Mitochonic Acid-5 (MA-5): A Novel Mitochondrial and Longevity Molecule
After a long wait, my lab has finally completed the synthesis and isolation of the S-enantiomer of Mitochonic Acid-5 (MA-5) with 99% enantiomeric purity.
The original paper that caught my attention on biorxiv is named:
Non-DNA-damaging DNA-PK activation improving hearing and prolonging life due to NAD+ and SIRT upregulation
I can’t post links right now.
MA-5 is a modified version of the natural plant hormone indole-3-acetic acid.
Across multiple studies, MA-5 has been shown to:
- Increase ATP production
- Reduce mitochondrial ROS generation at the source
- Elevate intracellular NAD⁺ levels
- Increase and stabilize SIRT1–7 protein expression
- Improve cellular survival and stress resistance
- Extend lifespan and healthspan in animal models
- Protect against hearing loss and improve auditory resilience
I have just tried the R-enantiomer so far and it gives an increase in energy, endurance, mood, and has a very nice effect of making your hearing sharper. The S-enantiomer should have even stronger effects.
To understand how MA-5 actually works, let’s first establish a clear picture of how mitochondria produce energy:
The Engine: Proton Pressure and Turbines Mitochondria generate ATP by creating a high-pressure buildup of protons across the inner mitochondrial membrane and using that pressure to spin a biological turbine called ATP synthase (Complex V).
To fuel this process, the Krebs cycle (or Citric Acid Cycle) first acts as a refinery within the mitochondrial matrix. It processes breakdown products from carbohydrates, fats, and ketones to strip away high-energy electrons, loading them onto specialized carrier molecules (primarily NADH).
These carriers deliver the electrons to four protein complexes (Complexes I–IV) embedded along the folded inner membrane. As electrons pass through these complexes, their energy is used to pump protons from the matrix into the intermembrane space, creating a positive proton gradient.
Finally, ATP synthase uses the mechanical force of these protons flowing back into the matrix to join ADP and inorganic phosphate together. This spins the turbine and produces ATP.
Why Structure is Crucial Efficient energy capture depends entirely on the 3D architecture of the inner membrane. The membrane folds into tight, disc-like pockets called cristae, which act like pressurized batteries.
- The Pumps (Complexes I–IV): These sit along the flat sides of the cristae pocket, pumping protons inside to inflate it with chemical pressure.
- The Turbines (ATP Synthase): To capture this energy, ATP synthase molecules cluster into long rows (oligomers) along the sharp, curved ridges of the cristae. This geometry concentrates the trapped protons at the tips, forcing them to exit through the turbines at maximum velocity.
The structural integrity of this system relies on the Crista Junction—the narrow “neck” where the crista pocket connects to the mitochondrial wall. The protein responsible for organizing this junction is Mitofilin (MIC60), a core component of the MICOS complex.
Mitofilin functions like a reinforced ring that lines the junction opening. It circles the narrow neck to prevent it from tearing open or collapsing. Simultaneously, it acts as a structural staple, pinning this ring to the outer mitochondrial membrane.
This architecture maintains a tight, reinforced “bottleneck” at the junction, which is critical for two reasons:
- It traps protons: By keeping the neck narrow, it prevents protons from leaking out of the pocket, maintaining high pressure for the turbines.
- It stabilizes the ridges: By anchoring the base, it allows the cristae to extend deep into the matrix without collapsing, enabling ATP synthase to align properly at the tips.
How MA-5 Improves Mitochondrial Structure MA-5 is effective because it strengthens the Mitofilin (MIC60) at the crista junction by binding to it, preventing it from widening or breaking, a common failure in stressed or aging mitochondria that leads to depressurization and structural collapse.
When the Mitofilin is reinforced by MA-5, the downstream benefits are profound:
- Restored Geometry: The cristae pockets remain inflated and structurally sound.
- Optimized Alignment: ATP synthase at the distant ridges is forced into its efficient, oligomerized state.
- Smoother Flow: With the structure intact, the electron transport chain (Complexes I–IV) operates without stalling, significantly reducing the leakage of electrons that causes oxidative stress (ROS).
Rather than just pushing the engine to run harder, MA-5 optimizes and restores the physical conditions that allow energy production to occur efficiently and cleanly.
Mitofilin (Mic60) levels drop significantly with age and disease, and this appears to be a major driver of mitochondrial breakdown across multiple conditions including Parkinson’s. MA-5 may help prevent or delay onset of different mitochondrial-driven diseases.
Part 2: The Signaling Mechanism
Molecular Pharmacology of the S-Enantiomer While the structural stabilization of mitofilin provides the physical scaffold for energy production, the S-enantiomer of MA-5 drives a distinct metabolic and signaling cascade. The study identifies this enantiomer as the pharmacologically active form responsible for upregulating the NAD⁺/Sirtuin axis through a novel “non-DNA-damaging” signaling pathway.
1. Direct Agonism of NAMPT Increases NAD⁺ NAD⁺ levels are critical for mitochondrial function and sirtuin activity but naturally decline with age. The S-enantiomer addresses this by acting as a direct chemical agonist of NAMPT (nicotinamide phosphoribosyltransferase), the rate-limiting enzyme in the NAD⁺ salvage pathway.
- Binding Mechanism: Structural analysis and docking simulations confirm that the S-enantiomer binds to the active site of NAMPT.
- Enzymatic Activation: This binding allosterically enhances the enzyme’s activity, resulting in a significant dose-dependent increase in intracellular NAD⁺ levels. Notably, this effect is specific to the S-enantiomer; the racemic mixture and R-enantiomer show significantly weaker or negligible effects on NAD⁺ synthesis.
2. Sirtuin Stabilization: Stopping the “Disposal” System Typically, increasing NAD⁺ just gives the existing sirtuins more fuel. MA-5 is unique because it actually increases the number of sirtuin proteins. It achieves this by blocking the cellular process that normally identifies and destroys them.
- The “Safe” Repair Signal: MA-5 activates DNA-PK, a master sensor usually linked to DNA repair. Crucially, it triggers this sensor without causing any actual damage to the DNA. It effectively tricks the cell into entering a “protective repair mode” without the stress of an actual injury.
- Halting Degradation: This signal modifies a regulator protein called TRIM28. Once modified, TRIM28 stops the cell from tagging sirtuins for destruction (a process called ubiquitination).
- The Result: Instead of being broken down and recycled as usual, sirtuin proteins are preserved and allowed to accumulate. This ensures that the newly boosted NAD⁺ levels have a larger pool of enzymes ready to use that fuel for cellular repair.
The ability of MA-5 to optimize structure for ATP production, raise NAD⁺ levels, and stabilize sirtuins makes it, in my opinion, the most compelling mitochondrial therapeutic currently in human trials.
I will add more study references in future posts or edit this one.