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Molecular Mechanism of Action of Mitochondrial Therapeutic SS-31 (Elamipretide): Membrane Interactions and Effects on Surface Electrostatics

Wayne Mitchell, Emily A. Ng, Jeffrey D. Tamucci, Kevin Boyd, Murugappan Sathappa, Adrian Coscia, Meixia Pan, Xianlin Han, Nicholas A. Eddy, Eric R. May, Hazel H. Szeto, Nathan N. Alder
doi: https://doi.org/10.1101/735001
Wayne Mitchell
aDepartment of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269
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Emily A. Ng
aDepartment of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269
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Jeffrey D. Tamucci
aDepartment of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269
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Kevin Boyd
aDepartment of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269
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Murugappan Sathappa
bCenter for the Development of Therapeutics, Broad Institute, Cambridge, MA, 02142
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Adrian Coscia
cDepartment of Microbiology, Harvard Medical School, Boston, MA, 02115
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Meixia Pan
dBarshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78829
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Xianlin Han
dBarshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78829
eDepartment of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78829
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Nicholas A. Eddy
fInstitute of Materials Science, University of Connecticut, Storrs, CT 06269
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Eric R. May
aDepartment of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269
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Hazel H. Szeto
gSocial Profit Network Research Lab, Alexandria LaunchLabs, New York, NY, 10016
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Nathan N. Alder
aDepartment of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269
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  • For correspondence: nathan.alder@uconn.edu
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Abstract

Mitochondrial dysfunction includes heritable diseases, acquired pathologies, and age-related declines in health. Szeto-Schiller (SS) peptides comprise a class of amphipathic tetrapeptides that have demonstrated efficacy in treating a wide array of mitochondrial disorders, and are believed to target mitochondrial membranes due to their enrichment in the anionic phospholipid cardiolipin (CL). However, little is known regarding how SS peptides interact with or alter the physical properties of lipid bilayers. In this study, we have analyzed the interactions of the lead compound SS-31 (Elamipretide) with model and mitochondrial membranes using biophysical and computational approaches. Our results show that this polybasic peptide partitions into the membrane interfacial region with affinity and binding density that are directly related to surface charge. SS-31 binding does not destabilize lamellar bilayers even at the highest binding concentrations; however, it does cause saturable alterations in lipid packing. Most notably, SS-31 modulates the surface electrostatic properties of model and mitochondrial membranes, which could play a significant role in the mitoprotective properties of this compound. As a proof of concept, we show that SS-31 alters ion distribution at the membrane interface with implications for maintaining mitochondrial membranes subject to divalent cation (calcium) stress. Taken together, these results support a mechanism of action in which SS peptides interact with lipid bilayers and alter the biophysical (primarily electrostatic) properties of mitochondrial membranes as their primary mechanism of action. Understanding this molecular mechanism is key to the development of future compound variants with enhanced efficacy.

Significance Szeto-Schiller (SS) peptides are among the most promising therapeutic compounds for mitochondrial dysfunction. However, the molecular target(s) and the mechanism of action of SS peptides are poorly understood. In this study, we evaluate the interaction of the lead compound SS-31 (Elamipretide) with mitochondrial and synthetic model membranes using a host of biophysical techniques. Our results show that SS-31 membrane interaction is driven largely by the negative surface charge of mitochondrial membranes and that SS-31 alters lipid bilayer properties, most notably electrostatics at the membrane interface. This work supports a mechanism in which SS peptides act on a key physical property of mitochondrial membranes rather than with a specific protein complex, consistent with the exceptionally broad therapeutic efficacy of these compounds.

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Posted August 14, 2019.
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Molecular Mechanism of Action of Mitochondrial Therapeutic SS-31 (Elamipretide): Membrane Interactions and Effects on Surface Electrostatics
Wayne Mitchell, Emily A. Ng, Jeffrey D. Tamucci, Kevin Boyd, Murugappan Sathappa, Adrian Coscia, Meixia Pan, Xianlin Han, Nicholas A. Eddy, Eric R. May, Hazel H. Szeto, Nathan N. Alder
bioRxiv 735001; doi: https://doi.org/10.1101/735001
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Molecular Mechanism of Action of Mitochondrial Therapeutic SS-31 (Elamipretide): Membrane Interactions and Effects on Surface Electrostatics
Wayne Mitchell, Emily A. Ng, Jeffrey D. Tamucci, Kevin Boyd, Murugappan Sathappa, Adrian Coscia, Meixia Pan, Xianlin Han, Nicholas A. Eddy, Eric R. May, Hazel H. Szeto, Nathan N. Alder
bioRxiv 735001; doi: https://doi.org/10.1101/735001

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