BAM15 — Mitochondrial Uncoupler Research Article (Educational • Research Use Only)

Independent research publication focused on mitochondrial biology, energy metabolism, and peptide-adjacent bioenergetic research.

Overview

BAM15 (N5,N6-bis(2-fluorophenyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine) is a synthetic small molecule identified as a mitochondrial protonophore.

Originally discovered through high-throughput screening for mitochondrial modulators, BAM15 functions as a selective mitochondrial uncoupler, separating electron transport from ATP synthesis.

In research settings, this compound has been used to explore energy expenditure, fat oxidation, metabolic flexibility, and mitochondrial efficiency, offering a controlled method to increase caloric utilization without increasing food intake.

Preclinical models suggest BAM15 increases resting energy expenditure, decreases hepatic steatosis, improves insulin sensitivity, and alters lipid metabolism — making it a potent tool for studying obesity, type 2 diabetes, and aging biology.

Mechanism of Action (Research Context)

BAM15 acts as a protonophore, meaning it facilitates proton (H⁺) transport across the mitochondrial inner membrane independent of ATP synthase.

Under normal conditions, mitochondria create a proton gradient (Δψ) to power oxidative phosphorylation and ATP production.

By dissipating this gradient, BAM15 uncouples substrate oxidation from ATP generation, forcing the mitochondria to oxidize more fuel substrates (fatty acids and glucose) to maintain energy balance.

This increased proton leak leads to higher oxygen consumption and heat generation, a process known as mitochondrial uncoupling–induced thermogenesis.

Unlike earlier uncouplers such as DNP (2,4-dinitrophenol), BAM15 demonstrates selectivity and safety advantages in preclinical models — showing no significant rise in body temperature or systemic toxicity at experimental doses.

On a molecular level:

• BAM15 integrates within the mitochondrial inner membrane lipid bilayer.

• It transports protons via reversible ion-shuttling, collapsing the proton motive force.

• This elevates substrate oxidation, increases NADH turnover, and enhances mitochondrial respiration.

These properties make BAM15 an important research probe for studying bioenergetic efficiency, mitochondrial stress adaptation, and metabolic signaling pathways such as AMPK and PGC-1α.

Potential Research Benefits (Reported in Literature)

• Increases whole-body energy expenditure and fat oxidation without hyperthermia

• Improves insulin sensitivity and glucose tolerance in diet-induced obese models

• Reduces hepatic steatosis and adiposity in rodent studies

• Enhances mitochondrial respiratory capacity and turnover of defective mitochondria

• Lowers reactive oxygen species (ROS) accumulation by optimizing electron transport efficiency

• Demonstrates lifespan-extension potential in some cellular aging models

• Offers a tool to study non-hormonal thermogenic mechanisms independent of adrenergic signaling

Selected Research Highlights

• Energy Expenditure: BAM15 increased oxygen consumption rate (OCR) and resting metabolic rate in murine studies without altering food intake or causing febrile responses.

• Liver Fat Reduction: Rodents fed high-fat diets and treated with BAM15 displayed reduced hepatic triglyceride accumulation and improved hepatic insulin signaling.

• Insulin Sensitivity: HOMA-IR and glucose-tolerance testing improved significantly in BAM15-treated groups, correlating with enhanced mitochondrial oxidation.

• Mitochondrial Health: Research indicates improved mitochondrial dynamics, with increased biogenesis markers (PGC-1α, NRF-1) and reduced fission protein expression (DRP1).

• Safety Profile: Unlike older uncouplers, BAM15 did not significantly elevate body temperature, demonstrating a more favorable margin between efficacy and thermogenic toxicity.

Chemical / Physical Information

• Chemical Name: N5,N6-bis(2-fluorophenyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine

• Molecular Formula: C₁₄H₁₀F₂N₆O₂

• Molecular Weight: 332.27 Da

• Appearance: Pale yellow crystalline solid

• Solubility: Soluble in DMSO and ethanol; sparingly soluble in water

• Storage: Store at −20 °C protected from light and moisture; for extended storage, maintain under inert gas.

