Correspondence
Mitochondrial DNA and Disease
N Engl J Med 1996; 334:270-271January 25, 1996
- Article
To the Editor:
We were quite surprised that the remarkable review of mitochondrial DNA and disease by Johns (Sept. 7 issue)1 ended with the assumption that the American cyclist Greg LeMond retired in 1994 because of a “mitochondrial myopathy.” The genetics of mitochondrial DNA still present several enigmas, and certain mutations can be present at birth and become clinically manifest only in adulthood.2 Nevertheless, we think that the ATP-generating capacity of Greg LeMond's muscles should have fallen below their energy threshold well before 1993, the year of his last Tour de France race. The mitochondrial genome has an underdeveloped DNA-repair system and is liable to mutations provoked by exogenous as well as endogenous factors. So far, the only acquired mitochondrial myopathy identified is the one caused by long-term zidovudine therapy,3 and obviously, such an abnormality is not responsible for this champion's pathologic process.
Having had the privilege to follow Greg medically during certain of his races, we are very doubtful about the diagnosis of mitochondrial myopathy. Greg won the Tour de France three times (in 1986, 1989, and 1990). Each Tour de France includes at least 21 consecutive days of racing. The energy expenditure per day is estimated to be between 8000 and 9000 calories, especially when the course includes roads that wind up and down through the Alps and the Pyrenees.
A person with a genuine mitochondrial myopathy could not finish even one day of such a race and would not be selected to compete in this fantastic sporting event, which involves the 200 best cyclists in the world. Recently, Valberg et al.4 reported that, after running a mere five minutes, an Arabian mare had numerous abnormal mitochondria and complex I insufficiency (NADH coenzyme Q reductase) on muscle biopsy. It is very probable that Greg LeMond had a few modified mitochondria in his lower limbs, as we have found in other champion cyclists, especially those hampered by severe cramps.5 In addition, it is well known that abnormal mitochondria can be observed by electron-microscopical examination of muscle-biopsy specimens from patients with many disorders other than mitochondrial myopathy.5 Even though we know that age can reveal a mitochondrial myopathy,2 we think that such is not the case for Greg LeMond. He won his third Tour de France in 1990, and as enthusiastic fans of cycling races, we can hardly believe that such a gifted champion was already suffering from a mitochondrial myopathy. We think that all those who have won the Tour de France might have their mothers to thank for providing them with extraordinarily powerful mitochondria.
5 ReferencesHervé Stoicheff, M.D.
Claude Vital, M.D.
Université Bordeaux II, 33076 Bordeaux, France1
Johns DR . Mitochondrial DNA and disease. N Engl J Med 1995;333:638-644
Full Text | Web of Science | Medline2
Wallace DC . Diseases of the mitochondrial DNA. Annu Rev Biochem 1992;61:1175-1212
CrossRef | Web of Science | Medline3
Dalakas MC ,Illa I ,Pezeshkpour GH ,Laukaitis JP ,Cohen B ,Griffin JL . Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990;322:1098-1105
Full Text | Web of Science | Medline4
Valberg SJ ,Carlson GP ,Cardinet GH III , et al. Skeletal muscle mitochondrial myopathy as a cause of exercise intolerance in a horse. Muscle Nerve 1994;17:305-312
CrossRef | Web of Science | Medline5
Vital C ,Coquet M ,Bellocq F ,Letellier T ,Vital T ,Mazat JP . Anomalies mitochondriales régressives dans la biopsie musculaire d'un champion cycliste. Arch Anat Cytol Pathol 1993;41:145-148
Medline
To the Editor:
