The energy model of low mood
Classical psychiatry framed depression as a shortage of monoamines — serotonin, dopamine, noradrenaline. That model produced useful drugs but never explained why they take weeks to work, or why a third of people do not respond at all.
A parallel body of research points somewhere less glamorous: the mitochondria. Making and packaging neurotransmitters, maintaining ion gradients across neuronal membranes, and firing action potentials are all ATP-expensive. Studies in people with depression have reported reduced mitochondrial ATP production in muscle tissue, altered mitochondrial DNA copy number, and elevated markers of oxidative stress.
This does not replace the monoamine story. It sits underneath it. If a cell cannot make enough ATP, everything downstream of that cell — including neurotransmitter systems — runs degraded.
Three different things people mean by mitochondrial support
These get conflated constantly, and they are not the same intervention.
Making existing mitochondria run more efficiently. This is what SS-31 does — it stabilises cardiolipin in the inner membrane, reducing electron leak and the reactive oxygen species that come with it.
Clearing damaged mitochondria. This is mitophagy, and it is what Urolithin A induces. Fasting and exercise do it too. A cell full of broken mitochondria does not need better substrate; it needs housekeeping.
Making more mitochondria. This is biogenesis, driven by AMPK and PGC-1α. Exercise is the reference intervention. MOTS-c signals through the same AMPK pathway, which is why it is sometimes described as an exercise mimetic.
The honest comparison
Of the compounds on this pathway, only Urolithin A and NAD+ precursors have completed randomised human trials with functional endpoints, and their effect sizes are modest. SS-31 has reached late-stage trials but has missed primary endpoints more than once. MOTS-c and humanin have no human trials of exogenous administration at all.
Meanwhile, zone-2 cardiovascular training has decades of human evidence for mitochondrial biogenesis, and it is free. That is not a reason to ignore the compounds — it is a reason to be clear about which part of the stack is doing the work.