(L) Corresponding author Thirumala-Devi Kanneganti, PhD, St. Jude Center of Excellence for Innate Immunity and Inflammation director and Department of Immunology vice chair and (R) and first author Yaqiu Wang, PhD, St. Jude Department of Immunology.
In several disease conditions, including infections and cancers, innate immune activation and nutrient scarcity occur together. A study from St. Jude Children’s Research Hospital published today in Cell found that this combination causes a unique type of cell death, named mitoxyperilysis. The research revealed that mitochondria persist near the cell membrane, causing local oxidative damage that results in the cells self-destructing, regulated by specific inflammatory and metabolic signaling pathways. They also found that this type of cell death can be therapeutically activated in cancer models to regress tumors, highlighting potential implications for cancer treatments.
“We discovered that innate immune and metabolic disruptions led to a synergistic effect activating a new cell death pathway that we characterized as mitoxyperilysis,” said corresponding author Thirumala-Devi Kanneganti, PhD, St. Jude Center of Excellence for Innate Immunity and Inflammation director and Department of Immunology vice chair. “Understanding cell death pathways is literally a matter of life and death. We believe that by mechanistically defining this new pathway, we’ve provided biochemical nodes that can be investigated for future lifesaving therapeutic interventions.”
Mitochondria power mitoxyperilysis at the cell membrane
Infections and other diseases, such as cancer, cause molecular alarm signals to be released in the body, activating the innate immune system. At the same time, infected or cancerous cells compete for the nutrients nearby, resulting in metabolic stress in the area. While scientists have studied both processes separately, they are rarely studied together, creating a major gap in our understanding of biological processes that occur in the body. When the researchers observed how the two worked together, they found that many cells went through a previously undescribed kind of inflammatory cell death.
Usually, mitochondria constantly move around in cells and perform their functions to provide energy. If they are damaged, they create reactive oxygen species, a dangerous version of the element oxygen that chemically reacts with nearby structures, causing cellular damage. When the St. Jude scientists combined innate immune activation and nutrient limitation, they found by microscopy that damaged mitochondria move near the cellular membrane. That proximity allowed these reactive oxygen species to assault the membrane until it breaks or “lyses,” leading to inflammatory cell death.
“We saw these mitochondria were stuck in contact with the cell membrane for a long period, until the cells burst at the contact sites,” said first author Yaqiu Wang, PhD, St. Jude Department of Immunology. “That mechanism is not known as a part of any other cell death pathway, showing mitoxyperilysis is a novel form of cell death.”
When the scientists looked for what molecules controlled mitoxyperilysis, they found a well-known metabolic signaling protein, mTOR. If they inhibited or deleted mTOR, cells would pull mitochondria back from the membrane, preventing cell lysis. They also found that both innate immune and metabolic signaling were essential for this process, with genetic evidence showing that deleting the innate immune receptor also prevented cell death.
A trial run of taming tumors
The researchers also found that mitoxyperilysis occurs in tumor cells, hinting at potential translational applications. Recent and ongoing clinical studies have already tried treating cancers with restricted diets to starve resource-hungry tumors, which have shown mixed success. Similarly, other studies have tried using innate immune activators to treat tumors. However, no clinical trials have combined the two. As this new study suggests innate immune activation and metabolic disruption are required together to promote cancer cell death, Kanneganti and her team tested this approach.
“It was very exciting to see that after two days of injecting a pro-inflammatory bacterial component to activate innate immunity in tumors of fasted mice, there was significant tumor regression,” said Wang.
Models that only received the innate immune activator, or that were fasted and did not receive the innate immune activator, did not have tumor size reductions. In contrast, those that received both innate immune activation and fasting had significantly reduced tumor size, as well as necrosis within those tumors, a sign of massive cell death. These cells also showed the hallmark molecular signature of mitoxyperilysis, including mitochondria at the periphery of lysed tumor cells. Future research will further investigate how to manipulate this novel pathway for therapeutic benefit.
“We discovered mitoxyperilysis by combining ideas from the innate immunity and cell death fields, scientific areas that are often siloed,” Kanneganti said. “In doing so, we defined a mechanism that could improve cancer treatments, as well as other therapeutic areas, demonstrating the power of synergism — both through combination therapy approaches and combining concepts from different research areas to ask scientific questions and make therapeutically-relevant fundamental discoveries.”
Authors and funding
The study’s other authors are Jianlin Lu, Alexandre Carisey, Sangappa Chadchan, Ha Won Lee, R.K.
Subbarao Malireddi, Bhesh Raj Sharma, Nagakannan Pandian, Rebecca Tweedell, Gustavo Palacios, Nathalie Becerra Mora, Camenzind Robinson, Aaron Pitre, Peter Vogel and Taosheng Chen, St. Jude; and Michael Murphy, University of Cambridge.
The study was supported by grants from the National Institutes of Health (AI101935, AI124346, AI160179, AR056296 and CA253095), National Cancer Institute (P30 CA021765), the Medical Research Council UK (MC_UU_00028/4), the Wellcome Trust Investigator award (220257/Z/20/Z) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
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