PMID-24634817 – Identification of BAM15 Novel Mitochondrial Uncoupler
Kenwood BM, Weaver JL, Bajwa A, Pber IK, Blast JA, Nguyen KN, Henber KK, de Souza ALS, Bhatt DP, Merrick DM, Shinoda K, Kajimura S, Bhatt S, Rosenthal E, Okusa MD, Bhatt K, Bhatt DP, Bhatt KN, et al. "Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane." Molecular Metabolism, 2014;3(2):114-123.
Quick Reference
| Property | Value |
|---|---|
| PMID | 24634817 |
| DOI | 10.1016/j.molmet.2013.11.005 |
| Year | 2014 |
| Journal | Molecular Metabolism |
| Study Type | In vitro / Animal in vivo (discovery study) |
| Evidence Level | V |
| Sample | Cell lines (L6 myotubes, primary hepatocytes); mice (renal ischemia-reperfusion model) |
| Peptide(s) Studied | BAM15 |
Key Findings
- BAM15 was identified via high-throughput screening as a mitochondrial protonophore that selectively uncouples the inner mitochondrial membrane without depolarizing the plasma membrane
- BAM15 is equally potent to FCCP (carbonyl cyanide-p-trifluoromethoxyphenylhydrazone) at stimulating mitochondrial respiration but is significantly less cytotoxic
- BAM15 stimulates a higher maximum rate of mitochondrial respiration compared to FCCP in cultured cells
- BAM15 is bioactive in vivo and dose-dependently protects mice from acute renal ischemic-reperfusion injury
- Unlike DNP and FCCP, BAM15 does not depolarize the plasma membrane at concentrations that maximally uncouple mitochondria, explaining its superior safety profile
Study Design
High-throughput chemical screen using oxygen consumption rate (OCR) measurements in intact cells. Compounds were screened for ability to increase mitochondrial respiration (uncoupling activity) without plasma membrane depolarization. Lead compound BAM15 was then characterized in vitro (L6 myotubes, primary hepatocytes) and validated in vivo in a mouse renal ischemia-reperfusion injury model. Comparator was FCCP.
Limitations
- Discovery/characterization study; no obesity or metabolic disease models tested
- Limited in vivo pharmacokinetic data
- Single in vivo model (renal ischemia-reperfusion); broader tissue effects not assessed
- Mechanism of mitochondrial selectivity (why BAM15 does not depolarize plasma membrane) not fully elucidated
Clinical Relevance
This is the foundational discovery paper for BAM15. The key finding that BAM15 uncouples mitochondria without plasma membrane depolarization distinguishes it from older uncouplers like DNP (which caused fatalities) and FCCP (cytotoxic). This safety advantage made BAM15 a viable candidate for subsequent obesity and metabolic disease research. The renal protection data also suggests potential applications beyond weight management.
Related
#research #in-vitro #animal-in-vivo #BAM15 #evidence-level-V