Novel drug makes mice skinny even on sugary, fatty diet
News Release, World Mitochondria Society, Berlin - Germany – April 3, 2023
Researchers from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) have developed a small-molecule drug that prevents weight gain and adverse liver changes in mice fed a high-sugar, high-fat Western diet throughout life.
"When we give this drug to the mice for a short time, they start losing weight. They all become slim," said Madesh Muniswamy, PhD, professor of medicine in the health science center's Joe R. and Teresa Lozano Long School of Medicine.
Findings by the collaborators, also from the University of Pennsylvania and Cornell University, were published Feb. 27 in the high-impact journal Cell Reports. Muniswamy, director of the Center for Mitochondrial Medicine at UT Health San Antonio, is the senior author.
Fourth most common element
The research team discovered the drug by first exploring how magnesium impacts metabolism, which is the production and consumption of energy in cells. This energy, called ATP, fuels the body's processes.
Magnesium is the fourth most abundant element in the body after calcium, potassium and sodium, and plays many key roles in good health, including regulating blood sugar and blood pressure and building bones. But the researchers found that too much magnesium slows energy production in mitochondria, which are cells' power plants.
"It puts the brake on, it just slows down," said co-lead author Travis R. Madaris, doctoral student in the Muniswamy laboratory at UT Health San Antonio.
Deleting MRS2, a gene that promotes magnesium transport into the mitochondria, resulted in more efficient metabolism of sugar and fat in the power plants. The result: skinny, healthy mice.
Liver and adipose (fat) tissues in the rodents showed no evidence of fatty liver disease, a complication related to poor diet, obesity and type 2 diabetes.
Small-molecule agent
The drug, which the researchers call CPACC, accomplishes the same thing. It restricts the amount of magnesium transfer into the power plants. In experiments, the result was again: skinny, healthy mice. UT Health San Antonio has filed a patent application on the drug.
The mice served as a model system of long-term dietary stress precipitated by the calorie-rich, sugary and fatty Western diet. The familiar results of this stress are obesity, type 2 diabetes and cardiovascular complications.
"Lowering the mitochondrial magnesium mitigated the adverse effects of prolonged dietary stress," said co-lead author Manigandan Venkatesan, PhD, postdoctoral fellow in the Muniswamy lab.
Joseph A. Baur, PhD, of the University of Pennsylvania and Justin J. Wilson, PhD, of Cornell are among the collaborators. "We came up with the small molecule and Justin synthesized it," Madaris said.
Significant implications
"These findings are the result of several years of work," Muniswamy said. "A drug that can reduce the risk of cardiometabolic diseases such as heart attack and stroke, and also reduce the incidence of liver cancer, which can follow fatty liver disease, will make a huge impact. We will continue its development."
Funders of this project include the National Institutes of Health, the U.S. Department of Defense and the San Antonio Partnership for Precision Therapeutics.
Image Credit: Madaris, Travis R. et al. Cell Reports (2023)
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Key Information About The Function of Mitochondria in Cancer Cells
SBEM images and 3D reconstruction of representative type I (i), II (ii) and III (iii) crista structures identified in OXPHOSHI LUAD cells and OXPHOSLO LUSC cells.
News Release, World Mitochondria Society, Berlin - Germany – March 16, 2023
Scientists have long known that mitochondria play a crucial role in the metabolism and energy production of cancer cells. However, until now, little was known about the relationship between the structural organization of mitochondrial networks and their functional bioenergetic activity at the level of whole tumors.
In a new study, published in Nature, researchers from the UCLA Jonsson Comprehensive Cancer Center used positron emission tomography (PET) in combination with electron microscopy to generate 3-dimensional ultra-resolution maps of mitochondrial networks in lung tumors of genetically engineered mice.
They categorized the tumors based on mitochondrial activity and other factors using an artificial intelligence technique called deep learning, quantifying the mitochondrial architecture across hundreds of cells and thousands of mitochondria throughout the tumor.
The authors examined two main subtypes of non-small cell lung cancer (NSCLC)—adenocarcinomas and squamous-cell carcinomas and found distinct subpopulations of mitochondrial networks within these tumors. Importantly, they discovered that the mitochondria frequently organize themselves with organelles such as lipid droplets to create unique subcellular structures that support tumor cell metabolism and mitochondrial activity.
