Mitocondrias

638

THE NEW ENGLAND JOURNAL OF MEDICINE

Sept. 7, 1995

REVIEW ARTICLE
SEMINARS IN MEDICINE
OF THE
BETH ISRAEL HOSPITAL, BOSTON

JEFFREY S. FLIER, M.D., Editor
LISA H. UNDERHILL, Assistant Editor

MITOCHONDRIAL DNA AND DISEASE
DONALD R. JOHNS, M.D.

T

HE mitochondrial encephalomyopathies are a diverse group of disorders that result from the structural, biochemical, or geneticderangement of mitochondria.1 Since mitochondrial dysfunction can affect
virtually all organ systems (Fig. 1), physicians in many
specialties see patients with mitochondrial diseases.
Despite a bewildering array of clinical manifestations
(Tables 1 and 2) and variations in the mode of onset,
course, and progression of disease, many mitochondrial disorders share prominent systemic effects(Table 2)
that contribute to their morbidity.
Our understanding of the role of mitochondrial
DNA in certain diseases has evolved rapidly since 1988,
when the first mutations in mitochondrial DNA were
discovered.2,3 Such mutations have subsequently been
identified in a variety of diseases,4-7 and the pathogenic
role of cumulative mitochondrial-DNA damage is being
explored in many common diseasesthat develop late in
life, and even in the aging process itself.
FUNCTION OF MITOCHONDRIAL
DNA
To understand mitochondrial disease, one must first
examine the unique features of mitochondrial DNA. Mitochondria generate energy for cellular processes by producing ATP through oxidative phosphorylation. These
organelles contain their own, extrachromosomal DNA,
which is distinct from DNA in thenucleus.8 Human
mitochondrial DNA (known as “the other human genome”) is a double-stranded, circular molecule that encodes 13 protein subunits of 4 biochemical complexes and the 24 structural RNAs (2 ribosomal RNAs
[rRNAs] and 22 transfer RNAs [tRNAs]) that are required for the intramitochondrial translation of the protein-coding units.9 Mitochondrial-DNA mutations have
been found in each typeof mitochondrial gene (Fig. 2).
STRUCTURE

A ND

From the Division of Neuromuscular Disease, Department of Neurology, Beth
Israel Hospital and Harvard Medical School, Boston. Address reprint requests to
Dr. Johns at Harvard Medical School, Bldg. B1-242, 220 Longwood Ave., Boston, MA 02115.
Supported by a grant (R01-EY10864) from the National Eye Institute.

Mitochondria, which probablyevolved from independent organisms that became part of the cell, are
able to replicate, transcribe, and translate their DNA
independently of nuclear DNA. However, cellular function and mitochondrial function are interdependent.10
Nuclear DNA encodes protein subunits of oxidative
phosphorylation and the myriad macromolecular compounds required for mitochondrial structure and function (e.g.,replication, transcription, and translation).
Proteins encoded by nuclear DNA must be imported
from the cytoplasm into the correct position within the
mitochondria.8 During oxidative phosphorylation, energy is derived from intermediary metabolites to produce
ATP by means of an electrochemical gradient. This biochemical process depends on the mitochondrial-DNA–
encoded tRNAs that cleave multigenetranscripts into
individual messenger RNAs and tRNAs.10
Several features of mitochondrial DNA may be related to its frequent association with disease. Mitochondrial DNA mutates more than 10 times as frequently as
nuclear DNA and has no introns, so that a random mutation will usually strike a coding DNA sequence. In addition, mitochondrial DNA has neither protective histones nor an effectiverepair system, and it is exposed
to oxygen free radicals generated by oxidative phosphorylation.
Mitochondrial DNA is inherited maternally and does
not recombine; mutations thus accumulate sequentially
through maternal lineages. Each mitochondrion contains 2 to 10 DNA molecules, and each cell contains
multiple mitochondria. Thus, normal and mutant mitochondrial DNA can coexist within the same...