In his excellent review of mitochondrial DNA and disease, Johns indicated that mitochondria can replicate, transcribe, and translate their DNA independently of nuclear DNA. This does not seem to be quite correct, though he referred to the interdependency of cellular and mitochondrial function. It is now generally accepted that all of the mitochondrial-DNA replication enzymes are encoded by the nucleus.1 The nucleus contains DNA encoding proteins for the replication, transcription, and translation of mitochondria as well as 80 percent of the subunits for oxidative phosphorylation.1 In some patients with familial chronic progressive external ophthalmoplegia with multiple deletions of mitochondrial DNA and in patients with idiopathic cardiomyopathy, the mutations are transmitted in an autosomal dominant fashion,2 instead of maternally, supporting the hypothesis of a nuclear gene defect in these patients.3 Duplications of mitochondrial DNA are generally observed in autosomal dominant cases of mitochondrial myopathy, as well as in the maternally inherited form, and it has been suggested that some duplicated mitochondrial DNA may be transmitted in the germ line.4 These observations suggest that nuclear DNA is involved in the replication, transcription, or translation of mitochondrial DNA. In fact, in a recent study,5 an autosomal dominant progressive external ophthalmoplegia was assigned to locus 10q23.3–24.3 of the nuclear chromosome by linkage analysis. The gene encoding mitochondrial transcription factor A (previously called mtTF1), which is located on 10q, has also been reported to regulate the transcription of mitochondrial DNA through binding to mitochondrial DNA promoters.5 It seems likely that after a long process of evolution, mitochondria, which presumably used to be independent organisms, have become dependent on the nucleus for their replication and transcription.
5 ReferencesMasato Odawara, M.D.
Kamejiro Yamashita, M.D.
University of Tsukuba, 305, Japan1
Wallace DC . Diseases of the mitochondrial DNA. Annu Rev Biochem 1992;61:1175-1212
CrossRef | Web of Science | Medline2
Odawara M ,Yamashita K . Idiopathic dilated cardiomyopathy. N Engl J Med 1995;332:1385-1385
Web of Science | Medline3
Poulton J ,Deadman ME ,Ramacharan S ,Gardiner RM . Germ-line deletions of mtDNA in mitochondrial myopathy. Am J Hum Genet 1991;48:649-653
Web of Science | Medline4
Poulton J ,Holt IJ . Mitochondrial DNA: does more lead to less? Nat Genet 1994;8:313-315
CrossRef | Web of Science | Medline5
Suomalainen A ,Kaukonen J ,Amati P , et al. An autosomal locus predisposing to deletions of mitochondrial DNA. Nat Genet 1995;9:146-151
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Johns replies:
To the Editor: I concur with Drs. Odawara and Yamashita that there is a great deal of interdependence of the nuclear and mitochondrial genomes. All mitochondrial proteins, except the 13 mitochondrial-DNA–encoded subunits of oxidative phosphorylation, are encoded by nuclear DNA. However, the processes of mitochondrial-DNA replication, transcription, and translation are distinctive from and independent of the equivalent processes for nuclear DNA. Two separate, independent sets of nuclear-DNA–encoded factors subserve these processes for mitochondrial and nuclear DNA. The precision of the intergenomic communication is illustrated by the coordinate regulation of nuclear-DNA–encoded oxidative phosphorylation genes and their mitochondrial-DNA–encoded counterparts. These genes must be coordinately transcribed and translated, and the proteins must ultimately be assembled in the correct stoichiometric ratio in the inner mitochondrial membrane to form functional complexes I, III, IV, and V of oxidative phosphorylation.
At a press conference in Los Angeles in December 1994, the American cyclist Greg LeMond announced his retirement from competitive cycling because of a “mitochondrial myopathy.”1 This announcement has been a seminal event in the public awareness of the mitochondrial disorders. I have received numerous calls from patients known to have mitochondrial disease and those who suspect that they might be so afflicted who have conveyed the importance of having a public figure associated with these disorders. I do not know the basis of the diagnosis in the case of Mr. LeMond, but given the ever-expanding phenotypic spectrum of the mitochondrial disorders, one must not be dogmatic and rigid about these emerging diseases.
1 ReferencesDonald R. Johns, M.D.
Beth Israel Hospital, Boston, MA 02215