The study was led by Mingqi Han, Ph.D., a post-doctoral researcher in the lab of David Shackelford, Ph.D. Dr. Shackelford is a UCLA Jonsson Comprehensive Cancer Center member and Associate Professor of Pulmonary and Critical Care Medicine at the UCLA David Geffen School of Medicine.
The authors anticipate that mitochondrial populations in human cancer samples will not be mutually exclusive to their respective tumor subtype, but rather there will be a spectrum of activity.
The investigators say these findings provide key information about the function of mitochondria in cancer cells and could lead to new approaches to cancer treatment.
"Our study represents a first step towards generating highly detailed 3-dimensional maps of lung tumors using genetically engineered mouse models," said Dr. Shackelford.
"Using these maps, we have begun to create a structural and functional atlas of lung tumors, which has provided us valuable insight into how tumor cells structurally organize their cellular architecture in response to the high metabolic demands of tumor growth. Our findings hold promise to inform and improve current treatment strategies while illuminating new directions from which to target lung cancer."
"Our study has uncovered a novel finding in the metabolic flux of lung tumors, revealing that their nutrient preference may be determined by the compartmentalization of their mitochondria with other organelles, either relying on glucose ('sugar') or free fatty acids ('fat')," said Dr. Han.
"This discovery has important implications for developing effective anti-cancer therapies that target tumor-specific nutrient preferences. Our multi-modality imaging approach has enabled us to uncover this previously unknown aspect of cancer metabolism, and we believe that it can be applied to other types of cancer, paving the way for further research in this area."
Image Credit: David Shackelford et al, Nature (2023)
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An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets
Drosophila that represents one of the models of neurodegeneration used in the lab to screen for things (both chemically and genetically) that regulate mitophagy. Credit: Angus McQuibban (CC-BY 4.0) News Release, World Mitochondria Society, Berlin - Germany – March 6, 2023
AI analyzes the descriptions of compounds to identify potential new drug candidates.
A new study, published in the journal PLOS Biology, suggests that the language used by researchers in describing their results can be utilized to uncover new treatments for Parkinson’s disease. The study, led by Angus McQuibban of the University of Toronto in Canada, utilized AI to find an existing anti-cholesterol medication that has the capability to enhance the disposal of mitochondria, which are cellular components responsible for energy production and are affected in Parkinson’s disease.
The full pathogenic pathway leading to Parkinson’s disease (PD) is unknown, but one clear contributor is mitochondrial dysfunction and the inability to dispose of defective mitochondria, a process called mitophagy. At least five genes implicated in PD are linked to impaired mitophagy, either directly or indirectly, and so the authors sought compounds that could enhance the mitophagy process.
Several such compounds have been identified, but most of them also cause harm to cells, ruling them out as drug candidates. That led the authors to ask whether the literature describing these compounds might lead them to other compounds, ones not previously linked to mitophagy enhancement but which are described with terms that also appear in papers that discuss the known enhancers.
Identifying patterns of such “semantic similarity” is one of the core skills of IBM Watson for Drug Discovery, an AI program run on a supercomputer that analyzes the published literature for patterns of keywords, phrases, and juxtapositions. The team used the program to develop a semantic “fingerprint” of bona fide mitophagy enhancers, and then looked for similar fingerprints in the literature on a set of over three thousand candidates from a drug database.
The top 79 candidates were screened in cell culture against a mitochondrial poison. The three top candidates from that assay were then tested on several other mitophagy assays, which identified probucol, a cholesterol-lowering drug, as the compound with the best combination of effectiveness and likely safety. Probucol was also found to improve motor function, survival, and neuron loss in two different animal models of Parkinson’s disease (PD is primarily a movement disorder).
Probucol’s effect on mitophagy required the formation and action of lipid droplets, transient cell structures that help maintain mitochondrial integrity during stress, and that accumulate abnormally in Parkinson’s disease. Probucol is known to target ABCA1, a protein involved in lipid transport, and reduction in levels of ABCA1 reduced probucol’s ability to promote mitophagy, suggesting that ABCA1 is a likely mediator of the role of lipid droplets in mitophagy.
“Our study showcased a dual in silico/cell-based screening methodology that identified known and new mechanisms leading to mitophagy enhancement,” McQuibban said. “Given the linkage between lipid droplet accumulation and ABCA1, it seems likely that probucol enhances mitophagy through mobilization of lipid droplets. Targeting this mechanism may be advantageous.”
