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MITT-Stack: SS-31, MOTS-c, and NAD+ for Cellular Energy
The MITT-Stack (Mitochondrial Integration & Transformation Triad) combines three compounds that target different aspects of mitochondrial dysfunction: SS-31 repairs the membrane, MOTS-c retrains metabolic signaling, and NAD+ restores redox currency. Together they address the root cause of cellular energy failure rather than masking symptoms.
This matters because most chronic fatigue, metabolic inflexibility, and slow recovery trace back to mitochondria that can't produce enough ATP. Traditional approaches treat downstream effects; the MITT-Stack targets the organelles themselves.
These peptides lack FDA approval for most indications. SS-31 (Elamipretide) has Phase 2 data in cardiomyopathies; MOTS-c and NAD+ are used off-label. Work with a licensed clinician.
At a Glance
- SS-31: Repairs cardiolipin in mitochondrial membranes, reducing electron leak and ROS
- MOTS-c: Activates AMPK/PGC-1α signaling for metabolic flexibility and mitochondrial biogenesis
- NAD+: Restores redox currency for sirtuins, DNA repair, and energy metabolism
- Protocol: 12-week cycles with loading and maintenance phases
- Applications: Fatigue, metabolic dysfunction, injury recovery support, longevity
The Three Axes of Mitochondrial Health
| Axis | Function | How It Fails | Result |
|---|---|---|---|
| Cardiolipin integrity | Anchors electron transport chain | Oxidized membranes leak electrons | Low ATP, high ROS, inflammation |
| Redox currency (NAD+) | Powers enzymes, activates sirtuins | Depleted by stress, aging, alcohol | Fatigue, DNA damage, metabolic rigidity |
| Adaptive signaling (AMPK → PGC-1α) | Drives mitochondrial biogenesis | Blunted by cortisol, nutrient overload | Slow recovery, weight gain |
The MITT-Stack addresses all three axes simultaneously.
Component 1: SS-31 — Membrane Repair
SS-31 (also called Elamipretide) is a tetrapeptide that binds to cardiolipin in the inner mitochondrial membrane. Cardiolipin anchors the electron transport chain; when it oxidizes, electrons leak, ATP production drops, and reactive oxygen species (ROS) spike.
Mechanism: SS-31 stabilizes cardiolipin, tightening respiratory supercomplexes and reducing ROS production by up to 60% in preclinical models.
Translation: More ATP from each oxygen molecule, less oxidative damage, rapid improvement in fatigue.
Evidence: Phase 2 trials in Barth syndrome and cardiomyopathies show improved ATP kinetics and functional endpoints.
Component 2: MOTS-c — Metabolic Reprogramming
MOTS-c is a mitochondrial DNA-encoded peptide that acts as an exercise mimetic. It signals from mitochondria back to the nucleus, activating metabolic adaptation pathways.
Mechanism: Activates AMPK and PGC-1α, increases GLUT4 expression, improves fatty-acid oxidation, and restores insulin sensitivity.
Translation: Cells shift from glucose hoarding to flexible fuel use. Endurance improves, metabolic rate stabilizes, and the body responds better to caloric deficits.
Evidence: Published in Cell Metabolism (2015), with follow-up studies confirming metabolic benefits in humans.
Component 3: NAD+ — Redox Currency
NAD+ is the central cofactor for energy metabolism, DNA repair, and sirtuin activation. Levels decline ~50% between age 20 and 50, and faster under chronic stress or inflammation.
Mechanism: Restores NAD+/NADH ratio, activates sirtuins (SIRT1–3), calms PARP overactivation, and synchronizes circadian rhythms.
Translation: Sustained energy, better sleep, deeper recovery, improved mental clarity.
Evidence: Multiple RCTs with NMN/NR precursors show tissue NAD+ elevation; IV/IM NAD+ provides higher peak levels.
See NAD+ Guide for complete coverage.
How the Components Work Together
The synergy matters more than any single component:
- SS-31 + NAD+: Efficient electron transport plus abundant redox fuel = higher ATP output without oxidative damage
- MOTS-c + NAD+: New mitochondria (from biogenesis) need charged batteries (NAD+) to function
- SS-31 + MOTS-c: Repair existing mitochondria while building new, metabolically intelligent copies
Once ATP production exceeds maintenance cost, cells stop triaging and start investing in repair: collagen renews, nerves fire cleanly, hormones regain sensitivity.
