Deletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease

doi:10.1016/0092-8674(90)90238-A

Cell

Volume 62, Issue 1, 13 July 1990, Pages 43-49

https://doi.org/10.1016/0092-8674(90)90238-A Get rights and content

Abstract

We mapped the distribution and expression of wild-type and deleted mitochondrial DNA (mtDNA) molecules in skeletal muscle fibers of patients with mitochondrial disease. We show that ragged red fiber segments, which are characteristic histological features of these myopathies, represent focal accumulations of mitochondria containing predominantly deleted mtDNAs and that the mutant genomes are absent or extremely rare in normal fiber segments. This suggests that the mtDNA mutations play a direct role in focal mitochondrial accumulation. Although levels of wild-type mtDNAs and mRNAs in ragged red fiber segments are near normal, mitochondrial function, as revealed by cytochrome oxidase cytochemistry, is severely impaired. This suggests that the presence of mutant mtDNAs interferes with the expression of co-existing wild-type mtDNAs in these segments at a posttranscriptional level.

References (30)

D. Bogenhagen et al.
The number of mitochondrial deoxyribonucleic acid genomes in mouse L and human HeLa cells
Quantitative isolation of mitochondrial deoxyribonucleic acid
J. Biol. Chem.
(1974)
E. Byrne et al.
Partial cytochrome oxidase (aa₃) deficiency in chronic progressive external ophthalmoplegia
Histochemical and biochemical studies
J. Neurol. Sci.
(1985)
M.A. Johnson et al.
A partial deficiency of cytochrome c oxidase in chronic progressive external ophthalmoplegia
J. Neurol. Sci.
(1983)
R.I. Koppe et al.
cDNA clone and expression analysis of rodent fast and slow skeletal muscle troponin I mRNAs
J. Biol. Chem.
(1989)
P. Lestienne et al.
Kearns-Sayre syndrome with muscle mitochondrial deletion
Lancet
(1988)
C.V. Lowry et al.
Enzyme patterns in single human muscle fibers
J. Biol. Chem.
(1978)
C.T. Moraes et al.
Heteroplasmy of mitochondrial genomes in clonal cultures from patients with Kearns-Sayre syndrome
Biochem. Biophys. Res. Commun.
(1989)
D.C. Wallace et al.
Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease
Cell
(1988)
R.S. Williams et al.
Regulation of nuclear and mitochondrial gene expression by contractile activity in skeletal muscle
J. Biol. Chem.
(1986)
S. Andersen et al.
Sequence and organization of the human mitochondrial genome
Nature
(1981)

N. Bresolin et al.

Progressive cytochrome c oxidase deficiency in a case of Kearns-Sayre syndrome: morphological, immunological and biochemical studies in muscle biopsies and autopsy tissues

Ann. Neurol.

(1987)

I.J. Holt et al.

Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies

Nature

(1988)

I.J. Holt et al.

Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA

Ann. Neurol.

(1989)

R. Manzanet et al.

The satellite cell

S. Mita et al.

Detection of “deleted” mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome

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Cell

ArticleDeletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease

Abstract

J. Biol. Chem.

J. Neurol. Sci.

J. Neurol. Sci.

J. Biol. Chem.

Lancet

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Cell

J. Biol. Chem.

Sequence and organization of the human mitochondrial genome

Nature

Progressive cytochrome c oxidase deficiency in a case of Kearns-Sayre syndrome: morphological, immunological and biochemical studies in muscle biopsies and autopsy tissues

Ann. Neurol.

Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies

Nature

Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA

Ann. Neurol.

The satellite cell

Detection of “deleted” mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome

Article
Deletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease