Mitochonic Acid-5

Mitochonic acid 5 (MA-5) is a synthetic small molecule derived from the plant hormone indole-3-acetic acid. A Tohoku University group picked it from a screen of indole-3-acetic acid analogs for raising ATP in Hep3B human hepatocellular carcinoma cells, and found that it increased the survival of stressed fibroblasts from people with mitochondrial diseases (Suzuki et al., 2015).

They later reported that it binds mitofilin, an inner mitochondrial membrane protein (Suzuki et al., 2016). MA-5 is not a peptide, and its published research is preclinical.

The two sources do not conflict.

Most published MA-5 work falls into six areas, all preclinical: the founding papers come from the Tohoku group that developed MA-5, and independent labs have added cell and rodent studies.

Discovery in patient-derived fibroblasts

The first paper tested MA-5 on fibroblasts from people with Leigh syndrome, MELAS, Leber's hereditary optic neuropathy and Kearns-Sayre syndrome. Under stress it raised cellular ATP and survival, and the survival effect held with oxidative phosphorylation or the electron transport chain inhibited (Suzuki et al., 2015). A follow-up stressed 25 patient fibroblast lines with L-buthionine sulfoximine, a glutathione synthesis blocker.

MA-5 protected 24; the 25th could not be assessed because the stressor did not affect it (Matsuhashi et al., 2017). In myoblasts from people with sporadic inclusion body myositis, which made less ATP than controls, MA-5 raised ATP, lowered mitochondrial ROS and reduced cell death (Oikawa et al., 2020). Models: patient-derived fibroblasts and myoblasts.

Mitochonic acid 5 and mitofilin

The developers pulled binding proteins from cell lysates on MA-5-coated beads; hits included mitofilin, HSP70 and ATP synthase subunits. Mitofilin binding gave a Kd of about 28 µM by mass spectrometry but 364 µM by surface plasmon resonance with a truncated protein. Labeled MA-5 gathered in fibroblast mitochondria, and MA-5 amplified the ATP rise from mitofilin overexpression in Hep3B cells. In isolated mitochondria it increased ATP production and lowered ROS without changing complex I to IV activity (Suzuki et al., 2016).

A follow-up linked it to ATP synthase oligomerization and supercomplex formation with mitofilin, also called Mic60 (Matsuhashi et al., 2017). Mitofilin may not be its only partner: an independent lab found that MA-5 inhibits the mitochondrial carnitine/acylcarnitine carrier in proteoliposomes, at IC50 values of 58 to 73 µM (Giangregorio et al., 2026). Models: cell lysates, recombinant proteins, fibroblasts and isolated mitochondria.

Mitochondrial disease models in mice and flies

In a handful of Mitomice, which carry a pathogenic mitochondrial DNA deletion, MA-5 at 50 mg/kg per day was associated with better heart and kidney mitochondrial respiration; survival data were too few for statistics (Suzuki et al., 2016). A 2026 study in Mitomice started after disease onset, with 50 mg/kg by oral gavage daily for 27 days and 7 mice per group.

Against vehicle, MA-5 mice had lower plasma creatinine, lower blood lactate after a glucose load, slower body weight decline and fewer respiration-deficient kidney cells; heart effects were milder, and the authors flag the small sample (Ogasawara et al., 2026). In Barth syndrome models, MA-5 raised ATP in iPSC-derived myoblasts and lessened locomotor deficits and tachycardia in Drosophila (Tongu et al., 2025). Models: mice, flies and stem-cell-derived muscle cells.

Kidney injury models

In male C57BL/6 mice, MA-5 given by gavage at 50 mg/kg before bilateral renal ischemia lowered plasma creatinine, KIM-1 staining and tubular necrosis at 48 hours. In mice given cisplatin, daily MA-5 lowered plasma BUN and tubular necrosis at 96 hours (Suzuki et al., 2016). Model: mouse acute kidney injury.

Nervous system and inflammation models

In mouse BV-2 microglial cells exposed to TNF-α, MA-5 reduced apoptosis through Bnip3-related mitophagy and MAPK-ERK-Yap signaling (Lei et al., 2018). A separate group found that it raised ATP-linked respiration in SH-SY5Y cells after oxygen-glucose deprivation and reduced neurological deficits and infarct volume in mice after transient cerebral ischemia (Sasaibe et al., 2025).

In ALS model flies expressing mutant human SOD1 (G85R) in neurons, MA-5 slowed climbing decline and extended lifespan, and it restored ATP production in ALS patient fibroblasts and iPSC-derived motor neurons (Oikawa et al., 2026). Models: cell lines, mice, flies and patient-derived cells.

Heart and inner ear models, including a negative finding

In mice and rat H9c2 heart cells exposed to doxorubicin, MA-5 reduced cardiac enzyme changes, inflammation, pyroptosis and intracellular ROS (Zha et al., 2023). In Cdk5rap1 knockout mice, which develop early age-related hearing loss, MA-5 in drinking water at 2 or 4 mg/kg daily for 2 months slowed hearing threshold rise and spiral ganglion loss, best at 2 mg/kg; 4 mg/kg increased outer hair cell loss (Kouga et al., 2025).

A San Diego lab found MA-5 (1 to 10 µM) failed to protect mouse cochlear explant hair cells from gentamicin or cisplatin; 10 µM proved toxic (Ryan et al., 2025). Models: rat heart cells, mice and mouse cochlear explants.