Mitochondrial protein interaction landscape of SS-31

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 26; pp. 15363 - 15373
• Main Authors: Chavez, Juan D., Tang, Xiaoting, Campbell, Matthew D., Reyes, Gustavo, Kramer, Philip A., Stuppard, Rudy, Keller, Andrew, Zhang, Huiliang, Rabinovitch, Peter S., Marcinek, David J., Bruce, James E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30.06.2020
• Subjects: Aging; Animals; Binders; Biological Sciences; Cardiolipin; Cardiovascular diseases; Coronary artery disease; Crosslinking; Etiology; Heart diseases; Ketoglutaric acid; Male; Mass spectrometry; Mass spectroscopy; Mice; Mitochondria; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Models, Chemical; Molecular Dynamics Simulation; Neurodegenerative diseases; Oligopeptides - metabolism; Oligopeptides - pharmacology; Oxidative phosphorylation; Phospholipids; Phosphorylation; Protein Binding; Proteins; Recovery of function; aging; interactome; cross-linking; mitochondria
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2002250117

Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin–protein interacting regions. These results offer a glimpse of the protein interaction landscape of SS-31 and provide mechanistic insight relevant to SS-31 mitochondrial therapy.