Drilling For Energy In Mitochondrial Disease

EDITORIAL

Drilling for Energy in Mitochondrial Disease

T

HE CATALOG OF MITOCHONDRIAL AND

nuclear DNA mutations that impair the synthesis, assembly, or maintenance of proteins necessary for the function of the mitochondrial respiratory chain is large and growing1; and mitochondrial dysfunction due to mechanisms that are not yet completely understood likely play important roles in numerous degenerative diseases, including amyotrophic lateral sclerosis and Alzheimer, Parkinson, and Huntington diseases.2 The manner in which mitochondrial disease impairs cellular function and viability is multifaceted and includes increased production of reactive oxygen species with oxidative degradation of proteins, lipids, and DNA; initiating or accelerating programmed cell death; and limiting cellular energy availability by restricting the rate of oxidative phosphorylation. The energy crisis that accompanies impaired function of the respiratory chain has generally been considered to be the central pathophysiologic mechanism of mitochondrial disease, and attempts to augment cellular energy production have been the focus of most therapeutic trials in mitochondrial disease.

See also page 951 Gene therapy has been used successfully in cell cultures and in animal models to replace defective genes or compensate for mitochondrial defects and to rescue oxidative energy production,3 but for the immediate future these are not therapies ready to be applied to patient treatment. Strategies designed to correct or bypass the block in respiratory chain function, using supplements of vitamins and cofactors, have generally been disappointing. A notable exception is the provision of coenzyme Q10 to patients with selective coenzyme Q deficiency, which often has achieved significant therapeutic benefit.4 However, that benefit may relate more to antioxidant effects of coenzyme Q10 or its analogues than directly to enhancing oxidative phosphorylation.5 In selective complex I defects due to nuclear or mitochondrial complex I subunit mutations or to mitochondrial transfer RNA Leu (UUR) mutations associated with predominantly complex I deficiency, the administration of succinate and/or riboflavin (a precursor of flavin adenine dinucleotide) has been suggested as therapy.4 Flavin adenine dinucleotide–dependent succinate oxidation occurs via complex II, so the expected benefit would be to increase oxidative phosphorylation by promoting electron flux through complex II, thus bypassing complex I. However, reports of benefit from using

this approach have been few and anecdotal. Another respiratory chain bypass strategy was attempted in a patient with a selective complex III deficiency due to a mutation in cytochrome b. The patient was treated with menadione (vitamin K3) and ascorbate (vitamin C), which are capable of directly reducing cytochrome c, to compensate for the block in complex III–mediated reduction of cytochrome c.6 Evidence of improved oxidative phosphorylation after this treatment was indicated by phosphorous 31 magnetic resonance spectroscopy findings and clinical improvement, but the toxicity of menadione has led to its withdrawal as a nutritional supplement. Ascorbate, administered alone or (more often) with other vitamins and cofactors, has not been demonstrated to augment mitochondrial energy production.7 A more successful approach to augmenting oxidative phosphorylation in mitochondrial disorders, which preserves some level of residual oxidative capacity, is to stimulate mitochondrial biogenesis. In patients with mitochondrial myopathy attributable to heteroplasmic mitochondrial DNA mutation, regular aerobic exercise has been shown to increase levels of functional mitochondria and capacity for oxidative phosphorylation, likely by increasing levels or transcription of wild-type mitochondrial DNA.8,9 Recent experimental results indicate that agonists of transcription factors regulating mitochondrial biogenesis can magnify the oxidative and endurance gains of exercise training (using peroxisome proliferator–activated receptor agonists) or achieve the oxidative effects of training in the absence of regular exercise (using adenosine monophosphate–activated protein kinase agonists).10 The administration of bezafibrate, a peroxisome proliferator–activated receptor panactivator, has been shown to increase mitochondrial biogenesis and levels of deficient mitochondrial enzymes in an experimental model of cytochrome c oxidase deficiency and in humans with adult carnitine palmitoyl transferase II deficiency.11,12 While increasing the capacity for oxidative phosphorylation is key to the effective treatment of the energy crisis in mitochondrial disorders, enhancing or modulating nonoxidative anaerobic energy pathways has also been a therapeutic target. Glycolysis is the major source of anaerobic energy production. It provides a buffer of energy availability that is independent of oxygen availability, and the rate of adenosine 5⬘-triphosphate (ATP) production as well as the rate of acceleration to peak levels of ATP production achieved from anaerobic glycolysis 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 pyruvate dehydrogenase by inhibiting pyruvate dehydrogenase kinase and has been effective in lowering lactate levels in respiratory chain diseases. Although dichloroacetate lowers lactate levels, it does not improve oxidative metabolism, and unacceptable toxic effects—primarily peripheral neuropathy—accompany its use.13,14 Creatine phosphate is another important source of anaerobic energy, and creatine administration has been shown to be protective in experimental models of neurodegeneration. However, creatine supplements have not been shown consistently to improve muscle energy metabolism in mitochondrial disease.7 In this issue of Archives, Sgarbi and colleagues15 have exploited another site of substrate-level phosphorylation in the cell and have shown it to be a potential therapeutic target that is capable of maintaining cellular ATP and cell viability in mitochondrial defects. While mitochondrial 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 approximately 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 (mitochondrial complex V) and cybrids homoplasmic for the T8993G mutation in the A6 subunit of ATP synthase to evaluate a novel therapeutic strategy. The T8993G mutation of mitochondrial DNA is responsible for the mitochondrial syndromes neuropathy, ataxia, and retinitis pigmentosa and maternally inherited Leigh syndrome. When the cells were incubated in a glucose-free medium (to eliminate the substrate-level phosphorylation of glycolysis), cellular ATP levels and viability were preserved when cells were incubated with ␣-ketoglutarate (the precursor of succinyl coenzyme A) and aspartate (the precursor, via transamination, of oxaloacetate). Because the ␣-ketoglutarate dehydrogenase reaction generates reduced nicotinamide adenine dinucleotide and H⫹, the accumulation of which would ultimately inhibit the production of succinyl coenzyme A, success of this treatment depends on reversal of the normal flux of the tricarboxylic acid cycle with oxaloacetate converted to malate. Augmenting cellular ATP production using this approach could potentially avoid the buildup of toxic intermediates that accompany substrate-level phosphorylation 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 syndrome, maintained cell ATP levels and cell viability, whether or not they were treated with ␣-ketoglutarate

