T
HE CATALOG OF MITOCHONDRIAL AND this approach have been few and anecdotal. Another res-
nuclear DNA mutations that impair the piratory chain bypass strategy was attempted in a pa-
synthesis, assembly, or maintenance of pro- tient with a selective complex III deficiency due to a mu-
teins necessary for the function of the mi- tation in cytochrome b. The patient was treated with
tochondrial respiratory chain is large and menadione (vitamin K3) and ascorbate (vitamin C), which
growing1; and mitochondrial dysfunction due to mecha- are capable of directly reducing cytochrome c, to com-
nisms that are not yet completely understood likely play pensate for the block in complex III–mediated reduc-
important roles in numerous degenerative diseases, in- tion of cytochrome c.6 Evidence of improved oxidative
cluding amyotrophic lateral sclerosis and Alzheimer, Par- phosphorylation after this treatment was indicated by
kinson, and Huntington diseases.2 The manner in which phosphorous 31 magnetic resonance spectroscopy find-
mitochondrial disease impairs cellular function and vi- ings and clinical improvement, but the toxicity of mena-
ability is multifaceted and includes increased produc- dione has led to its withdrawal as a nutritional supple-
tion of reactive oxygen species with oxidative degrada- ment. Ascorbate, administered alone or (more often) with
tion of proteins, lipids, and DNA; initiating or accelerating other vitamins and cofactors, has not been demon-
programmed cell death; and limiting cellular energy avail- strated to augment mitochondrial energy production.7
ability by restricting the rate of oxidative phosphoryla- A more successful approach to augmenting oxidative
tion. The energy crisis that accompanies impaired func- phosphorylation in mitochondrial disorders, which pre-
tion of the respiratory chain has generally been considered serves some level of residual oxidative capacity, is to stimu-
to be the central pathophysiologic mechanism of mito- late mitochondrial biogenesis. In patients with mito-
chondrial disease, and attempts to augment cellular en-
chondrial myopathy attributable to heteroplasmic
ergy production have been the focus of most therapeu-
mitochondrial DNA mutation, regular aerobic exercise
tic trials in mitochondrial disease.
has been shown to increase levels of functional mito-
chondria and capacity for oxidative phosphorylation,
See also page 951 likely by increasing levels or transcription of wild-type
Gene therapy has been used successfully in cell cul- mitochondrial DNA.8,9 Recent experimental results in-
tures and in animal models to replace defective genes or dicate that agonists of transcription factors regulating mi-
compensate for mitochondrial defects and to rescue oxi- tochondrial biogenesis can magnify the oxidative and en-
dative energy production,3 but for the immediate future durance gains of exercise training (using peroxisome
these are not therapies ready to be applied to patient treat- proliferator–activated receptor agonists) or achieve the
ment. Strategies designed to correct or bypass the block oxidative effects of training in the absence of regular ex-
in respiratory chain function, using supplements of vi- ercise (using adenosine monophosphate–activated pro-
tamins and cofactors, have generally been disappoint- tein kinase agonists).10 The administration of bezafi-
ing. A notable exception is the provision of coenzyme brate, a peroxisome proliferator–activated receptor
Q10 to patients with selective coenzyme Q deficiency, panactivator, has been shown to increase mitochondrial
which often has achieved significant therapeutic ben- biogenesis and levels of deficient mitochondrial en-
efit.4 However, that benefit may relate more to antioxi- zymes in an experimental model of cytochrome c oxi-
dant effects of coenzyme Q10 or its analogues than di- dase deficiency and in humans with adult carnitine pal-
rectly to enhancing oxidative phosphorylation.5 mitoyl transferase II deficiency.11,12
In selective complex I defects due to nuclear or mi- While increasing the capacity for oxidative phosphory-
tochondrial complex I subunit mutations or to mito- lation is key to the effective treatment of the energy cri-
chondrial transfer RNA Leu (UUR) mutations associ- sis in mitochondrial disorders, enhancing or modulat-
ated with predominantly complex I deficiency, the ing nonoxidative anaerobic energy pathways has also been
administration of succinate and/or riboflavin (a precur- a therapeutic target. Glycolysis is the major source of an-
sor of flavin adenine dinucleotide) has been suggested aerobic energy production. It provides a buffer of en-
as therapy.4 Flavin adenine dinucleotide–dependent suc- ergy availability that is independent of oxygen availabil-
cinate oxidation occurs via complex II, so the expected ity, and the rate of adenosine 5⬘-triphosphate (ATP)
benefit would be to increase oxidative phosphorylation production as well as the rate of acceleration to peak lev-
by promoting electron flux through complex II, thus by- els of ATP production achieved from anaerobic glycoly-
passing complex I. However, reports of benefit from using sis far exceed those of oxidative phosphorylation. Sus-