (2018) MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A. Science 360:336-341 |
| Corbalan, J Jose; Kitsis, Richard N (2018) RCAN1-Calcineurin Axis and the Set-Point for Myocardial Damage During Ischemia-Reperfusion. Circ Res 122:796-798 |
| Kitsis, Richard N; Riquelme, Jaime A; Lavandero, Sergio (2018) Heart Disease and Cancer. Circulation 138:692-695 |
| Riascos-Bernal, Dario F; Sibinga, Nicholas E S; Kitsis, Richard N (2018) PDCD5 says no to NO. Proc Natl Acad Sci U S A 115:4535-4537 |
| McKimpson, Wendy M; Kitsis, Richard N (2017) A New Role for the ER Unfolded Protein Response Mediator ATF6: Induction of a Generalized Antioxidant Program. Circ Res 120:759-761 |
| Amgalan, Dulguun; Chen, Yun; Kitsis, Richard N (2017) Death Receptor Signaling in the Heart: Cell Survival, Apoptosis, and Necroptosis. Circulation 136:743-746 |
| Shires, Sarah E; Kitsis, Richard N; Gustafsson, Åsa B (2017) Beyond Mitophagy: The Diversity and Complexity of Parkin Function. Circ Res 120:1234-1236 |
| Hammerling, Babette C; Najor, Rita H; Cortez, Melissa Q et al. (2017) A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance. Nat Commun 8:14050 |
| Song, Moshi; Franco, Antonietta; Fleischer, Julie A et al. (2017) Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence. Cell Metab 26:872-883.e5 |
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