Coordinate Induction of Energy Gene Expression in Tissues of Mitochondrial Disease Patients

doi:10.1074/jbc.274.33.22968

Coordinate Induction of Energy Gene Expression in Tissues of Mitochondrial Disease Patients*

From the ^‡Department of Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, the ^§Laboratoire de Biologie Appliquée, INSA-INRA, UA 203, INSA bâtiment 406, 20 avenue Albert Einstein, 69621 Villeurbanne cedex, France, the ^**Division of Medical Genetics, University of Miami School of Medicine, Mailman Center, Miami, Florida 33101, and the ^‖Laboratoire de Biochimie et Biologie Moléculaire A, CHU d’Angers, 4 rue Larrey, 49000 Angers, France

Abstract

We have examined the transcript levels of a variety of oxidative phosphorylation (OXPHOS) and associated bioenergetic genes in tissues of a patient carrying the myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) A3243G mitochondrial DNA (mtDNA) mutation and the skeletal muscles of 14 patients harboring other pathogenic mtDNA mutations. The patients’ tissues, which harbored 88% or more mutant mtDNA, had increased levels of mtDNA transcripts, increased nuclear OXPHOS gene transcripts including the ATP synthase β subunit and the heart-muscle isoform of the adenine nucleotide translocator, and increased ancillary gene transcripts including muscle mitochondrial creatine phosphokinase, muscle glycogen phosphorylase, hexokinase I, muscle phosphofructokinase, the E1α subunit of pyruvate dehydrogenase, and the ubiquinone oxidoreductase. A similar coordinate induction of bioenergetic genes was observed in the muscle biopsies of severe pathologic mtDNA mutations. The more significant coordinated expression was found in muscle from patients with the MELAS, myoclonic epilepsy with ragged red fibers, and chronic progressive external ophthalmoplegia deletion syndromes, with ragged red muscle fibers and mitochondrial paracrystalline inclusions. High levels of mutant mtDNAs were linked to a high induction of the mtDNA and nuclear OXPHOS genes and of several associated bioenergetic genes. These observations suggest that human tissues attempt to compensate for OXPHOS defects associated with mtDNA mutations by stimulating mitochondrial biogenesis, possibly mediated through redox-sensitive transcription factors.

Footnotes

↵* This work was supported by National Institutes of Health Grants HL45572, NS21328, and AG/3154 (to D. C. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¶ To whom correspondence should be addressed. Present address: Laboratoire de Biologie Appliquée, Bât. 406, INSA de Lyon, 20 av. Albert Einstein, 69621 Villeurbanne, France. Tel.: 33-4-72-43-88-68; Fax: 33-4-72-43-85-11; E-mail: heddi@insa.insa-lyon.fr.
Abbreviations:

mtDNA

mitochondrial DNA

ATPsynβ

ATPsynthase β

COI and COII

cytochrome coxidase I and II

CPEO

chronic progressive external ophthalmoplegia

FSHMD

facio-scapulo-humeral muscular dystrophy

HKI

hexokinase I

KSS

Kearn’s-Sayre Syndrome

LHON

Leber’s hereditary optic neuropathy

mCCK

muscle cytosolic creatine kinase

MDMD

maternally transmitted diabetes mellitus and deafness

MELAS

myopathy, encephalopathy, lactic acidosis, and stroke-like episodes

MERRF

myoclonic epilepsy with ragged red fibers

mGP

muscle glycogen phosphorylase

mMtCK

muscle mitochondrial creatine phosphokinase

mPFK

muscle phosphofructokinase

mPK

muscle pyruvate kinase

NARP

neurogenic muscle weakness, ataxia, and retinitis pigmentosis

ND

NADH dehydrogenase

nDNA

nuclear DNA

OXPHOS

oxidative phosphorylation

PCI

paracrystalline inclusions

PDH

pyruvate dehydrogenase

ElαPDH

Elα subunit of pyruvate dehydrogenase

RRF

ragged red muscle fiber

kb

kilobase(s)

np

nucleotide pair

Ub

ubiquitin

cytb

cytochromeb

ANT1

adenine nucleotide translocator isoform 1
- Received March 2, 1999.
- Revision received May 20, 1999.
The American Society for Biochemistry and Molecular Biology, Inc.