Investigators led by a group at Massachusetts General Hospital (MGH) have made discoveries on the single cell degree to uncover new particulars regarding mitochondrial diseases—inherited issues that intervene with vitality manufacturing within the physique and presently don’t have any treatment. The findings, that are revealed within the New England Journal of Medicine, may finally profit affected sufferers.
Mitochondrial diseases outcome from failure of mitochondria, specialised compartments inside cells that include their very own DNA and produce the vitality wanted to maintain life. Inherited mutations in mitochondrial DNA (mtDNA) usually trigger these diseases, and affected sufferers’ cells include a mix of mutant and nonmutant mtDNA—a phenomenon referred to as heteroplasmy. The proportion of mutant mtDNA varies throughout sufferers and amongst tissues inside a affected person. Also, signs vary from delicate to extreme and depend upon which cells of the physique are affected.
“It is generally accepted that the fraction of mutant heteroplasmy is what determines whether or not a tissue will exhibit disease. To better understand heteroplasmic dynamics, we applied a brand new genomics technology—with single cell resolution—in which we could simultaneously determine the cell type and the fraction of mutant heteroplasmy in thousands of individual blood cells,” mentioned senior creator Vamsi Ok. Mootha, MD, investigator within the Department of Molecular Biology at MGH.
The researchers examined mtDNA inside completely different blood cell varieties from 9 people with MELAS, probably the most widespread types of mtDNA illness related to mind dysfunction and stroke-like episodes, with a variety of severity throughout sufferers.
“What makes this study unique is that it is, to our knowledge, the first time anyone has been able to quantify the percentage of disease-causing mitochondrial DNA mutations in thousands of individual cells of different types from the same patient, as well as in multiple patients with inherited mitochondrial disease,” mentioned lead creator Melissa A. Walker, MD, Ph.D., an investigator within the Department of Neurology at MGH.
The analysis revealed particularly low ranges of heteroplasmy in T cells, which play essential roles in killing contaminated cells, activating different immune cells, and regulating immune responses.
“Our observations suggest that certain cell lineages within our body may have a process by which to guard against problematic mtDNA mutations, which is a potentially very exciting finding,” mentioned Walker.
Additional research are wanted to find out whether or not variations in heteroplasmy throughout immune cell varieties have an effect on the cells‘ perform, and whether or not assessing such heteroplasmy might assist clinicians diagnose and monitor mitochondrial diseases. “Our long-term vision is that single cell genomics may lead to improved blood tests for monitoring the progression of these diseases,” mentioned Mootha.
In addition, understanding the determinants of lowered T-cell heteroplasmy might encourage new therapeutic methods for mitochondrial diseases, which presently lack any FDA-approved therapies.
Mootha added that mtDNA mutations additionally happen spontaneously throughout regular getting old. “Although our work focused on rare, inherited diseases, it has potential implications for the heteroplasmic dynamics of aging as well,” he mentioned.
Melissa A. Walker et al, Purifying Selection towards Pathogenic Mitochondrial DNA in Human T Cells, New England Journal of Medicine (2020). DOI: 10.1056/NEJMoa2001265
Massachusetts General Hospital
Single-cell analysis provides new insights into mitochondrial diseases (2020, August 13)
retrieved 13 August 2020
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