EDITORIAL
Drilling for Energy in Mitochondrial Disease
T
HE CATALOG OF MITOCHONDRIAL AND
nuclear DNA mutations that impair the
synthesis, assembly, or maintenance of pro-
teins necessary for the function of the mi-
tochondrial respiratory chain is large and
growing1; and mitochondrial dysfunction due to mecha-
nisms that are not yet completely understood likely play
important roles in numerous degenerative diseases, in-
cluding amyotrophic lateral sclerosis and Alzheimer, Par-
kinson, and Huntington diseases.2 The manner in which
mitochondrial disease impairs cellular function and vi-
ability is multifaceted and includes increased produc-
tion of reactive oxygen species with oxidative degrada-
tion of proteins, lipids, and DNA; initiating or accelerating
programmed cell death; and limiting cellular energy avail-
ability by restricting the rate of oxidative phosphoryla-
tion. The energy crisis that accompanies impaired func-
tion of the respiratory chain has generally been considered
to be the central pathophysiologic mechanism of mito-
chondrial disease, and attempts to augment cellular en-
ergy production have been the focus of most therapeu-
tic trials in mitochondrial disease.
See also page 951
Gene therapy has been used successfully in cell cul-
tures and in animal models to replace defective genes or
compensate for mitochondrial defects and to rescue oxi-
dative energy production,3 but for the immediate future
these are not therapies ready to be applied to patient treat-
ment. Strategies designed to correct or bypass the block
in respiratory chain function, using supplements of vi-
tamins and cofactors, have generally been disappoint-
ing. A notable exception is the provision of coenzyme
Q10 to patients with selective coenzyme Q deficiency,
which often has achieved significant therapeutic ben-
efit.4 However, that benefit may relate more to antioxi-
dant effects of coenzyme Q10 or its analogues than di-
rectly to enhancing oxidative phosphorylation.5
In selective complex I defects due to nuclear or mi-
tochondrial complex I subunit mutations or to mito-
chondrial transfer RNA Leu (UUR) mutations associ-
ated with predominantly complex I deficiency, the
administration of succinate and/or riboflavin (a precur-
sor of flavin adenine dinucleotide) has been suggested
as therapy.4 Flavin adenine dinucleotide–dependent suc-
cinate oxidation occurs via complex II, so the expected
benefit would be to increase oxidative phosphorylation
by promoting electron flux through complex II, thus by-
passing complex I. However, reports of benefit from using
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this approach have been few and anecdotal. Another res-
piratory chain bypass strategy was attempted in a pa-
tient with a selective complex III deficiency due to a mu-
tation in cytochrome b. The patient was treated with
menadione (vitamin K3) and ascorbate (vitamin C), which
are capable of directly reducing cytochrome c, to com-
pensate for the block in complex III–mediated reduc-
tion of cytochrome c.6 Evidence of improved oxidative
phosphorylation after this treatment was indicated by
phosphorous 31 magnetic resonance spectroscopy find-
ings and clinical improvement, but the toxicity of mena-
dione has led to its withdrawal as a nutritional supple-
ment. Ascorbate, administered alone or (more often) with
other vitamins and cofactors, has not been demon-
strated to augment mitochondrial energy production.7
A more successful approach to augmenting oxidative
phosphorylation in mitochondrial disorders, which pre-
serves some level of residual oxidative capacity, is to stimu-
late mitochondrial biogenesis. In patients with mito-
chondrial myopathy attributable to heteroplasmic
mitochondrial DNA mutation, regular aerobic exercise
has been shown to increase levels of functional mito-
chondria and capacity for oxidative phosphorylation,
likely by increasing levels or transcription of wild-type
mitochondrial DNA.8,9 Recent experimental results in-
dicate that agonists of transcription factors regulating mi-
tochondrial biogenesis can magnify the oxidative and en-
durance gains of exercise training (using peroxisome
proliferator–activated receptor agonists) or achieve the
oxidative effects of training in the absence of regular ex-
ercise (using adenosine monophosphate–activated pro-
tein kinase agonists).10 The administration of bezafi-
brate, a peroxisome proliferator–activated receptor
panactivator, has been shown to increase mitochondrial
biogenesis and levels of deficient mitochondrial en-
zymes in an experimental model of cytochrome c oxi-
dase deficiency and in humans with adult carnitine pal-
mitoyl transferase II deficiency.11,12
While increasing the capacity for oxidative phosphory-
lation is key to the effective treatment of the energy cri-
sis in mitochondrial disorders, enhancing or modulat-
