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PubMed2005

Mutation detection in four candidate genes (OXA1L, MRS2L, YME1L and MIPEP) for combined deficiencies in the oxidative phosphorylation system.

Mitochondria are the main energy-producing organelles of the cell. Five complexes embedded in the mitochondrial inner membrane, together constituting the oxidative phosphorylation (OXPHOS) system, comprise the final steps in cellular energy production. Many patients with a mitochondrial defect suffer from a so-called combined deficiency, meaning that the enzymatic activities of two or more complexes of the OXPHOS system are decreased. Numerous mutations have been described in nuclear genes that are involved in the functioning of a single complex of the OXPHOS system. However, little attention has been paid to patients with a deficiency of more than one complex of this particular system. In this study we have investigated four nuclear genes (OXA1L, MRS2L, YME1L and MIPEP) that might be involved in the pathology of combined enzymatic deficiencies of the OXPHOS system. Based on the results of yeast knockouts of these four proteins, we have sequenced the open reading frame of OXA1L in eight patients with an enzymatic deficiency of complexes I and IV. MRS2L, YME1L and MIPEP have been sequenced in three patients with a combined defect of complexes III and IV. No mutations were detected in these patients, showing that at least in these patients the OXPHOS system deficiency cannot be explained by a mutation in these four genes.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2006

Mitochondrial complex I: structure, function and pathology.

Oxidative phosphorylation (OXPHOS) has a prominent role in energy metabolism of the cell. Being under bigenomic control, correct biogenesis and functioning of the OXPHOS system is dependent on the finely tuned interaction between the nuclear and the mitochondrial genome. This suggests that disturbances of the system can be caused by numerous genetic defects and can result in a variety of metabolic and biochemical alterations. Consequently, OXPHOS deficiencies manifest as a broad clinical spectrum. Complex I, the biggest and most complicated enzyme complex of the OXPHOS system, has been subjected to thorough investigation in recent years. Significant progress has been made in the field of structure, composition, assembly, and pathology. Important gains in the understanding of the Goliath of the OXPHOS system are: exposing the electron transfer mechanism and solving the crystal structure of the peripheral arm, characterization of almost all subunits and some of their functions, and creating models to elucidate the assembly process with concomitant identification of assembly chaperones. Unravelling the intricate mechanisms underlying the functioning of this membrane-bound enzyme complex in health and disease will pave the way for developing adequate diagnostic procedures and advanced therapeutic treatment strategies.

Animals↗
PubMed2005

Evolution of nuclearly encoded mitochondrial genes in Metazoa.

All Metazoan nuclear genomes underwent a continuous process of both complete and partial genetic material gain and loss. The forces modulating these events are also subject to the strict interaction between nuclear and mitochondrial (mt) genome. In this context we investigate the evolution of nuclear genes encoding proteins which target the mitochondrion, with a particular attention to genes involved in oxidative phosphorylation (OXPHOS), one of the most ancient and conserved functions. To examine thoroughly the evolutionary strategies that preserve OXPHOS and coordinate the two cellular genomes, a comparative analysis has been carried out for 78 OXPHOS gene families in several Metazoa (insects, tunicates, fishes and mammals). We demonstrate that the duplication rate of OXPHOS genes increases passing from invertebrates to vertebrates consistently with the total increase in genome size, but all species are prone to negatively select OXPHOS duplicates compared to the general trend of nuclear gene families. These results are consistent with the 'balance hypothesis' and, at least in insects, the expression of duplicate genes is low and strongly testis-biased.

Animals↗
PubMed1997

Mutagenesis of some positive and negative residues occurring in repeat triad residues in the ADP/ATP carrier from yeast.

In AAC2 from Saccharomyces cerevisiae, nine additional charged residues (six positive, three negative) were neutralized by mutagenesis following the previous mutation of six arginines. Oxidative phosphorylation (OxPhos) in cells and mitochondria, the expression level of AAC protein, and the various transport modes of AAC in the reconstituted system were measured. Mutations are: within the first helix at K38A which is exclusive for AAC; K48A, and R152A, part of a positive triad occurring in the matrix portion of each repeat; two matrix lysines, K179M and K182I, and the negative triad helix-terminating residues, E45G, D149S, D249S. Cellular ATP synthesis (OxPhos) is nearly completely inhibited in K48A, R152A, D149S, and D249S, but still amounts to 10% in K38A and between 30% and 90% in the gly+ mutants K179M, K179I + K182I, and E45G. Comparison of the AAC content measured by ELISA and the binding of [3H]CAT and [3H]BKA reveals discrepancies in K48A, D149S, and D249S mitochondria, which provide evidence that these mutations largely abolish inhibitor binding. Also these mitochondria have undetectable OxPhos. Differently in K38A, CAT and BKA binding are retained at high AAC levels but OxPhos is very low. This reveals a special functional role of K38, different from the more structural role of R152, K48, D149, and D249. Transport activity was measured with reconstituted AAC. The electroneutral ADP/ADP exchange of gly- mutants is largely or fully suppressed in K48A, D149S, and D249S. K38A and R152A are still active at 18% and 30% of wt. The other three exchange modes, ATP/ADP, ADP/ATP, and ATP/ATP, are nearly suppressed in all gly- mutants but remain high in gly+ mutants. ATP-linked modes are higher than the ADP/ADP mode in gly+ but lower in gly- mutants, resulting in an exchange mode inversion (EMI). In the competition for AAC2 transport capacity, the weak ATP exporting modes are suppressed by the much stronger unproductive ADP/ADP mode causing inhibition of OxPhos. Together with previous results all members of three charge triads are now mutagenized, revealing drastic functional rotatory asymmetries within the three repeat domains. In the intrahelical arginine triad the third (R294A), in the positive matrix triad the second (R152A), and in the helix-terminating negative triad the first (E45G) still show high activity.