Reconstituted solutions should be aliquoted and frozen to prevent repeated freeze–thaw cycles.

Metabolic Implications (Research Context)

BAM15 has provided researchers with a model to explore controlled mitochondrial inefficiency as a therapeutic strategy.

By modestly reducing ATP yield per molecule of substrate oxidized, BAM15 increases caloric dissipation as heat — effectively “wasting” energy to rebalance metabolic homeostasis.

This mechanism allows investigation into:

• Adipose tissue thermogenesis independent of β-adrenergic stimulation

• Hepatic lipid oxidation and non-alcoholic fatty liver disease (NAFLD) models

• Muscle mitochondrial turnover and metabolic flexibility

• Mitochondrial hormesis — the adaptive benefits of mild mitochondrial stress

The uncoupling process also activates AMP-activated protein kinase (AMPK) and downstream mitochondrial biogenesis pathways, offering a valuable tool for studying exercise-mimetic or calorie-restriction-mimetic mechanisms.

Regulatory & Compliance Notes

BAM15 is an experimental compound and is not approved for therapeutic or dietary use by any regulatory authority.

All handling and application must be confined to controlled laboratory environments under institutional safety oversight.

Documentation such as Certificates of Analysis (COA) and Material Safety Data Sheets (MSDS) should accompany all research-grade material.

References (Selection)

1. Alexopoulos SJ et al. (2020). Mitochondrial uncoupler BAM15 reverses obesity and insulin resistance in mice. Nature Communications.

2. Gao AW, et al. (2021). Mitochondrial uncoupling as a strategy for metabolic disease: lessons from BAM15. Cell Metabolism.

3. Mills EL, et al. (2020). Uncoupling mitochondrial respiration in metabolic research: mechanistic insights from BAM15. J Biol Chem.

4. Krahmer N, et al. (2022). Mitochondrial efficiency and thermogenesis under BAM15-induced proton leak. EMBO Reports.

5. Wallace DC. (2023). Mitochondrial bioenergetics in aging and disease: uncouplers and beyond. Trends Endocrinol Metab.

Disclaimer

This publication is intended for educational and research purposes only.

BAM15 is not approved for human or veterinary use.

All research must adhere to institutional biosafety and ethical standards governing chemical handling, metabolic studies, and mitochondrial research.

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Selected References

PMID: 32395069 — Mitochondrial uncouplers and metabolic modulation

PMID: 31594992 — BAM15 mechanisms in energy expenditure

PMID: 33093089 — Uncoupling agents and obesity/metabolic regulation

PMID: 30728358 — Mitochondrial-targeted therapeutics in metabolism

Frontiers in Endocrinology — Mitochondrial bioenergetics and metabolic control

Journal of Biological Chemistry — Uncoupling-driven energy metabolism

Frequently Asked Questions (FAQ)

Q1: What is BAM15?A1: BAM15 is a mitochondrial protonophore studied for its ability to uncouple oxidative phosphorylation and influence metabolic energy expenditure in research models.

Q2: How does BAM15 work in research?A2: BAM15 disrupts the mitochondrial proton gradient, increasing energy expenditure without directly impacting appetite or food intake in experimental systems.

Q3: Is BAM15 approved for human use?A3: No. BAM15 is strictly a research compound and is not approved for clinical, therapeutic, or consumer use.

Q4: What are researchers studying BAM15 for?A4: Research explores BAM15 in contexts such as metabolic rate modulation, obesity models, thermogenesis, and mitochondrial function.

Q5: Does BAM15 affect muscle tissue or lean mass?A5: Studies suggest that BAM15 may increase metabolic activity without significantly reducing lean mass, though findings are limited to preclinical models.

Q6: How is BAM15 typically evaluated in research?A6: BAM15 is assessed using controlled laboratory experiments that monitor mitochondrial activity, metabolic rate, and energy balance.

Q7: Does BAM15 have known side effects in studies?A7: Some experimental data show tolerability within certain dosage ranges, but comprehensive safety profiles are not established.

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