When it comes to repairing injured tissue, specialized cells in the body known as fibroblasts are called into action. Fibroblasts give rise to healing cells called myofibroblasts, which generally is good in the short term - but bad when myofibroblast activation gets out of hand. In new work researchers show how fibroblast activation and myofibroblast formation occurs, providing clues as to how to target fibrosis - which impacts several chronic diseases. Kickstarting the process are stress-induced changes in mitochondrial calcium uptake.
The report, published in the journal Nature Communications, describes in detail the novel signaling pathway by which reduced calcium uptake in mitochondria serves as the major regulator of myofibroblast differentiation and fibrosis. When mitochondrial calcium levels drop, cellular metabolism changes and a metabolite known as α-ketoglutarate is upregulated. Increased α-ketoglutarate levels in turn alter the packaging of cellular DNA, changing gene expression for the conversion of fibroblasts into fibrosis-mediating myofibroblasts.
"When fibroblast signaling alters mitochondrial calcium uptake, many metabolic changes occur to promote anabolic pathways to support the formation of these new cells and provide new sources of energy production," said senior investigator on the new study. "These changes are necessary for the new role of these cells to alter the cellular environment in an attempt to repair the injured tissue."
While myofibroblast formation is associated with acute wound healing - think the closing of a cut on the skin - the persistence of these cells can give rise to fibrotic diseases, such as liver cirrhosis, pulmonary fibrosis and heart failure.
"Our experiments show that the accumulation of fibrotic cells results directly from mitochondrial calcium-dependent genomic reprogramming involving α-ketoglutarate, which changes the structure of chromatin, or DNA packaging - a phenomenon referred to as epigenetics and that is important in regulating gene expression," the senior author said. This the first time that extracellular signals directly modifying mitochondrial function have been linked to alterations in the cell nucleus for the generation of myofibroblasts.
"The key finding, that a change in mitochondrial calcium uptake plays a central role in metabolic and genetic reprogramming, presents new opportunities for investigation," explained the senior author. "We hope that the new pathways we've identified as essential to myofibroblast formation can be manipulated to treat fibrotic disease."
https://www.templehealth.org/about/news/temple-scientists-identify-new-targets-to-treat-fibrosis-a-feature-of-many-chronic-diseases
https://www.nature.com/articles/s41467-019-12103-x
Linking metabolism with the epigenome to control cellular differentiation via mitochondrial calcium exchange
- 1,326 views
- Added
Edited
Latest News
Metabolic rewiring promotes…
By newseditor
Posted 18 Apr
A drug to prevent flu-induc…
By newseditor
Posted 18 Apr
New origin of deep brain waves
By newseditor
Posted 17 Apr
Starving cells hijack prote…
By newseditor
Posted 17 Apr
Miniature battery-free epid…
By newseditor
Posted 17 Apr
Other Top Stories
Mature heart muscle cells created in the laboratory from stem cells
Read more
Cell of origin affects malignancy and drug sensitivity of brain tumors
Read more
Protein essential for healthy gut cell development identified!
Read more
Reprogramming of liver cells to pancreas progenitor cells based on…
Read more
The intestine has a reservoir of stem cells that are resistant to c…
Read more
Protocols
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Modular dual-color BiAD sen…
By newseditor
Posted 31 Mar
Publications
How does the microbiota con…
By newseditor
Posted 18 Apr
The integrated stress respo…
By newseditor
Posted 18 Apr
The immunobiology of herpes…
By newseditor
Posted 17 Apr
Circulating microbiome DNA…
By newseditor
Posted 17 Apr
Spindle oscillations in com…
By newseditor
Posted 17 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar