Mitochondrial protein interaction landscape of SS-31, 2020, Chavez et al.

[Jaybee00]

https://www.pnas.org/content/early/2020/06/16/2002250117

popular article here https://newsroom.uw.edu/news/study-yields-clues-how-drug-may-boost-aged-mitochondria

Significance
SS-31 is a synthetic peptide that improves mitochondrial function and is currently undergoing clinical trials for treatments of heart failure, primary mitochondrial myopathy, and other mitochondrial diseases. SS-31 interacts with cardiolipin which is abundant in the inner mitochondrial membrane, but mechanistic details of its pharmacological effects are unknown. Here we apply a chemical cross-linking/mass spectrometry method to provide direct evidence for specific interactions between SS-31 and mitochondrial proteins. The identified SS-31 interactors are functional components in ATP production and 2-oxoglutarate metabolism and signaling, consistent with improved mitochondrial function resultant from SS-31 treatment. These results offer a glimpse of the protein interaction landscape of SS-31 and provide mechanistic insight relevant to SS-31 mitochondrial therapy.

Abstract
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.

 

[Ravn]

Much too technical for my understanding but there do seem to be a few interesting points here (IIRC SS31 was the molecule that had the best effect in the "something in the blood" nano-needle tests).

• SS31 has no effect on mitochondrial function in young, healthy mitochondria, only on old or sick ones - hmm, what does that imply about our mitos?
• SS31 improves function of complex V - the very complex which may not be working efficiently in ME.
• SS31 may affect 2-OG signalling, 2-OG being thought a sort of master regulator metabolite affecting ATP synthase and target of rapamycin (TOR) and also being involved in hypoxia signalling - all stuff that keeps turning up in ME studies.
• SS31 interacts with cardiolipin - antibodies against cardiolipin have been found in ME.

I've no idea of the true relevance of any of this.