Biochemistry - Oxidative Phosphorylation

Mitochondrial respiratory-chain diseases.

DiMauro, S & Schon, EA, 2003. N. Engl. J. Med. 348(26):2656-2668.

Intro Comments

...More than a billion years ago, aerobic bacteria colonized primordial eukaryotic cells that lacked the ability to use oxygen metabolically. A symbiotic relationship developed and became permanent. The bacteria evolved into mitochondria, thus endowing the host cells with aerobic metabolism, a much more efficient way to produce energy than anaerobic glycolysis. Structurally, mitochondria have four compartments: the outer membrane, the inner membrane, the intermembrane space, and the matrix (the region inside the inner membrane). They perform numerous tasks, such as pyruvate oxidation, the Krebs cycle, and metabolism of amino acids, fatty acids, and steroids, but the most crucial is probably the generation of energy as adenosine triphosphate (ATP), by means of the electron-transport chain and the oxidative-phosphorylation system (the "respiratory chain") ... The respiratory chain, located in the inner mitochondrial membrane, consists of five multimeric protein complexes: reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase-ubiquinone oxidoreductase (complex I, approximately 46 subunits), succinate dehydrogenase-ubiquinone oxidoreductase (complex II, 4 subunits), ubiquinone-cytochrome c oxidoreductase (complex III, 11 subunits), cytochrome c oxidase (complex IV, 13 subunits), and ATP synthase (complex V, approximately 16 subunits). The respiratory chain also requires two small electron carriers, ubiquinone (coenzyme Q10) and cytochrome c.

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Comment

A very well illustrated review and discussion of the genetics and functional gene products of human mitochondrial DNA.  The biochemistry and physiology of these mitochondrial processes are nicely presented with excellent figures and tables.  Numerous examples of complex disease states are correlated with well characterized genetic deficiencies of this organelle's DNA.

Review: Mitochondrial medicine--cardiomyopathy caused by defective oxidative phosphorylation.

Fosslien, E, 2003. Ann Clin Lab Sci. 33(4):371-395.

Abstract

During experimental hypertensive cardiac hypertrophy, the heart energy metabolism reverts from the normal adult type that obtains the majority of its requirement for adenosine triphosphate (ATP) from metabolism of fatty acids and oxidative phosphorylation (OXPHOS), to the fetal form, which metabolizes glucose and lactate. Mitochondrial synthesis and function require an estimated 1000 polypeptides, 37 of which are encoded by mitochondrial (mt) DNA, the rest by nuclear (n) DNA. Inherited or acquired aberrations of either mtDNA or nDNA mitochondrial genes cause mitochondrial dysfunction. Tissue expression of OXPHOS enzyme defects is often heterogeneous. As a result, cardiomyopathy and cardiac failure are frequent but unpredictable complications of mitochondrial encephalopathy, neuropathy, and myopathy. Several nuclear genes that encode mitochondrial proteins have been sequenced and specific defects associated with nuclear genes that affect mitochondrial structure and function have been linked to hypertrophic and dilated cardiomyopathies and to cardiac conduction defects. Thyroid hormone and exercise stimulate expression of a nuclear respiratory factor (NRF) that induces the nuclear gene TFAM, which encodes the mitochondrial transcription factor A that controls mitochondrial replication and transcription. TFAM-null mouse embryos lack mitochondria and fail to develop a heart. Mitochondrial dysfunction enhances the generation of radical oxygen species (ROS), which damage mtDNA, nDNA, proteins, and lipid membranes. Mice lacking the mitochondrial antioxidant enzyme manganese-superoxide dismutase (SOD) develop dilated cardiomyopathy. Palliative mitochondrial therapy with L-acetyl-carnitine and coenzyme Q10 improves cardiac function in patients with cardiomyopathy. Cure is only achievable by mitochondrial gene therapy. Experimental direct gene therapy uses vectors or targeting signal sequences to insert genes into mtDNA; indirect gene therapy employs viral or non-viral vectors to introduce genes into nDNA. Clinical repair of damaged somatic and germline genes that encode mitochondrial proteins may soon be within reach.

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Mitochondrial defects may play role in the Metabolic Syndrome

Hampton, T, 2004. JAMA 292(23):2823-2824.

Intro. comments

...While the metabolic syndrome has been thrust into the spotlight because of the obesity epidemic, it is clear that the condition is not simply caused by lifestyle habits such as overeating and inactivity. Genetic components likely play a role, and scientists have now identified a potential genetic culprit for some individuals with the condition. ... An estimated 47 million people in the United States have the metabolic syndrome, which is associated with the development of diabetes and heart disease. Factors characteristic of the syndrome include central obesity (excessive fat tissue in and around the abdomen), atherogenic dyslipidemia (high triglycerides and low HDL cholesterol), raised blood pressure (130/85 mm Hg or higher), insulin resistance (with or without glucose intolerance), prothrombotic state (eg, high fibrinogen or plasminogen activator inhibitor in the blood), proinflammatory state, and hypomagnesemia is another possible associated finding.

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Comment

This is a short overview of the research paper by Wilson et al. (see below) and presents a very good summary of its findings in a broader clinical context.

The mitochondrial theory of aging and its relationship to reactive oxygen species damage and somatic mtDNA mutations.

Loeb, LA et al., 2006. Proc. Natl. Acad. Sci. USA 102(52):18769-18770.

Intro. Comments:

Mitochondria are cellular energy factories that generate ATP via the reaction of hydrocarbons with oxygen. Every human cell contains hundreds of mitochondria, and each mitochondrion contains multiple copies of mitochondrial DNA (mtDNA). The ancestry of the mitochondrial genome can be traced to early eubacteria, and it is therefore unexpected that this organelle may have a major role in governing the pace of human aging. Three recent papers (1–3) plus a work published in a recent issue of PNAS (4) have demonstrated that accelerating the mtDNA mutation rate can result in some features suggestive of premature aging, consistent with the view that loss of mitochondrial function is a major causal factor in aging.

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A cluster of metabolic defects caused by mutation in a mitochondrial tRNA

Wilson et al., 2004.  Science 306(5699):1190-1194.

Abstract

Hypertension and dyslipidemia are risk factors for atherosclerosis and occur together more often than expected by chance. Although this clustering suggests shared causation, unifying factors remain unknown. We describe a large kindred with a syndrome including hypertension, hypercholesterolemia, and hypomagnesemia. Each phenotype is transmitted on the maternal lineage with a pattern indicating mitochondrial inheritance. Analysis of the mitochondrial genome of the maternal lineage identified a homoplasmic mutation substituting cytidine for uridine immediately 5' to the mitochondrial transfer RNA(Ile) anticodon. Uridine at this position is nearly invariate among transfer RNAs because of its role in stabilizing the anticodon loop. Given the known loss of mitochondrial function with aging, these findings may have implications for the common clustering of these metabolic disorders.

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Comment

A good illustration of how classical pedigree analysis can be combined with genomics approaches to characterize the genetic basis of complex diseases.  Surprisingly, the findings reveal a causal relationship between a mitochondrial mutation and hypertension, hypercholesterolemia, and hypomagnesemia (Metabolic Syndrome).  These approaches are incorporated with a very good discussion of the physiological aspects of the affected patients, including such variables as age, sex and BMI.