Elamipretide Increases Mitochondrial Production of ATP for a Short Time After Administration

Stealth BioTherapeutics develops elamipretide, a mitochondrially targeted peptide that appears to improve mitochondrial function in older individuals. Mitochondria are the power plants of the cell, producing the chemical energy store molecule ATP to power cellular operations. Mitochondria falter with age, however, negatively affecting tissue function throughout the body.

Here, researchers note a short term gain in ATP production following elamipretide infusion. The results in detail make it clear that individual responses are highly variable, but the average settles down to a statistically significant 27% gain. Like other present approaches to improving mitochondrial function (e.g. various forms of NAD+ upregulation), demonstrating improved tissue function as a result of biochemical differences of this nature remains a challenge. Muscle function did not show compelling improvement in this study.

Loss of mitochondrial function contributes to fatigue, exercise intolerance, and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial.

Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions.

A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI.

These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.

Link: https://doi.org/10.1371/journal.pone.0253849


It sure does...

Competing interests: Stealth BioTherapeutics provided funding for this work. Baback Roshanravan, Kevin Conley, and David Marcinek served as paid consultants for Stealth BioTherapeutics from 2014-2016. The authors worked with Stealth BioTherapeutics on the design of this study.

Btw... Rev-ErbAα agonists probably do better work with regard to treatment of fatigue resistance and mitochondrial health. Not just a bit of short lived extra ATP output.

Posted by: Jones at July 27th, 2021 6:00 AM

This seems a good target for commercialization. A drug that has to be taken on regular basis and it seems to provide measurable benefits.

let's hope that the study is still good, though

Posted by: Cuberat at July 27th, 2021 8:05 AM

interesting, but, The wide range of results makes its potential as a therapeutic problematic. Perhaps if they stratified the results based upon the subject's baseline ATP level it might show that it is reliably effective for those with significantly subpar ATP numbers. There is a lot I don't know about ATP, it is possible ATP levels vary greatly throughout the day naturally, and what we are seeing here is just noise.

Posted by: JohnD at July 27th, 2021 11:04 AM

@cube rat
Good target for commercialization, agreed.
Still, it does not induce mitophagy, it does not induce mitogenesis. It squeezes more ATP out of 'poorly functioning mitochondria', causing more oxidative load (i.e. improves oxidative phosphorylation).
Compounds that induce mitophagy and/or mitogenesis are a better approach to fixing the dimished energy levels in cells with 'poorly functioning mitochondria'.

27% more ATP produced but muscle function did not show compelling improvement in this study... nuff said.

Posted by: Jones at July 27th, 2021 12:35 PM
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