Mitochondrial peptides, cardiolipin and the NAD+ pool

A peptide encoded by the mitochondrion

The mitochondrial genome is small and was long assumed to encode only respiratory-chain subunits, two rRNAs and a set of tRNAs. That picture has been revised: short open reading frames within mitochondrial DNA encode peptides that act outside the organelle, a class now called mitochondrial-derived peptides. MOTS-c, from the 12S rRNA region, is the most studied.

Lee and colleagues described it in Cell Metabolism in 2015. In the reported experiments, MOTS-c administration in mice was associated with activation of AMP-activated protein kinase and with changes in the folate-methionine cycle and purine biosynthesis, and the treated animals showed differences in insulin sensitivity and adiposity relative to controls, including under a high-fat diet.

The conceptual claim is the more durable part: a signal originating in the mitochondrial genome that reports on mitochondrial state to the rest of the cell. Later work, including Kim and colleagues in Physiological Reports in 2019, extended the metabolite profiling.

Targeting the inner membrane by electrostatics

SS-31, known in clinical development as elamipretide, is a short tetrapeptide carrying an aromatic-cationic motif. Its defining property is localisation: it accumulates at the inner mitochondrial membrane through an interaction with cardiolipin, the phospholipid essentially unique to that membrane and required for the proper organisation of respiratory-chain supercomplexes.

Mitchell, Szeto and colleagues reported in the Journal of Biological Chemistry that the peptide binds lipid bilayers and modulates surface electrostatics, and argued that this — rather than a conventional receptor interaction or a direct antioxidant effect — is the core of its mechanism. Subsequent work has examined cardiac mitochondrial morphology and mitophagy in disease models, including a 2024 report in Scientific Reports in a murine Barth syndrome model.

Unusually for this catalog, the compound has a genuine clinical development record: it has been evaluated in human trials in primary mitochondrial myopathy and related conditions, with published results that are mixed on efficacy endpoints. A 2025 review in Pharmacological Research collates the current mechanistic and clinical picture. That record is a real distinction from compounds whose evidence stops at rodents — and it is also not an approval.

Cofactors, which are a different kind of thing

NAD+ and glutathione sit in this world for biochemical reasons and should not be read as members of the same pharmacological class. NAD+ is the central redox cofactor of metabolism and the substrate consumed by sirtuins, PARPs and CD38. Covarrubias, Perrone, Grozio and Verdin reviewed its metabolism in Nature Reviews Molecular Cell Biology in 2021, including the observation across multiple tissues and organisms that NAD+ availability declines with age and that the enzymes consuming it are themselves implicated in that decline.

Glutathione is a tripeptide — glutamate, cysteine, glycine — and the principal intracellular thiol buffer. Forman, Zhang and Rinna's 2009 overview in Molecular Aspects of Medicine covers its biosynthesis, its role in redox homeostasis, and the considerable difficulty of measuring it accurately, which is a recurring problem in the literature that cites it.

Both are foundational biochemistry. Neither review makes, and neither article here implies, a claim about an outcome from administering either compound to a person.

What ties the world together

The Cellular world on this site groups compounds whose research targets are mitochondrial function, redox state and immune signalling. That is a grouping by research question, not by established effect, and the four lines of work above sit at four quite different levels of evidence — from a well-characterised cofactor to a clinically evaluated membrane-targeting peptide to a mouse-level signalling story.

Reading them as equivalent because they share a catalog section would be a mistake. None of these compounds is an approved drug for any general indication, and nothing here describes a result in a person outside the trials named.