SS-31, MOTS-c and NAD+ all appear under the word ‘mitochondrial’. They ask three separate questions about the same organelle, and evidence for one says nothing about the others.
Mitochondria turn fuel into usable energy, and a great deal can go wrong along the way. Researchers approach the organelle from different sides: the structure of its inner membrane, the signals it sends to the rest of the cell, and the chemical carriers its enzymes depend on. Three compounds in this catalogue map onto those three questions. They are not versions of one idea.
A mitochondrion is often drawn as a bean-shaped power station. Inside it, an assembly line of enzyme complexes called the electron transport chain passes electrons along and uses the energy released to make ATP, the molecule cells spend when they do work. That line depends on at least three separate things: a membrane holding the complexes in the right arrangement, a steady supply of carrier molecules (NADH, formed from NAD+) delivering electrons, and a flow of messages telling the rest of the cell how the energy budget is going.
Each of those is a research field of its own, with its own models, its own measurements and its own failures. When a supplier lists several compounds under a single ‘mitochondrial’ heading, the heading describes where they act, not what they do.
SS-31, known in clinical work as elamipretide, is a four-amino-acid peptide that concentrates in the inner mitochondrial membrane and binds cardiolipin, a fat found almost only there. Cardiolipin helps hold the electron transport chain in its working arrangement, and it is readily damaged by oxidative stress, the situation in which reactive molecules outpace the systems that keep them in check. The proposed mechanism is physical rather than receptor-based: by associating with cardiolipin the peptide is thought to stabilise membrane structure (Szeto 2014).
That is a question about architecture. It has been tested furthest in people: randomised trials in Barth syndrome, mitochondrial myopathy and heart failure, with mixed results, and a narrow 2025 US approval for Barth syndrome. The MMPOWER-3 trial in primary mitochondrial myopathy missed its primary endpoints, which is worth remembering when the word ‘mitochondrial’ is used loosely.
MOTS-c is a 16-amino-acid peptide encoded by the mitochondrion’s own small genome. It does not repair anything. The research question is whether it acts as a message: in cultured cells under glucose shortage it moves to the nucleus and alters stress-response genes, and in mice injected peptide changed insulin sensitivity and muscle metabolism (Lee et al. 2015). Human data describe how much of the native peptide circulates and when it changes, not what happens when it is supplied; no randomised trial of administered MOTS-c in people was identified.
A signalling peptide and a membrane-binding peptide are different experiments. Finding that one changes gene expression in a mouse tells a reader nothing about whether the other stabilises a membrane, and the reverse.
NAD+ is not a peptide. It is a coenzyme, a helper molecule that enzymes need in order to work, and its central job is electron transfer: NAD+ accepts electrons from broken-down fuel to become NADH, and NADH donates them to the transport chain. Tissue levels appear to fall with age, which is the observation that drives the field (Covarrubias et al. 2021). Most human studies have used oral precursors such as NR or NMN rather than NAD+ itself, and a small infusion pilot found NAD+ is broken down quickly in plasma. Findings for a precursor by one route do not transfer to the coenzyme by another.
Glutathione sits nearby but asks a fourth question, redox: how cells neutralise the reactive molecules that normal metabolism produces. It is measured as a marker of oxidative stress far more often than it is tested as an intervention (Forman et al. 2009), and whether supplied glutathione reaches cells intact is unresolved.
It is tempting to read structure, signal and supply as three parts of one plan. No published study testing SS-31 with MOTS-c, either with NAD+, or any of them with glutathione was identified. Each evidence base was built in a different model, measuring a different endpoint, in a different population: isolated mitochondria and rare-disease patients for SS-31, cells and mice for MOTS-c, healthy volunteers taking precursors for NAD+.
The useful habit is to ask, for each compound, which of the three questions it addresses and at what evidence stage. A reader who can answer that will not mistake a membrane result for a signalling result, or a rodent result for a human one.
Sources checked 2026-09-22