Mitochondrial Energetics and Therapeutics

Overview

Journal Annu Rev Pathol

Publisher Annual Reviews

Specialty Pathology

Date 2010 Jan 19

PMID 20078222

Citations 318

Authors

Douglas C Wallace

Weiwei Fan

Vincent Procaccio

Affiliations

Soon will be listed here.

Abstract

Mitochondrial dysfunction has been linked to a wide range of degenerative and metabolic diseases, cancer, and aging. All these clinical manifestations arise from the central role of bioenergetics in cell biology. Although genetic therapies are maturing as the rules of bioenergetic genetics are clarified, metabolic therapies have been ineffectual. This failure results from our limited appreciation of the role of bioenergetics as the interface between the environment and the cell. A systems approach, which, ironically, was first successfully applied over 80 years ago with the introduction of the ketogenic diet, is required. Analysis of the many ways that a shift from carbohydrate glycolytic metabolism to fatty acid and ketone oxidative metabolism may modulate metabolism, signal transduction pathways, and the epigenome gives us an appreciation of the ketogenic diet and the potential for bioenergetic therapeutics.

Citing Articles

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References

Rustin P, von Kleist-Retzow J, Chantrel-Groussard K, Sidi D, Munnich A, Rotig A . Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study. Lancet. 1999; 354(9177):477-9. DOI: 10.1016/S0140-6736(99)01341-0. View

Schriner S, Linford N, Martin G, Treuting P, Ogburn C, Emond M . Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005; 308(5730):1909-11. DOI: 10.1126/science.1106653. View

Manfredi G, Fu J, Ojaimi J, Sadlock J, Kwong J, Guy J . Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nat Genet. 2002; 30(4):394-9. DOI: 10.1038/ng851. View

Ruiz-Pesini E, Wallace D . Evidence for adaptive selection acting on the tRNA and rRNA genes of human mitochondrial DNA. Hum Mutat. 2006; 27(11):1072-81. DOI: 10.1002/humu.20378. View

Milne J, Lambert P, Schenk S, Carney D, Smith J, Gagne D . Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007; 450(7170):712-6. PMC: 2753457. DOI: 10.1038/nature06261. View

Schafer F, Buettner G . Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med. 2001; 30(11):1191-212. DOI: 10.1016/s0891-5849(01)00480-4. View

Kelley M, Parsons S . Redox regulation of the DNA repair function of the human AP endonuclease Ape1/ref-1. Antioxid Redox Signal. 2001; 3(4):671-83. DOI: 10.1089/15230860152543014. View

Goto Y, Nonaka I, Horai S . A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990; 348(6302):651-3. DOI: 10.1038/348651a0. View

Zhu Z, Yao J, Johns T, Fu K, De Bie I, MacMillan C . SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet. 1998; 20(4):337-43. DOI: 10.1038/3804. View

10.

Ruiz-Pesini E, Mishmar D, Brandon M, Procaccio V, Wallace D . Effects of purifying and adaptive selection on regional variation in human mtDNA. Science. 2004; 303(5655):223-6. DOI: 10.1126/science.1088434. View

11.

Seo B, Nakamaru-Ogiso E, Cruz P, Flotte T, Yagi T, Matsuno-Yagi A . Functional expression of the single subunit NADH dehydrogenase in mitochondria in vivo: a potential therapy for complex I deficiencies. Hum Gene Ther. 2004; 15(9):887-95. DOI: 10.1089/hum.2004.15.887. View

12.

Crispim D, Canani L, Gross J, Tschiedel B, Souto K, Roisenberg I . The European-specific mitochondrial cluster J/T could confer an increased risk of insulin-resistance and type 2 diabetes: an analysis of the m.4216T > C and m.4917A > G variants. Ann Hum Genet. 2006; 70(Pt 4):488-95. DOI: 10.1111/j.1469-1809.2005.00249.x. View

13.

van der Walt J, Nicodemus K, Martin E, Scott W, Nance M, Watts R . Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet. 2003; 72(4):804-11. PMC: 1180345. DOI: 10.1086/373937. View

14.

Geromel V, Darin N, Chretien D, Benit P, Delonlay P, Rotig A . Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab. 2002; 77(1-2):21-30. DOI: 10.1016/s1096-7192(02)00145-2. View

15.

Brown M, Starikovskaya E, Derbeneva O, Hosseini S, Allen J, Mikhailovskaya I . The role of mtDNA background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup J. Hum Genet. 2002; 110(2):130-8. DOI: 10.1007/s00439-001-0660-8. View

16.

Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J . Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol. 2003; 5(8):741-7. PMC: 4940195. DOI: 10.1038/ncb1024. View

17.

Kang H, Lee Y, Kim H, Lee J, Slama A . Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects. Epilepsia. 2007; 48(1):82-8. DOI: 10.1111/j.1528-1167.2006.00906.x. View

18.

Yudkoff M, Daikhin Y, Grunstein R, Nissim I . Effects of ketone bodies on astrocyte amino acid metabolism. J Neurochem. 1997; 69(2):682-92. DOI: 10.1046/j.1471-4159.1997.69020682.x. View

19.

Taylor R, Chinnery P, Turnbull D, Lightowlers R . Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids. Nat Genet. 1997; 15(2):212-5. DOI: 10.1038/ng0297-212. View

20.

Brandon M, Baldi P, Wallace D . Mitochondrial mutations in cancer. Oncogene. 2006; 25(34):4647-62. DOI: 10.1038/sj.onc.1209607. View