and aspartate. This reminds us of the multiple dimensions of mitochondrial disease that makes understanding of pathogenesis and devising appropriate approaches 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 energy 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, Institute for Exercise and Environmental Medicine of Presbyterian Hospital, 7232 Greenville Ave, Ste 339, Dallas, TX 75231 ([email protected]). Author Contributions: Study concept and design: Haller and Vissing. Acquisition of data: Haller. Analysis and interpretation of data: Vissing. Drafting of the manuscript: Haller. Critical revision of the manuscript for important intellectual content: Vissing. Financial Disclosure: None reported. 1. DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci. 2008;31:91-123. 2. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60(5):748-766. 3. Koene S, Smeitink J. Mitochondrial medicine: entering the era of treatment. J Intern Med. 2009;265(2):193-209. 4. DiMauro S, Mancuso M. Mitochondrial diseases: therapeutic approaches. Biosci Rep. 2007;27(1-3):125-137. 5. James AM, Cocheme HM, Smith RA, Murphy MP. Interactions of mitochondriatargeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species: implications for the use of exogenous ubiquinones as therapies and experimental tools. J Biol Chem. 2005;280(22):21295-21312. 6. Eleff S, Kennaway NG, Buist NR, et al. 31P NMR study of improvement in oxidative phosphorylation by vitamins K3 and C in a patient with a defect in electron transport at complex III in skeletal muscle. Proc Natl Acad Sci U S A. 1984; 81(11):3529-3533. 7. Tarnopolsky MA. The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. Adv Drug Deliv Rev. 2008;60(13-14): 1561-1567. 8. Taivassalo T, Gardner JL, Taylor RW, et al. Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions. Brain. 2006; 129(Pt 12):3391-3401. 9. Jeppesen TD, Schwartz M, Olsen DB, et al. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain. 2006;129 (pt 12):3402-3412. 10. Narkar VA, Downes M, Yu RT, et al. AMPK and PPAR␦ agonists are exercise mimetics. Cell. 2008;134(3):405-415. 11. Wenz T, Diaz F, Spiegelman BM, Moraes CT. Activation of the PPAR/PGC1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab. 2008;8(3):249-256. 12. Bonnefont JP, Bastin J, Behin A, Djouadi F. Bezafibrate for an inborn mitochondrial beta-oxidation defect. N Engl J Med. 2009;360(8):838-840. 13. Vissing J, Gansted U, Quistorff B. Exercise intolerance in mitochondrial myopathy is not related to lactic acidosis. Ann Neurol. 2001;49(5):672-676. 14. Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006;66(3):324330. 15. Sgarbi G, Casalena GA, Baracca A, Lenaz G, DiMauro S, Solaini G. Human NARP mitochondrial mutation metabolism corrected with ␣-ketoglutarate/aspartate: a potential new therapy. Arch Neurol. 2009;66(8):951-957. 16. Lambeth DO, Tews KN, Adkins S, Frohlich D, Milavetz BI. Expression of two succinylCoA synthetases with different nucleotide specificities in mammalian tissues. J Biol Chem. 2004;279(35):36621-36624.

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