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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10 Years on Ferroptosis Discovery: Potential in Disease Treatment

News Release, World Mitochondria Society, Berlin - Germany – February 20, 2023

A new journal article by Columbia professor Brent R. Stockwell marks the ten-year anniversary of the discovery of ferroptosis, a form of cell death that could help treat life-threatening illnesses like cancer.

The average person’s body replaces around 1% of its cells – roughly 330 billion of them – per day. Some cells, like the webbing between fetuses’ fingers and toes, which grows and then disappears before birth, die as a normal part of development. Other cells die of something much like old age; they’re simply programmed to turn out the lights once they’ve done their job. Far scarier than cell death is when cells that should die, don’t, and instead accumulate, causing problems like autoimmune conditions and cancer.

Ten years ago, a team of researchers at Columbia led by Professor Brent R. Stockwell announced a new discovery: A novel kind of cell death that they named “ferroptosis.” When cells undergo ferroptosis, their inner and outer membranes degrade, springing leaks that eventually cause the cell to die. A decade after that initial discovery, Professor Stockwell has released a journal article in Cell this month that assesses what researchers have discovered about ferroptosis in the last 10 years, and how their findings may help treat life-threatening illnesses like cancer and neurodegenerative disease.

“In the ten years since my lab identified its existence, ferroptosis has offered crucial new information on how cells function, and providing insights on how it can help treat disease,” Stockwell said. “We’re confident that over the next decade, ferroptosis will teach us even more.”

Scientists generally recognized three “classic” forms of cell death: Apoptosis, autophagic cell death, and necrosis. Apoptosis occurs naturally in various contexts, such as during fetal development and when cells program themselves to turn off once they’ve aged. In autophagy, damaged cells self-destruct, allowing healthier cells to incorporate their remaining viable material. Necrosis occurs when cells experience trauma, like being cut off from blood supply or infected by disease.

Each of these forms of cell death follows a pattern: In the case of apoptosis, for example, the cell and its nucleus shrink as the cell’s outer layer forms blisters known as blebs. Then, the nucleus collapses as the blisters continue to form. Eventually, the entire cell ruptures, breaking into smaller pieces that float through the bloodstream until they’re swept up by the body’s clean-up cells.

In 2001, while working in his lab, Professor Stockwell started to notice something new: In certain tumor cells treated with a novel chemical he identified, the cells were dying differently and in a manner that depended on their store of iron. Rather than following the patterns observed in apoptosis, these cells were being destroyed primarily because the lipids that form their outer membrane were disintegrating, as he later discovered. The well-known patterns of apoptosis (blebbing, a shrinking nucleus, and so on) didn’t apply. He later ruled out other known forms of cell death as well.

“When I first saw this in my lab, I couldn’t believe it; I had never seen cells die this way, and we knew the implications for the world would be enormous,” Stockwell said. It took 11 years from his initial observation in 2001 until he and his labmembers published their results in 2012, and named the new cell death ferroptosis.

Since 2012, Stockwell and other researchers around the world have conducted numerous studies to understand more about ferroptosis and how it works. They’ve demonstrated that ferroptosis occurs naturally across a range of species, helping execute normal processes that keep organisms running smoothly, like suppressing tumors, and regulating aging.

Researchers have discovered that ferroptosis also occurs in harmful contexts, killing healthy cells in patients with diseases like Parkinson’s, Alzheimer’s and Lou Gehrig’s disease. Ferroptosis can also be triggered by invasive pathogens: A 2021 study indicates that COVID-19 may activate ferroptosis, killing healthy cells during infection.

Though ferroptosis can be destructive, recent studies indicate that it could also be harnessed for good, and may eventually prove a vital tool for fighting disease. Both cancer and autoimmune conditions occur when cells that should die fail to do so. Intentionally inducing ferroptosis could counteract that process, killing cells that should die naturally. 

Recent research into links between cancer and ferroptosis has proved particularly fruitful. Several studies conducted over the last several years have shown that deliberately inducing ferroptosis may help stop rampant cancer cell growth in a range of tissues, including lung and pancreas tissue. As scientists learn more, they’ll understand how to best harness ferroptosis to kill dangerous tumor cells in a targeted way.

“We’re so committed to this research because we can see its vast potential,” Stockwell said. “Over the next decade, we hope to unlock all of the life-saving possibilities we can from this discovery. This is a whole new area of of biology that we have unlocked, and we think it will continue to transform biology and medicine.”

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Image Credit: Illustration by Nicoletta Barolini

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.

Acess full article.

Image credit: © Surma et al. Commun Biol (2023).

The secret of slow human brain growth

Mouse neurons (left) and a human neuron (right). Mitochondria displayed in green.

News Release, World Mitochondria Society, Berlin - Germany – January 30, 2023

It takes several years for the human brain to develop fully, whereas this happens much faster in other species. The slow maturation of the human brain is thought to be important for its function, but it was unknown what caused this. Now, a team of researchers led by Ryohei Iwata, Pierre Casimir, and Pierre Vanderhaeghen (VIB-KU Leuven Center for Brain & Disease Research and ULB) found that the mitochondria, the energy factory in the brain cells, are responsible for the rate at which the brain develops. This discovery sheds light on human evolution and may have important implications for brain function and diseases. Their work was published in Science.

Pierre Vanderhaeghen: “We discovered that mitochondria set the tempo of neuronal maturation. Neurons have an hourglass inside to measure time, and mitochondria provide that hourglass. This revelation is an important step to understand one of the greatest mysteries in biology: what makes the human brain so distinct from other species, and why is it so sensitive to some diseases? Our findings can also be used to speed up basic and pharmaceutical research into human neurological or psychiatric diseases, which up until now was greatly hindered by slow human neuronal development.”