More on the Safe Mitochondrial Uncoupling Compound BAM15

Mitochondrial uncoupling is a mechanism by which mammals maintain body temperature. It diverts the activity of the hundreds of mitochondria present in every cell from production of the chemical energy store molecule adenosine triphosphate (ATP), used to power cellular processes, to the production of heat. Additional mitochondrial uncoupling, above and beyond that which occurs naturally, produces beneficial effects on long term health, as is true of a range of manipulations that influence mitochondrial function. In this case, however, it doesn't appear to slow aging, even while resulting in desirable outcomes such as a reduction in visceral fat tissue.

Mild additional mitochondrial uncoupling is a good thing. Excessive mitochondrial uncoupling can produce severe side-effects and death, however, and that makes it a tricky process to produce drugs targeting this mechanism. One of the world's more dangerous and interesting drugs is a mitochondrial uncoupler, 2,4-dinitrophenol (DNP). In addition to being an explosive compound, it stays in the body long enough to make it all too easy to slip from a safe dose to potentially fatal dose. It is thus no longer used, after a period of interest as a weight loss treatment many decades ago.

The effects of mitochondrial uncoupling on long term health are interesting enough, in this era of widespread obesity, for the research community to have worked towards safe mitochondrial uncoupling compounds. One of these, BAM15, is the subject of today's research materials. You may recall that this line of work was discussed here a few years ago. There is progress towards a potential path to the clinic, but only slowly, as is usually the case.

Chemical Compound Promotes Healthy Aging

Researchers have provided the first evidence that BAM15, a mitochondrial uncoupler, prevents sarcopenic obesity, or age-related muscle loss accompanied by an increase in fat tissue. The weakness and frailty common to sarcopenic obesity are offset in older mice - the equivalent of aged 60-65 in human years - given BAM15. The mice, all of whom had obesity, were fed high-fat diets. Despite that, the mice given BAM15 lost weight and got stronger and more active. "In this study, the aged mice increased their muscle mass by an average of 8 percent, their strength by 40 percent, while they lost more than 20 percent of their fat."

BAM15 improves many of the key determinants of health and aging, including: (a) removing damaged mitochondria, the power plants of the cell; (b) making more healthy mitochondria, and; (c) reducing "inflammaging," or age-related inflammation, linked to muscle loss.

Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control

Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet-induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.

BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g) which was attributable to increased energy expenditure. BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g), and locomotor activity. Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation, enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control, increased mitochondrial activity, restricted endoplasmic reticulum (ER) misfolding, while limiting ER stress, apoptotic signalling, and muscle protein degradation.

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.