R35HL171080

Mitofusin 2 as a nodal regulator of mitochondrial function in cardiomyopathy - abstract
Cardiomyocyte mitochondria generate ATP that fuels contraction and normal or reparative cardiomyocyte growth.
The preferred metabolic substrates of cardiomyocyte mitochondria evolve during cardiac development from a fetal preference for carbohydrates to the normal adult preference for fatty acids, with reversion to fetal-like utilization of carbohydrates in adult cardiomyopathy.

Much as gasoline and electric versions of the same automobile are not interconvertible by software “reprogramming”, we discovered that myocardial metabolic transitions require mitophagic elimination and biogenic replacement of carbohydrate-processing by fatty acid-processing mitochondria.
We identified Mitofusin (MFN) 2, which in other tissues is a mitochondrial fusion protein, as the key nodal regulator of mitophagic mitochondrial replacement in perinatal myocardial mitochondria, i.e. the hub of a mitochondrial dynamics-mitophagy interactome.

However, our understanding of specific mechanisms that direct cardiac substrate utilization in adult hearts is incomplete, and forced biogenic production of cardiomyocyte mitochondria has not proven therapeutic in experimental models of heart disease.
Although there is much work to be done before our findings can be translated into effective treatments for human heart disease, our research over the past several years has engendered a solid foundation for this goal.

The conceptual breakthrough for this research was our discovery that MFN2 orchestration of mitochondrial fusion and mitophagy is the consequence of different MFN2 protein pairing events directed by specific PINK1-kinase phosphorylation events.
A consequence of this mechanism is that mitochondrial fusion (MFN-MFN pairing) and mitophagy (MFN-PARKIN pairing) are mutually exclusive.

The biophysical process linking MFN2 phosphorylation to differential protein pairing is MFN2 conformational switching from a closed state favoring mitophagy to an open state favoring mitochondrial fusion.
Research products generated from this work include the first Mitofusin activating small molecules and an expanding catalog of MFN2 mutants available in adenoviral vectors and knock-in mice.

Translationally, our work is beginning to identify clinical applications for pharmacological Mitofusin activation.
Here, we propose to translate what we have learned in basic mechanistic studies of mitochondrial dynamics factors to a preclinical delineation of disease mechanisms and evaluation of potential therapeutic approaches.

Accordingly, we propose two goals: a basic research goal to determine how MFN2 multifunctionality relates to differential protein-partnering evoked by phosphorylation-induced changes in MFN2 conformation that expose or hide specific MFN2 protein binding domains.
We posit that the unusually broad spectrum of mutational MFN2 dysfunction reflects, at least in part, differences in MFN2 protein partnering.

Our translational research goal will determine if tissue-specific disease phenotypes caused by different human MFN2 mutations accrue from distinct patterns of MFN2 dysfunction due to mutational perturbation of specific protein pairing events.
We predict that impaired MFN2-PARKIN mediated mitophagy preferentially affects cardiac myocytes, while impaired MFN2-MIRO regulated mitochondrial motility preferentially affects neurons.

In pursuing these goals we will employ new concepts and reagents that we developed to dissect molecular mechanisms that drive metabolic remodeling in normal and diseased hearts, and to develop translatable means of optimizing myocardial metabolism by fine-tuning mitochondrial quality and quantity via precision manipulations within the mitochondrial fusion/motility/mitophagy interactome.

Washington University

NOT APPLICABLE

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Missouri United States

State-Wide

NHLBI Outstanding Investigator Award (OIA) (R35 Clinical Trial Optional) (RFA-HL-23-004)

Amendment Since initial award the End Date has been shortened from 12/31/30 to 01/02/25 and the total obligations have increased 193% from $1,088,500 to $3,184,510.