Protocol: 12-Week MITT Cycle
| Phase | SS-31 | MOTS-c | NAD+ | Support |
|---|---|---|---|---|
| Weeks 1–2 (loading) | 10 mg daily × 5–7 days, then 3×/week | 10 mg 3×/week | 200 mg 5×/week | Electrolytes, zone-2 cardio |
| Weeks 3–6 | 10 mg 3×/week | 10 mg 3×/week | 150–200 mg 4–5×/week | Resistance training, protein ≥1.6 g/kg |
| Weeks 7–12 | 10 mg 2–3×/week | 5–10 mg 2×/week | 150 mg 3–4×/week | Sleep 7–9 hours, glycine + collagen |
Cycling: 12 weeks on, 4 weeks off. Repeat twice yearly or maintain lighter cadence (SS-31 weekly, MOTS-c pulses, NAD+ 2–3×/week).
Timeline of Effects
| Timeframe | Cellular changes | What you notice |
|---|---|---|
| Weeks 1–2 | SS-31 tightens ETC, ROS drops | Warm steady energy, less soreness |
| Weeks 3–4 | MOTS-c activates AMPK/PGC-1α | Cardio feels easier, cravings decrease |
| Weeks 5–8 | NAD+ + sirtuins repair DNA/membranes | Better sleep, clearer skin, mental sharpness |
| Weeks 9–12 | Mitochondrial density peaks | Resilience under stress, faster recovery |
Applications
Metabolic support for GLP-1 therapy
MITT pairs naturally with GLP-1 protocols once patients move beyond basic appetite control. The enhanced mitochondrial capacity makes caloric deficits feel easier and protects lean mass by improving fat oxidation.
See Mitochondrial Stack for GLP-1.
Injury recovery
The MITT-Stack provides the ATP foundation that tissue repair requires. It's typically used after vascular restoration (BPC-157/TB-500) when cellular energy becomes the limiting factor.
Longevity and anti-aging
By sustaining sirtuin activity, supporting DNA repair, and maintaining mitochondrial density, the MITT-Stack addresses the metabolic decline that underlies aging.
Safety
SS-31: Generally well tolerated. IV use can cause transient warmth or flushing.
MOTS-c: Early-week fatigue is common (AMPK activation adjusting metabolism). Eat adequately on training days.
NAD+: Slow injection rate to avoid chest tightness. Hydration is important.
Contraindications: Active malignancy, uncontrolled hypertension, acute infection — pause until resolved.
Monitoring: Consider baseline and month-2 checks for CMP, lipids, and hs-CRP.
FAQ
Can I run MITT without NAD+ injections?
You'll blunt the synergy. NAD+ is the currency the other peptides spend. Oral NMN/NR is an alternative but provides lower peak levels than injection.
How does MITT differ from NAD+ therapy alone?
NAD+ provides fuel but doesn't repair damaged membranes or build new mitochondria. The full MITT-Stack addresses structure (SS-31), signaling (MOTS-c), and fuel (NAD+).
Is MITT anabolic?
Not directly muscle-building, but by improving ATP production and reducing inflammation, it makes training and any growth-hormone protocol more effective.
Related Guides
- NAD+ Guide — complete NAD+ overview
- BPC-157 + TB-500 for Injury Recovery — vascular restoration (often precedes MITT)
- Mitochondrial Stack for GLP-1 — MITT application for metabolic protocols
References
SS-31 (Elamipretide)
- Phase 2 trials: Cardiomyopathies, Barth syndrome — improved ATP kinetics
- Mechanism: Cardiolipin binding, electron transport stabilization, ROS reduction
MOTS-c
- Cell Metabolism (2015, Lee et al.) — foundational discovery
- Mechanism: AMPK/PGC-1α activation, metabolic flexibility, insulin sensitivity
NAD+
- Nature Reviews Molecular Cell Biology (2021) — comprehensive aging review
- Multiple RCTs: NMN/NR precursors elevate tissue NAD+
- Mechanism: Sirtuin activation, PARP regulation, circadian synchronization
Medical Disclaimer
The content in this protocol guide is for informational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before beginning any new protocol, supplement, or medication.