ing nonoxidative anaerobic energy pathways has also been
a therapeutic target. Glycolysis is the major source of an-
aerobic energy production. It provides a buffer of en-
ergy availability that is independent of oxygen availabil-
ity, and the rate of adenosine 5⬘-triphosphate (ATP)
production as well as the rate of acceleration to peak lev-
els of ATP production achieved from anaerobic glycoly-
sis far exceed those of oxidative phosphorylation. Sus-
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tained anaerobic glycolysis, however, causes accumulation
of lactic acid, which may be associated with deleterious
effects on cellular function. A strategy to combat lactic
acidosis, and to potentially increase pyruvate oxidation,
is to administer dichloroacetate, which activates pyru-
vate dehydrogenase by inhibiting pyruvate dehydroge-
nase kinase and has been effective in lowering lactate lev-
els in respiratory chain diseases. Although dichloroacetate
lowers lactate levels, it does not improve oxidative me-
tabolism, and unacceptable toxic effects—primarily pe-
ripheral neuropathy—accompany its use.13,14 Creatine
phosphate is another important source of anaerobic en-
ergy, and creatine administration has been shown to be
protective in experimental models of neurodegenera-
tion. However, creatine supplements have not been shown
consistently to improve muscle energy metabolism in mi-
tochondrial disease.7
In this issue of Archives, Sgarbi and colleagues15 have
exploited another site of substrate-level phosphoryla-
tion in the cell and have shown it to be a potential thera-
peutic target that is capable of maintaining cellular ATP
and cell viability in mitochondrial defects. While mito-
chondrial energy production proceeds predominantly via
oxidative phosphorylation, one enzyme reaction in the
tricarboxylic acid cycle, succinyl coenzyme A synthase,
catalyzes substrate-level phosphorylation of adenosine
5⬘-diphosphate (or guanosine 5⬘-diphosphate).16 In fact,
substrate-level phosphorylation accounts for approxi-
mately 8% of the energy generated from the metabolism
of acetyl coenzyme A in the tricarboxylic acid cycle. These
investigators used normal human fibroblasts incubated
with oligomycin to inhibit ATP synthase (mitochon-
drial complex V) and cybrids homoplasmic for the
T8993G mutation in the A6 subunit of ATP synthase to
evaluate a novel therapeutic strategy. The T8993G mu-
tation of mitochondrial DNA is responsible for the mi-
tochondrial syndromes neuropathy, ataxia, and retinitis
pigmentosa and maternally inherited Leigh syndrome.
When the cells were incubated in a glucose-free me-
dium (to eliminate the substrate-level phosphorylation
of glycolysis), cellular ATP levels and viability were pre-
served when cells were incubated with ␣-ketoglutarate
(the precursor of succinyl coenzyme A) and aspartate (the
precursor, via transamination, of oxaloacetate). Be-
cause the ␣-ketoglutarate dehydrogenase reaction gen-
erates reduced nicotinamide adenine dinucleotide and H⫹,
the accumulation of which would ultimately inhibit the
production of succinyl coenzyme A, success of this treat-
ment depends on reversal of the normal flux of the tri-
carboxylic acid cycle with oxaloacetate converted to ma-
late. Augmenting cellular ATP production using this
approach could potentially avoid the buildup of toxic in-
termediates that accompany substrate-level phosphory-
lation in glycolysis.
Another interesting aspect of the study by Sgarbi et
al is the finding that cybrids containing a homoplasmic
T8993C mutation, another cause of neuropathy, ataxia,
and retinitis pigmentosa/maternally inherited Leigh syn-
drome, maintained cell ATP levels and cell viability,
whether or not they were treated with ␣-ketoglutarate
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(REPRINTED WITH CORRECTIONS)
and aspartate. This reminds us of the multiple dimen-
sions of mitochondrial disease that makes understand-
ing of pathogenesis and devising appropriate ap-
proaches to treatment for these conditions so challenging.
Exploration for new and better sources of energy is a
challenge of our time and so is the quest to enhance en-
ergy production and to correct the collateral damage
when mitochondria fail. There is only one thing to do:
keep drilling.
Ronald G. Haller, MD
John Vissing, MD
Correspondence: Dr Haller, Neuromuscular Center, In-
stitute for Exercise and Environmental Medicine of Pres-
byterian Hospital, 7232 Greenville Ave, Ste 339, Dallas,
TX 75231 (ronald.haller@utsouthwestern.edu).
Author Contributions: Study concept and design: Haller
and Vissing. Acquisition of data: Haller. Analysis and in-
terpretation of data: Vissing. Drafting of the manuscript:
Haller. Critical revision of the manuscript for important in-
tellectual content: Vissing.
Financial Disclosure: None reported.
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