Background
Mitochondrial dysfunction, including decreased mitochondrial respiration and increased mitochondrial stress, is associated with many major human diseases and casual to many pathological defects. Identifying methods that can promote mitochondrial activity and homeostasis have been a focus of R&D in many biotech companies. Since raising the activity of ATP synthase may boost mitochondrial respiration and energy production, a chemical agonist of ATP synthase would have high therapeutic potential in this regard. Peptidoglycan (PG) is a unique structural component of the bacterial cell wall that is routinely degraded, resulting in fragments known as muropeptides. These PG fragments (muropeptides) are released into the environment, such as the host intestine for commensal bacteria. While PG is known to interact with host proteins for roles in bacterial pathogenicity and host innate immune response, the “symbiosis” concept that describes the interdependent relationship between commensal microbes and host suggests that animals might utilize muropeptidesto enhance their fitness. Therefore, uncovering such previously unknown roles may potentially identify nutrient or therapeutic value of muropeptides.
Technology
Using innovative assays, researchers at the University of Colorado Boulder have discovered an unexpected and striking role of PG-derived muropeptides to support animal growth and behaviors using C. elegansas a model. They further uncovered that muropeptides benefit the host by suppressing mitochondrial stress and associated oxidative stress. Using several enzymes, the beneficial muropeptides were determined to be disaccharide molecules containing a short AA chain. Mechanistically, these muropeptides were shown to enter intestinal-cell mitochondria to interact with the F1 complex of ATP synthase, stabilizing the complex and increasing mitochondrial respiration. Importantly, such a novel function of muropeptideas the first discovered ATP synthase agonist is also conserved in mammals. Muropeptides were found to naturally accumulate in the mitochondria of mouse intestine. Using several mammalian cells lines, including human intestinal epithelial cells, isolated muropeptidewas found to also interact with human ATP synthase, promote mitochondrial respiration, and suppress oxidative stress. As a POC test, addition of muropeptideswas found to dramatically improve the survival and mitochondrial functions in fibroblast cells containing a mutation in a mitochondrial ATP6 gene (Leigh syndrome). Moreover, addition of muropeptideswas shown to significantly suppress oxidative stress in antibiotic-treated mice.
Advantages
Besides mitochondria-related diseases that are directly caused by failure of mitochondria to produce sufficient energy, mitochondrial dysfunction, that includes increases in mitochondrial stress/oxidative stress and decreases in mitochondrial respiration, is commonly associated with nearly all of the highly prevalent human diseases, including various cancers, major neuronal degenerative diseases or other neuronal disorders, metabolic diseases, cardio or muscular diseases, developmental defects (mitocure.org), and aging. For most of these diseases, the mitochondrial dysfunction can be causal to some key pathological defects even if it may not be the primary cause of the disease. For these reasons, many biotech and pharmaceutical companies have set out to invent intervening methods that would boost mitochondrial functions or improve mitochondrial homeostasis. The discovery of PG-derived muropeptidesas the first ATP synthase agonist, along with its proven beneficial roles in live animals and cultured cells, indicates an extremely beneficial therapy that may be used to improve clinical conditions of major human diseases.
Future Applications
What's Next?
Available for licensing
Nicole Forsberg: nicole.forsberg@colorado.edu
