Posted on Nov 14, 2023, 4 p.m.
Researchers from the Buck Institute have identified a new pathway for mitophagy which highlights the gut-brain connection. The new drug-like molecule extends lifespan, ameliorates pathology in worms, and boosts mitochondria function in mammalian muscle cells. The compound dubbed MIC is a naturally occurring compound, and the findings have been published in Nature Aging.
Defective mitophagy is implicated in many age-related diseases and neurodegenerative disorders, as well as playing roles in cardiovascular diseases, and influencing metabolic disorders, it is also implicated in muscle wasting and sarcopenia, and has a relationship with cancer progression. Interventions that restore mitophagy and facilitate the elimination of damaged mitochondria hold the potential for addressing these conditions, however, not a single treatment has been approved for human uses despite advancements in the field.
Mitophagy-Inducing Compound (MIC) is a natural compound called coumarin, these are bioactive compounds with anticoagulant, antibacterial, antifungal, antiviral, anticancer, and antihyperglycemic properties, among others. Coumarin is also an antioxidant and has neuroprotective effects, and it is found in many plants as well as in high concentrations in certain types of cinnamon which is one of the most frequent sources for human exposure.
"Co-author Shankar Chinta, Ph.D., started screening natural compounds in neuronal cells and MIC came up as a major hit," said Julie Andersen, Ph.D., a senior author of the paper. "Rather than taking MIC immediately into a mouse model we wanted to understand its impact on overall aging and identify its mechanism of action, so we took the work into the worm where we found that MIC is in a different class of molecules that enhance the expression of a key protein, TFEB."
Manish Chamoli, Ph.D., lead author of the study, found that MIC enhanced the activity of transcription factor TFEB, which is a master regulator of genes involved in autophagy and lysosomal functions. Autophagy is like a recycling process that cleans up damaged proteins deriving abilities from the lysosome. MIC was found to robustly increase the lifespan of C. elegans and prevent mitochondrial dysfunction in mammalian cells, according to the researchers.
"This paper helps support the overall notion of TFEB being a key autophagy regulator that extends lifespan," said Buck professor and Chief Scientific Officer Malene Hansen, PhD, who collaborated on the paper. She added, "Mitophagy is a selective and very significant form of autophagy. The field has recognized TFEB as a player when it comes to quality control in mitochondria. This study provides a possible translational route to induce mitophagy in a TFEB-dependent fashion."
Additionally, the researchers report that MIC works upstream of TFEB by inhibiting ligand-induced activation of DAF-12 (FXR in humans) which in turn induces mitophagy and extends lifespan. FXR (regulated by bile salts formed in the gut microbiome) is known for the ability to act in the liver and gut to maintain lipid homeostasis, acting to regulate levels of TFEB which has recently been shown to be present within brain neurons; providing needed clues to piece together MIC’s potential mechanisms.
"This study provides another piece of the puzzle when it comes to understanding the brain/gut connection in terms of health and disease," said Andersen.
"The gut microbiome impacts the body's use of bile acids. Aging impacts our microbiome," said Chamoli. "If levels of bile acids aren't correct it hinders mitophagy. That's how FXR can impact neuronal health. Neurons have a lot of mitochondria which makes mitophagy important in terms of neurodegeneration."
"There's a bottleneck in efforts to develop potential therapeutics in the field of geroscience, and the bottleneck is that we don't have enough molecules in the pipeline," said Gordon Lithgow, Ph.D., Buck Professor and Vice President of Academic Affairs and senior co-author. "MIC is a great candidate to bring forward given its therapeutic effect across multiple models and the fact that it is a naturally occurring molecule."
It was noted that experiments are underway to explore FXR as a therapeutic target for Alzheimer’s disease and that the direct links between aging and mitophagy suggest that drug enhancement of this process could possibly offer treatment well being muscle wasting and neurodegeneration.
"All these possibilities can be explored at the Buck where the research environment supports such endeavors,” said Chamoli.
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