UCI-led research team catalogs mitochondria deletions in the human brain using a single test

Irvine, Calif. - April 11, 2019 – In a recent University of California, Irvine-led study published in Nucleic Acids Research, a team of scientists described a catalog of 4489 putative mitochondrial DNA (mtDNA) deletions, including their frequency and relative read rate.  This catalog comprises the first comprehensive database of mitochondrial deletions derived from human brain.

Mitochondria have the principal responsibility of providing every nucleated cell in the body with the energy it needs to function properly. Humans who suffer from missing or broken mitochondrial genes often display muscular and/or neurological symptoms. 

The results of the study, involving the analyses of 93 samples from postmortem brain and blood, found the mitochondria 4977 bp ‘common deletion’ was neither the most frequent deletion nor the most abundant indicating that the brain and blood contained a spectrum of large deletions in mtDNA. Many high-frequency deletions were previously reported in MitoBreak, the mitochondrial DNA breakpoints database, suggesting the spectrum of mtDNA deletions are present at low levels in metabolically active tissues and are not exclusive to individuals with diagnosed mitochondrial pathologies. Many individual deletions (and cumulative metrics) had significant and positive correlations with age. The highest deletion burdens were observed in major depressive disorder brain, at levels comparable to or greater than Kearns–Sayre Syndrome, a neuromuscular disease with a mitochondria cause. Collectively, these data suggest the Splice-Break pipeline, developed by former UCI postdoctoral researcher Brooke Hjelm, PhD, can detect and quantify mtDNA deletions at a high level of resolution.

“Taken together, the pipeline will enable us to look in many brain regions for an accumulation of damage to mitochondria DNA for individuals with various psychiatric symptoms such as depression and psychosis.  The ultimate use will be to test other more accessible samples such as blood, saliva, or cerebrospinal fluid from patients to estimate the damage to mitochondria, and quickly identify those individuals who may benefit from drugs and other treatments that give a mitochondria boost and improve psychiatric symptoms,” said Marquis P. Vawter, PhD, who led the UCI team in the Department of Psychiatry and Human Behavior at the UCI School of Medicine.

Previously, using conventional techniques, high levels of mitochondria deletions could only be detected by looking at one mutation at a time in a sequencing reaction. The Splice-Break pipeline speeds the discovery of damaged mitochondria and is sensitive to small amounts of deletions, allowing researchers to find literally hundreds of different breakpoint regions in mitochondria.

“This technique allows us to use a single test to measure the accumulation of many types of these deletions and to determine an overall burden of these deletions upon mitochondria functions,” said Vawter who is conducting larger-scale studies with a potentially faster turn-around of one day.

Large mitochondrial DNA (mtDNA) deletions causing human disease were first reported for ‘mitochondrial myopathies’ and Kearns–Sayre syndrome (KSS) roughly 30 years ago. Other disorders that are attributed to large mtDNA deletions include Pearson Syndrome (PS), chronic progressive external ophthalmoplegia (CPEO), Leigh syndrome, and diabetes mellitus. There is evidence that mitochondrial deletions may be responsible for other human disorders, especially in diseases that present with neurological or muscular dysfunction, are progressive or degenerative, and/or affect multiple tissues and organ systems. Further study of schizophrenia, bipolar disorder, and major depression are underway using the Splice-Break pipeline and other rapid testing protocols.

The principal investigator of the study, Marquis P. Vawter, PhD received support from the National Institute of Mental Health (NIMH) to study mitochondria dysfunction in psychiatric disorders (R01MH08580, R21MH099440). This study was funded by the Della Martin Foundation award to Brooke Hjelm, PhD, a Della Martin Fellow.  The collection of human brain samples at UCI was funded by Pritzker Neuropsychiatric Disorders Research Consortium.

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