McQuibban adds, “In our study, we used the AI platform IBM Watson to efficiently identify currently approved drugs that could potentially be re-purposed as therapies for Parkinson’s disease.”
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Researchers discover therapeutic target to aid in glaucoma treatment
News Release, World Mitochondria Society, Berlin - Germany – March 13, 2023
Indiana University School of Medicine researchers have identified a new therapeutic target that could lead to more effective treatment of glaucoma.
Glaucoma is a neurodegenerative disease that causes vision loss and blindness due to a damaged optic nerve. More than 200,000 people are affected by glaucoma in the United States each year. Unfortunately, there is currently no treatment. In a newly published paper in Communications Biology, researchers found neurons use mitochondria for a steady source of energy, and restoring mitochondrial homeostasis in the diseased neurons can protect the optic nerve cells from being damaged.
“Age-related neurodegenerative disease, which includes glaucoma, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), is the biggest global health problem,” said Arupratan Das, PhD, assistant professor of ophthalmology and principal investigator of the study. “The fundamental mechanisms that we discovered can be used to protect neurons in glaucoma and be tested for the other diseases. We have identified a critical step of complex mitochondrial homeostasis process, which rejuvenates the dying neuron, similar to giving a lifeline to a dying person.”
The research team, led by Michelle Surma and Kavitha Anbarasu from the Department of Ophthalmology, used induced pluripotent stem cells (iPSCs) from patients with and without glaucoma as well as clustered regularly interspaced short palindromic repeats (CRISPR) engineered human embryonic stem cells with glaucoma mutation. Using stem cell differentiated retinal ganglion cells (hRGCs) of the optic nerve, electron microscopy and metabolic analysis, researchers identified glaucomatous retinal ganglion cells suffer mitochondrial deficiency with more metabolic burden on each mitochondrion. This leads to mitochondrial damage and degeneration. Mitochondria are the tube like structures in cells which produce adenosine triphosphate, cell’s energy source.
However, the process could be reversed by enhancing mitochondrial biogenesis by a pharmacological agent. The team showed retinal ganglion cells are highly efficient in degrading bad mitochondria, but at the same time producing more to maintain homeostasis.
“Finding that retinal ganglion cells with glaucoma produce more adenosine triphosphate even with less mitochondria was astonishing,” Das said. “However, when triggered to produce more mitochondria, the adenosine triphosphate production load was distributed among more mitochondrion which restored the organelle physiology. It is similar to a situation where a heavy stone is carried by fewer people versus a greater number of people—each person will have less pain and injury, just like each mitochondrion will have less difficulty and damage.”
In the future, Das would like to test if these mechanisms protect the optic nerve in animal models under injury before testing in humans to hopefully lead to new clinical interventions.
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Enhanced Mitochondrial Biogenesis Promotes Neuroprotection
News Release, World Mitochondria Society, Berlin - Germany – March 3, 2023
Transmission electron microscopy images of H7-hRGCWT and H7-hRGCE50K after 24 h DMSO or BX795 (1 μg/ml) treatment, at 49000X magnification. Asterisks represent mitochondria.
Mitochondrial dysfunctions are widely afflicted in central nervous system (CNS) disorders with minimal understanding on how to improve mitochondrial homeostasis to promote neuroprotection.
Surma et al. have used human stem cell differentiated retinal ganglion cells (hRGCs) of the CNS, which are highly sensitive towards mitochondrial dysfunctions due to their unique structure and function, to identify mechanisms for improving mitochondrial quality control (MQC).
They showed that hRGCs are efficient in maintaining mitochondrial homeostasis through rapid degradation and biogenesis of mitochondria under acute damage.
Using a glaucomatous Optineurin mutant (E50K) stem cell line, they showed that at basal level mutant hRGCs possess less mitochondrial mass and suffer mitochondrial swelling due to excess ATP production load.
Activation of mitochondrial biogenesis through pharmacological inhibition of the Tank binding kinase 1 (TBK1) restores energy homeostasis, mitigates mitochondrial swelling with neuroprotection against acute mitochondrial damage for glaucomatous E50K hRGCs, revealing a novel neuroprotection mechanism.
Image credit: © Surma et al. Commun Biol (2023).
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