Defense or repair: How immune cells are controlled during wound healing

A Cologne-based research team has discovered that the metabolism of mitochondria, the energy suppliers of cells, in macrophages coordinate wound healing to a significant degree. Macrophages belong to the white blood cells and are also known as scavenger cells. Professor Dr. Sabine Eming and her collaborators and colleagues at the CECAD Cluster of Excellence for Aging Research at the University of Cologne showed that wound macrophages undergo different metabolic programs during tissue repair, which are required to support the successive phases for skin reconstruction after injury. 

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Full article link: http://dx.doi.org/10.1016/j.cmet.2021.10.004

Image source:Hand photo created by shayne_ch13 - www.freepik.com

How some tissues can “breathe” without oxygen

Humans need oxygen molecules for a process called cellular respiration, which takes place in our cells’ mitochondria. Through a series of reactions called the electron transport chain, electrons are passed along in a sort of cellular relay race, allowing the cell to create ATP, the molecule that gives our cells energy to complete their vital functions. 

In the past, however, scientists have noticed that cells are able to maintain some functions of the electron transport chain, even in the absence of oxygen. “This indicated that mitochondria could actually have partial function, even when oxygen is not the electron acceptor,” said Whitehead Institute postdoctoral researcher Jessica Spinelli. “We wanted to understand, how does this work? How are mitochondria capable of maintaining these electron inputs when oxygen is not the terminal electron acceptor?”

In a paper published December 2 in the journal Science, Whitehead Institute scientists and collaborators led by Spinelli have found the answer to these questions. Their research shows that when cells are deprived of oxygen, another molecule called fumarate can step in and serve as a terminal electron acceptor to enable mitochondrial function in this environment. The research, which was completed in the laboratory of former Whitehead Member David Sabatini,  answers a long-standing mystery in the field of cellular metabolism, and could potentially inform research into diseases that cause low oxygen levels in tissues, including ischemia, diabetes and cancer.

The World Mitochondria Society will highlight this topic in the "13th Targeting Mitochondria Congress 2022".

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The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites

Submitochondrial localization of Mgm1/OPA1 protein as determined by immuno-electron microscopy. Credits: Loss of the Intermembrane Space Protein Mgm1/OPA1 Induces Swelling and Localized Constrictions along the Lengths of Mitochondria - Scientific Figure on ResearchGate.

The conversion of white to brown/beige adipocytes is a possible therapeutic strategy for tackling the current obesity epidemics. Mitochondria are known to be key for energy dissipation in brown fat, but it is unknown if they can drive adipocyte browning. In this study, they showed that the mitochondrial cristae biogenesis protein optic atrophy 1 (Opa1) facilitates cell-autonomous adipocyte browning.

They reported that, Adipose tissue OPA1 levels were reduced in two cohorts of patients with obesity. Also, the overexpression of Opa1 in mouse favored white adipose tissue expandability as well as browning, improving glucose tolerance and insulin sensitivity. 

They identified, using transcriptomics and metabolomics analyses, Jumanji family chromatin remodeling protein Kdm3a and urea cycle metabolites, including fumarate, as effectors of Opa1-dependent browning.

They indicated, using flux analyses, that Opa1-dependent fumarate accumulation is dependent on the urea cycle.

In conclusion, they stated that the urea cycle links the mitochondrial dynamics protein Opa1 to white adipocyte browning.

Authors: Bean, C., Audano, M., Varanita, T. et al.

DOI: https://doi.org/10.1038/s42255-021-00497-2

Cancer Cells Strengthen by Sucking Mitochondria out of Immune Cells Using ‘Tiny Tentacles’, Study Finds

Cancer cells gain strength by forming “tiny tentacles” that suck the power out of immune cells, a recent study that could help develop new drug targets against the malignant disease has suggested.

Credits to National Cancer Institute

Left: Microscopic image shows formation of a nanotube between a breast cancer cell and an immune cell.
Right: Image shows mitochondria (labeled with green fluorescence dye) traveling from a T cell to a cancer cell through the intercellular nanotube.

Scientists from Brigham and Women's Hospital and MIT employed nanotechnology to identify a novel method that cancer may neutralize its would-be cellular adversaries. Immune cells are depleted, and cancer cells are boosted by slurping out the immune cell's mitochondria. Research published in Nature Nanotechnology suggests that the next generation of cancer immunotherapy may have a different target.

Shiladitya Sengupta, the corresponding author of the study and co-director of the Brigham's Center for Engineered Therapeutics, stated, "Cancer kills when the immune system is inhibited, and cancer cells are allowed to spread, and it looks that nanotube may help them accomplish both." When it comes to cancer cells evading the immune system, "this is an entirely new process, and it provides us with a new target to pursue. "Sengupta and colleagues co-cultured breast cancer cells with immune cells such as T cells to study the nanoscale interactions between cancer cells and immune cells. They noticed something strange when they used field-emission scanning electron microscopy: Immune cells and cancer cells seemed to be physically linked by thin tendrils, with diameters ranging from 100 to 1000 nanometers. Some of the nanotubes formed thicker tubes as they came together. As a result, they used a fluorescent dye to label mitochondria from T cells. They observed that the mitochondria were sucked out of the immune cells and delivered to cancer cells through the nanotube system.

According to co-corresponding author Hae Lin Jang, Ph.D., a principal investigator at the Center for Engineered Therapeutics, "by carefully preserving the cell culture condition and observing intracellular structures, we saw these delicate nanotubes, and they were stealing the energy source of the immune cells." In cancer cells, this type of activity has never been seen previously. When working with nanotubes, which are pretty delicate, we had to be extremely careful with the cells to avoid damaging them.The scientists next investigated what would happen if they blocked the cancer cells from gaining access to mitochondria. Using mice models of lung and breast cancer, scientists found that tumor development was significantly reduced when an inhibitor of nanotube production was administered.

"Finding combinations of medicines that potentially enhance outcomes is one of the aims of cancer immunotherapy," said lead author Tanmoy Saha, Ph.D., a postdoctoral researcher at the Center for Engineered Therapeutics. "Based on our findings, it seems that a nanotube formation inhibitor might be paired with cancer immunotherapies and examined to determine whether it improves patient outcomes."

Reference:
Saha, T., Dash, C., Jayabalan, R. et al. Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nat. Nanotechnol. (2021). 

https://doi.org/10.1038/s41565-021-01000-4