Summary: Restoring mitochondrial homeostasis in diseased neurons can protect the optic nerve from being damaged and potentially reverse glaucoma symptoms.
Source: Indiana University
Indiana University School of Medicine researchers have identified a new therapeutic target that could lead to a 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 new paper published in Biology of communicationresearchers have found that neurons use mitochondria for a stable source of energy, and restoring mitochondrial homeostasis in diseased neurons can protect optic nerve cells from being damaged.
“Age-related neurodegenerative disease, which includes glaucoma, Parkinson’s disease and amyotrophic lateral sclerosis (ALS), is the largest global health problem,” said Arupratan Das, Ph.D., assistant professor of ophthalmology and principal investigator of the study.
“The fundamental mechanisms that we have discovered can be used to protect neurons in glaucoma and be tested for other diseases. We have identified a critical step of the complex process of mitochondrial homeostasis, which rejuvenates the dying neuron, similar to giving a salvation 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, and clustered regularly interspaced short palindromic repeats (CRISPR) engineered human embryonic stem cells. with glaucoma. mutation
Using retinal ganglion cells differentiated from optic nerve stem cells (hRGCs), electron microscopy and metabolic analysis, the researchers identified glaucomatous retinal ganglion cells suffering from mitochondrial deficiency with more metabolic load in each mitochondria. This leads to mitochondrial damage and degeneration. Mitochondria are tube-like structures in cells that produce adenosine triphosphate, the cell’s source of energy.
However, the process could be reversed by enhancing mitochondrial biogenesis by a pharmacological agent. The team showed that retinal ganglion cells are very efficient in degrading bad mitochondria, but at the same time they produce more to maintain homeostasis.
“Finding that retinal ganglion cells with glaucoma produce more adenosine triphosphate even with fewer mitochondria was amazing,” said Das.
“However, when it is activated to produce more mitochondria, the load of adenosine triphosphate production is distributed among more mitochondria that restore the physiology of the organ. It is similar to a situation where a heavy stone is carried by fewer people versus a larger number of people – each person will have less pain and injuries, as each mitochondria will have less difficulties and damage”.
In the future, Das wants to test whether these mechanisms protect the optic nerve in animal models under injury before testing in humans, hoping to lead to new clinical interventions.
About this visual neuroscience research news
Author: Press office
Source: Indiana University
Contact: Press Office – Indiana University
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Original search: Open access.
“Enhanced mitochondrial biogenesis promotes neuroprotection in human pluripotent stem cell-derived retinal ganglion cells” by Michelle Surma et al. Biology of communication
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Abstract
Enhanced mitochondrial biogenesis promotes neuroprotection in human pluripotent stem cell-derived retinal ganglion cells
Mitochondrial dysfunctions are widely afflicted in central nervous system (CNS) disorders with minimal understanding of how to improve mitochondrial homeostasis to promote neuroprotection.
Here we used retinal ganglion cells differentiated from human stem cells (hRGCs) of the CNS, which are very sensitive towards mitochondrial dysfunction due to their unique structure and function, to identify mechanisms to improve mitochondrial quality control (MQC) .
We show that hRGCs are effective in maintaining mitochondrial homeostasis through rapid degradation and biogenesis of mitochondria under acute damage.
Using a glaucomatous Optineurin mutant (E50K) stem cell line, we show that at the basal level mutant hRGCs possess less mitochondrial mass and suffer mitochondrial swelling due to the burden of excessive ATP production.
Activation of mitochondrial biogenesis through pharmacological inhibition of Tank binding kinase 1 (TBK1) restores energy homeostasis, mitigates mitochondrial inflammation with neuroprotection against acute glaucomatous mitochondrial damage. E50K hRGCs, which reveal a new mechanism of neuroprotection.