Adenosine Triphosphate↗
PubMed1995

Renal amino acid transport in adults with oxidative phosphorylation diseases.

The clinical manifestations of mitochondrial DNA (mtDNA) mutations depend on a variety of factors including ratios of normal to abnormal mtDNA and tissue-specific differences in ATP production by oxidative phosphorylation (OXPHOS). In order to investigate the effects of OXPHOS defects on renal tubule function, we characterized sodium-coupled transport processes in six individuals with OXPHOS diseases. Pathogenic mtDNA mutations were identified in five of these individuals. Sodium coupled transport processes were evaluated by determining fractional excretions of amino acids, glucose, lactate, urate, and phosphate in patients and controls. Four of the six individuals had high fractional excretions of neutral amino acids, indicating abnormal renal tubule reabsorbtion of these amino acids. Abnormalities in fractional excretions of lactate, glucose, urate, and phosphate were less pronounced. These results demonstrate that sodium-coupled transport processes in the kidney are sensitive to OXPHOS impairment. When abnormalities in these processes are encountered, an OXPHOS disease should be included in the differential diagnosis.

Adenosine Triphosphate↗
PubMed1999

Mitochondrial myopathies and encephalomyopathies.

Defects of mitochondrial metabolism result in a wide variety of human disorders, which can present at any time from infancy to late adulthood and involve virtually any tissue either alone or in combination. Abnormalities of the electron transport and oxidative phosphorylation (OXPHOS) system are probably the most common cause of mitochondrial diseases. Thirteen of the protein subunits of OXPHOS are encoded by mitochondrial DNA (mtDNA) and mutations of this genome are important causes of OXPHOS deficiency. The link between genotype and phenotype with respect to mtDNA mutations is not clear: the same mutation may result in a variety of phenotypes, and the same phenotype may be seen with a variety of different mtDNA mutations. The pathogenesis of mtDNA mutations is unclear although OXPHOS and ATP deficiency, and free radical generation, are thought to contribute to tissue dysfunction. There is now strong evidence for mitochondrial dysfunction in neurodegenerative disorders. In some cases, e.g. Friedreich's ataxia, hereditary spastic paraplegia, this is a result of a mutation of a nuclear gene encoding a mitochondrial protein, whilst in others, e.g. Huntington's disease, amyotrophic lateral sclerosis, the OXPHOS defect is secondary to events induced by a mutation in a nuclear gene encoding a non-mitochondrial protein. In yet a third group, e.g. Parkinson's disease, Alzheimer's disease, the relationship of the mitochondrial defect to aetiology and pathogenesis is unclear.

DNA, Mitochondrial↗
PubMed2005

Oxidative phosphorylation dysfunction modulates expression of extracellular matrix--remodeling genes and invasion.

A number of recent studies suggest that mitochondrial function is a player in tumor development and progression. In this study, we have used gene expression arrays to examine transcriptional differences between oxidative phosphorylation (OXPHOS)-competent and OXPHOS-impaired human osteosarcoma cells. Genes associated with extracellular matrix remodeling, including members of the matrix metalloproteinases (MMPs) and tissue inhibitors of the MMP (TIMP) family, urokinase plasminogen activator and its inhibitor plasminogen-activator inhibitor-1 (PAI1), and CTGF and CYR61 (members of the Cysteine-rich 61, Connective Tissue Growth Factor and Nephroblastoma-overexpressed (CCN) gene family of growth regulators), were among the ones significantly altered in the OXPHOS-deficient cells. These changes were confirmed by RT-PCR and promoter reporter assays. Alterations at the protein level for some of these factors were also observed, though at a lower magnitude, with the exception of TIMP1, where a marked change in steady-state levels of the protein was observed after induction of OXPHOS dysfunction. Repopulation of mitochondrial DNA (mtDNA)-less cells with wild-type mtDNA reduced matrigel invasion, whereas repopulation with a mutated mtDNA did not. Taken together our data suggests that OXPHOS dysfunction modulates the invasive phenotype by transcriptional regulation of genes coding for members of the MMP/TIMP system, urokinase plasminogen activator/plasminogen-activator inhibitor I and CCN proteins.

