Mitochondrial medicine: a metabolic perspective on the pathology of oxidative phosphorylation disorders.

The final steps in the production of adenosine triphosphate (ATP) in mitochondria are executed by a series of multisubunit complexes and electron carriers, which together constitute the oxidative phosphorylation (OXPHOS) system. OXPHOS is under dual genetic control, with communication between the nuclear and mitochondrial genomes essential for optimal assembly and function of the system. We describe the current understanding of the metabolic consequences of pathological OXPHOS defects, based on analyses of patients and of genetically engineered model systems. Understanding the metabolic consequences of OXPHOS disease is of key importance for elucidating pathogenic mechanisms, guiding diagnosis and developing therapies.

[1]  G. Saidel,et al.  Regulation of Cardiac Energetics: Role of Redox State and Cellular Compartmentation during Ischemia , 2005, Annals of the New York Academy of Sciences.

[2]  A. Munnich,et al.  Clinical aspects of mitochondrial disorders , 1992, Journal of Inherited Metabolic Disease.

[3]  J. Walker,et al.  Identification and functions of new transporters in yeast mitochondria. , 2000, Biochimica et biophysica acta.

[4]  D. Nicholls.  Mitochondria and calcium signaling. , 2005, Cell calcium.

[5]  M. S. Jafri,et al.  Mitochondrial Calcium Signaling and Energy Metabolism , 2005, Annals of the New York Academy of Sciences.

[6]  H. Nilsson,et al.  Secondary metabolic effects in complex I deficiency , 2005, Annals of neurology.

[7]  S. Dimauro,et al.  The genetics and pathology of oxidative phosphorylation , 2001, Nature Reviews Genetics.

[8]  J. Smeitink,et al.  Mitochondrial disorders: Clinical presentation and diagnostic dilemmas , 2003, Journal of Inherited Metabolic Disease.

[9]  H. Simmonds,et al.  Severe Impairment of Nucleotide Synthesis Through Inhibition of Mitochondrial Respiration , 2004, Nucleosides, nucleotides & nucleic acids.

[10]  K. Petersen,et al.  Decreased Insulin-Stimulated ATP Synthesis and Phosphate Transport in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Parents , 2005, PLoS medicine.

[11]  Massimo Zeviani,et al.  Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. , 2005, Cell metabolism.

[12]  A. Munnich,et al.  Persistent hypocitrullinaemia as a marker for mtDNA NARP T 8993 G mutation? , 1998, Journal of Inherited Metabolic Disease.

[13]  Charis Eng,et al.  A role for mitochondrial enzymes in inherited neoplasia and beyond , 2003, Nature Reviews Cancer.

[14]  Yuen-Li Chung,et al.  HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. , 2005, Cancer cell.

[15]  I. Tomlinson,et al.  The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase , 2003, Annals of medicine.

[16]  E. Padmore.  Nurse prescribing in diabetes care , 2005, Diabetic medicine : a journal of the British Diabetic Association.

[17]  Guido Davidzon,et al.  Mitochondrial DNA and disease , 2005, Annals of medicine.

[18]  M. Saraste.  Oxidative phosphorylation at the fin de siècle. , 1999, Science.

[19]  A. M. James,et al.  Interactions of Mitochondria-targeted and Untargeted Ubiquinones with the Mitochondrial Respiratory Chain and Reactive Oxygen Species , 2005, Journal of Biological Chemistry.

[20]  R. Naviaux,et al.  Chronic treatment of mitochondrial disease patients with dichloroacetate. , 2004, Molecular genetics and metabolism.

[21]  F. H. van der Westhuizen,et al.  Inhibition of complex I of the electron transport chain causes O2-. -mediated mitochondrial outgrowth. , 2005, American journal of physiology. Cell physiology.

[22]  P. Schumacker,et al.  Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. , 2005, Cell metabolism.

[23]  S. Dimauro,et al.  Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: A CoQ10-responsive condition , 2005, Neurology.

[24]  M. Berridge,et al.  Cardiac calcium signalling. , 2003, Biochemical Society transactions.

[25]  P. Schumacker,et al.  Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. , 2005, Cell metabolism.

[26]  E. Schon,et al.  A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency , 1999, Nature Medicine.

[27]  Robert S. Balaban,et al.  Mitochondria, Oxidants, and Aging , 2005, Cell.

[28]  G. Rutter,et al.  Inhibition of Mitochondrial Na (cid:1) -Ca 2 (cid:1) Exchange Restores Agonist-induced ATP Production and Ca 2 (cid:1) Handling in Human Complex I Deficiency* , 2004 .

[29]  D. Green,et al.  Apoptotic Pathways: Ten Minutes to Dead , 2005, Cell.

[30]  E. Shoubridge,et al.  Nuclear genetic control of mitochondrial DNA segregation , 2003, Nature Genetics.

[31]  T. Matsuishi,et al.  Effects of L-arginine on the acute phase of strokes in three patients with MELAS. , 2002, Neurology.

[32]  M. Brand,et al.  Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. , 2005, Cell metabolism.

[33]  F. Lang,et al.  A Novel Potassium Channel in Lymphocyte Mitochondria* , 2005, Journal of Biological Chemistry.

[34]  M. Valentino,et al.  Thymidine phosphorylase mutations cause instability of mitochondrial DNA. , 2005, Gene.

[35]  Robert W. Taylor,et al.  Mitochondrial DNA mutations in human disease , 2005, Nature Reviews Genetics.

[36]  J R Griffiths,et al.  Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. , 2005, Human molecular genetics.

[37]  H. Westerblad,et al.  Abnormal Ca(2+) release and catecholamine-induced arrhythmias in mitochondrial cardiomyopathy. , 2005, Human molecular genetics.

[38]  J. Mazat,et al.  Tissue variation in the control of oxidative phosphorylation: implication for mitochondrial diseases. , 2000, The Biochemical journal.

[39]  Chandan K Sen,et al.  Mitochondrial nitric oxide synthase. , 2005, Trends in pharmacological sciences.