Mitochondrial uncoupling is the mechanism by which cells generate heat. Mitochondria are the power plants of the cell, a herd of bacteria-like structures that conduct energetic processes to generate the chemical energy store molecule adenosine triphosphate (ATP). ATP is used to power all of the vital biochemical machinery of a cell. Mitochondrial uncoupling is a regulatory mechanism that changes the operation of a mitochondrion such that the energy it accumulates is dissipated as heat rather than powering the chemical reactions needed to generate ATP. This uncoupling is how mammals regulate body temperature.
Raised levels of mitochondrial uncoupling can produce useful outcomes to health over the long term. It can be protective of tissues by reducing the degree to which mitochondria generate oxidative molecules. Unfortunately, this class of intervention so far doesn’t appear to increase life span, despite tending to reduce excess visceral fat tissue, a significant contributing cause of age-related disease. The practice of calorie restriction does increase mitochondrial uncoupling, but it is unclear as to the degree to which this is important to the outcome of improved health and longevity that occurs in calorie restricted animals.
Nonetheless, there has been some effort over the years to produce drugs that can increase mitochondrial uncoupling. The primary objection to the use of such compounds in the clinic is that, historically, they have not been all that safe. They increase uncoupling in a dose-dependent manner, but increasing uncoupling to a sizable degree can result in severe trauma or death due to excess heat generation. The distance between a useful dose and a lethal dose just isn’t large enough for comfort. DNP is a good example of such a compound, one with the added safety concern of being explosive. There are signs of progress, however. Researchers here report on a mitochondrial uncoupling drug candidate that appears to be useful at reasonable doses and, more importantly, safe at high doses.
Researchers have recently identified a small mitochondrial uncoupler, named BAM15, that decreases the body fat mass of mice without affecting food intake and muscle mass or increasing body temperature. Additionally, the molecule decreases insulin resistance and has beneficial effects on oxidative stress and inflammation. The findings hold promise for future treatment and prevention of obesity, diabetes, and especially nonalcoholic steatohepatitis (NASH), a type of fatty liver disease that is characterized by inflammation and fat accumulation in the liver.
The mitochondria are commonly referred to as the powerhouses of the cell. The organelle generates ATP, a molecule that serves as the energy currency of the cell, which powers body movement and other biological processes that help our body to function properly. In order to make ATP, nutrients need to be burned and a proton motive force (PMF) needs to be established within the mitochondria. The PMF is generated from a proton gradient, where there is a higher concentration of protons outside of the inner membrane and a lower concentration of protons in the matrix, or the space within the inner membrane. The cell creates ATP whenever protons pass through an enzyme called ATP synthase, which is embedded in the membrane. Hence, nutrient oxidation, or nutrient burning, is coupled to ATP synthesis. Mitochondrial uncouplers transport protons into the matrix by bypassing ATP synthase, which throws off the PMF. To reestablish the gradient, protons must be exported out of the mitochondrial matrix. As a result, the cell begins to burn fuel at higher than necessary levels.
Knowing that these molecules can change a cell’s metabolism, researchers wanted to be sure that the drug was reaching its desired targets and that it was, above all, safe. Through a series of mouse studies, the researchers found that BAM15 is neither toxic, even at high doses, nor does it affect the satiety center in the brain, which tells our body if we are hungry or full. Another side effect of previous mitochondrial uncouplers was increased body temperature. Researchers measured the body temperature of mice who were fed BAM15. They found no change in body temperature. In the BAM15 mouse studies, animals ate the same amount as the control group – and they still lost fat mass.
Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity.
BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.