Bone Neoplasms↗
PubMed2005

Diagnostic value of immunostaining in cultured skin fibroblasts from patients with oxidative phosphorylation defects.

In the last decades, a large variety of oxidative phosphorylation (OXPHOS) defects have been reported, expressed as an increasing variety of clinical phenotypes. With the expanding number of genes and proteins involved, new screening techniques leading to more effective diagnostic routes are in ever-increasing demand. Cultured skin fibroblasts from a cohort of patients with various OXPHOS defects, previously recognized by enzyme activity studies and blue native PAGE, were investigated with an immunocytochemical technique. Cytospins of cultured fibroblasts were air dried, fixed, and stained with antibodies specifically directed against subunits of each OXPHOS complex. Control cells stained homogeneously and strongly. In fibroblasts from five out of seven patients with a severe deficiency of one of the OXPHOS complexes, a homogeneous reduction of cytoimmunoreactivity of the affected complex was observed. In five out of seven fibroblast strains harboring a mitochondrial tRNA mutation, a mosaic pattern of staining was observed for both complexes I and IV, reflecting the heteroplasmic nature of the defect. The proportion of deficient fibroblasts varied considerably between cell strains from different subjects. The method described offers a convenient and rapid approach to first-line screening of OXPHOS defects. In association with routine assays of enzyme activity, the technique is helpful in orienting molecular investigation further.

Adolescent↗
PubMed1997

Rapid isolation of muscle and heart mitochondria, the lability of oxidative phosphorylation and attempts to stabilize the process in vitro by taurine, carnitine and other compounds.

We modified the isolation procedure of muscle and heart mitochondria. In human muscle, this resulted in a 3.4 fold higher yield of better coupled mitochondria in half the isolation time. In a preparation from rat muscle we studied factors that affected the stability of oxidative phosphorylation (oxphos) and found that it decreased by shaking the preparation on a Vortex machine, by exposure to light and by an increase in storage temperature. The decay was found to be different for each substrate tested. The oxidation of ascorbate was most stable and less sensitive to the treatments. When mitochondria were stored in the dark and the cold, the decrease in oxidative phosphorylation followed first order kinetics. In individual preparations of muscle and heart mitochondria, protection of oxidative phosphorylation was found by adding candidate stabilizers, such as desferrioxamine, lazaroids, taurine, carnitine, phosphocreatine, N-acetylcysteine. Trolox-C and ruthenium red, implying a role for reactive oxygen species and calcium-ions in the in vitro damage at low temperature to oxidative phosphorylation. In heart mitochondria oxphos with pyruvate and palmitoylcarnitine was most labile followed by glutamate, succinate and ascorbate. We studied the effect of taurine, hypotaurine, carnitine, and desferrioxamine on the decay of oxphos with these substrates. 1 mM taurine (n = 6) caused a significant protection of oxphos with pyruvate, glutamate and palmitoylcarnitine, but not with the other substrates. 5 mM L-carnitine (n = 6), 1 mM hypotaurine (n = 3) and 0.1 mM desferrioxamine (n = 3) did not protect oxphos with any of the substrates at a significant level. These experiments were undertaken in the hope that the in vitro stabilizers can be used in future treatment of patients with defects in oxidative phosphorylation.

Animals↗
PubMed2025

Structural diversity and evolutionary constraints of oxidative phosphorylation.

The oxidative phosphorylation (OxPhos) system is central to metabolism. The more than 90 structural subunits are encoded by different chromosome categories (autosomal, X, and mtDNA). The system is envisioned as an invariant structure between cells and individuals. However, a comprehensive analysis of the 1,000 Genomes Project data reveals unexpected genetic intra-individual variability resulting from the heterozygosity of diploid autosomal genes, while diversity at the population level is generated by variability in mtDNA. We characterized the different levels of structural constriction at evolutionary and population levels for all OxPhos protein residues. To support this analysis, we developed ConScore, a conservation-based predictor of variant impact within OxPhos proteins (area under the receiver operating characteristic curve [ROC-AUC] = 0.97; area under the precision-recall curve [PR-AUC] = 0.94). Notably, for the nuclear-encoded subunits, we found mechanisms limiting individual variability as allelic imbalance or homozygosity bias. Integrating structural, functional, and genetic data, we highlight the significance of each OxPhos protein position, expanding insights into its role in speciation and disease.

