Single-cell analysis provides new insights into mitochondrial diseases


Date:
August 13, 2020
Source:
Massachusetts General Hospital
Summary:
Investigators have made discoveries at the single cell level to
uncover new details concerning mitochondrial diseases -- inherited
disorders that interfere with energy production in the body and
currently have no cure.



FULL STORY ========================================================================== Investigators led by a team at Massachusetts General Hospital (MGH)
have made discoveries at the single cell level to uncover new details concerning mitochondrial diseases -- inherited disorders that interfere
with energy production in the body and currently have no cure. The
findings, which are published in the New England Journal of Medicine,
could eventually benefit affected patients.


========================================================================== Mitochondrial diseases result from failure of mitochondria, specialized compartments within cells that contain their own DNA and produce the
energy needed to sustain life. Inherited mutations in mitochondrial
DNA (mtDNA) often cause these diseases, and affected patients' cells
contain a mixture of mutant and nonmutant mtDNA -- a phenomenon called heteroplasmy. The proportion of mutant mtDNA varies across patients and
among tissues within a patient. Also, symptoms range from mild to severe
and depend on which cells of the body 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," said senior author
Vamsi K. Mootha, MD, investigator in the Department of Molecular Biology
at MGH.

The researchers examined mtDNA within different blood cell types from
9 individuals with MELAS, one of the most common forms of mtDNA disease associated with brain dysfunction and stroke-like episodes, with a wide
range of severity across patients.

"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," said lead author Melissa A. Walker,
MD, PhD, an investigator in the Department of Neurology at MGH.

The analysis revealed especially low levels of heteroplasmy in T cells,
which play important roles in killing infected cells, activating other
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," said Walker.

Additional studies are needed to determine whether differences in
heteroplasmy across immune cell types affect the cells' function, and
whether assessing such heteroplasmy may help 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," said
Mootha.

In addition, understanding the determinants of reduced T-cell heteroplasmy
may motivate new therapeutic strategies for mitochondrial diseases,
which currently lack any FDA-approved treatments.

Mootha added that mtDNA mutations also occur spontaneously during
normal aging.

"Although our work focused on rare, inherited diseases, it has potential implications for the heteroplasmic dynamics of aging as well," he said.


========================================================================== Story Source: Materials provided by Massachusetts_General_Hospital. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Melissa A. Walker, Caleb A. Lareau, Leif S. Ludwig, Amel Karaa,
Vijay G.

Sankaran, Aviv Regev, Vamsi K. Mootha. Purifying Selection against
Pathogenic Mitochondrial DNA in Human T Cells. New England Journal
of Medicine, 2020; DOI: 10.1056/NEJMoa2001265 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200813131251.htm

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