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Ann Neurol. 2018 Jan;83(1):115-130. doi: 10.1002/ana.25127.

Pathological mechanisms underlying single large-scale mitochondrial DNA deletions.

Author information

1
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom.
2
National Health Service Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals, National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom.
3
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX.
4
Institute for Exercise and Environmental Medicine of Texas Health Presbyterian Hospital, Dallas, TX.

Abstract

OBJECTIVE:

Single, large-scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large-scale mtDNA deletions in skeletal muscle.

METHODS:

We investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large-scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction.

RESULTS:

We have defined 3 "classes" of single, large-scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class.

INTERPRETATION:

Combining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex-specific protein-encoding genes. Furthermore, removal of mt-tRNA genes impacts specific complexes only at high deletion levels, when complex-specific protein-encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115-130.

PMID:
29283441
PMCID:
PMC5893934
DOI:
10.1002/ana.25127
[Indexed for MEDLINE]
Free PMC Article

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