Oxidative Phosphorylation↗
PubMed2000

31P MRS measurement of mitochondrial function in skeletal muscle: reliability, force-level sensitivity and relation to whole body maximal oxygen uptake.

The reliability, relation to whole-body maximal oxygen uptake (VO(2max)), and force-level sensitivity of (31)P MRS markers of mitochondrial function were studied in 39 normal-weight women. Following 90 s isometric plantar-flexion exercises at 45, 70 and 100% of maximum voluntary contraction, skeletal muscle mitochondrial function was determined from the phosphocreatine recovery time constant (TC(PCr)), the ADP recovery time constant (TC(ADP)), and the rate of change in PCr during the first 14 s of recovery (OxPhos). VO(2max) was measured on a treadmill. Test-retest measurements were obtained in a subset of seven women. Overall, TC(PCr), TC(ADP) and OxPhos were reproducible for all exercises (coefficients of variation = 2.3-19.3%). With increasing force-level, TC(PCr) was prolonged (29.0 +/- 8.2, 31.9 +/- 9.0 and 35.4 +/- 9.5 s), OxPhos was increased (0.159 +/- 0.081, 0.247 +/- 0.090 and 0.310 +/- 0.114), and TC(ADP) was shortened (22.4 +/- 7.9, 21.3 +/- 6.2, and 19.5 +/- 6.7; p < 0.01). All MRS markers of mitochondrial function were correlated with VO(2max) (r = 0.41-0.72; p < 0.05). These results suggest that measurements of TC(PCr), TC(ADP) and OxPhos yield reproducible results that correlate with whole-body VO(2max) and that vary in force-level sensitivity.

Adenosine Diphosphate↗
PubMed2001

A mitochondrial paradigm for degenerative diseases and ageing.

A variety of degenerative diseases have now been shown to be caused by mutations in mitochondrial genes encoded by the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). The mitochondria generate most of the cellular energy by oxidative phosphorylation (OXPHOS), and produce most of the toxic reactive oxygen species (ROS) as a by-product. Genetic defects that inhibit OXPHOS also cause the redirection of OXPHOS electrons into ROS production, thus increasing oxidative stress. A decline in mitochondrial energy production and an increase in oxidative stress can impinge on the mitochondrial permeability transition pore (mtPTP) to initiate programmed cell death (apoptosis). The interaction of these three factors appear to play a major role on the pathophysiology of degenerative diseases. Inherited diseases can result from mtDNA base substitution and rearrangement mutations and can affect the CNS, heart and skeletal muscle, and renal, endocrine and haematological systems. In addition, somatic mtDNA mutations accumulate with age in post-mitotic tissues in association with the age-related decline in mitochondrial function and are thought to be an important factor in ageing and senescence. The importance of mitochondrial defects in degenerative diseases and ageing has been demonstrated using mouse models of mitochondrial disease. An mtDNA mutation imparting chloramphenical resistance (CAPR) to mitochondrial protein synthesis has been transferred into mice and resulted in growth retardation and cardiomyopathy. A nDNA mutation which inactivates the heart-muscle isoform of the adenine nucleotide translocator (Ant1) results in mitochondrial myopathy and cardiomyopathy; induction of ROS production; the compensatory up-regulation of energy, antioxidant, and apoptosis gene expression; and an increase in the mtDNA somatic mutation rate. Finally, a nDNA mutation which inactivates the mitochondrial Mn superoxide dismutase (MnSOD) results in death in about 8 days due to dilated cardiomyopathy, which can be ameliorated by treatment with catalytic anti-oxidants. A partial MnSOD deficiency chronically increases oxidative stress, decreases OXPHOS function, and stimulates apoptosis. Thus, the decline of mitochondrial energy production resulting in increased oxidative stress and apoptosis does play a significant role in degenerative diseases and ageing.

Aging↗
PubMed2000

Clinical differences in patients with mitochondriocytopathies due to nuclear versus mitochondrial DNA mutations.

Defects in oxidative phosphorylation (OXPHOS) are genetically unique because the different components involved in this process, respiratory chain enzyme complexes (I, III, and IV) and complex V, are encoded by nuclear and mitochondrial genome. The objective of the study was to assess whether there are clinical differences in patients suffering from OXPHOS defects caused by nuclear or mitochondrial DNA (mtDNA) mutations. We studied 16 families with > or = two siblings with a genetically established OXPHOS deficiency, four due to a nuclear gene mutation and 12 due to a mtDNA mutation. Siblings with a nuclear gene mutation showed very similar clinical pictures that became manifest in the first years (ranging from first months to early childhood). There was a severe progressive course. Seven of the eight children died in their first decade. Conversely, siblings with a mtDNA mutation had clinical pictures that varied from almost alike to very distinct. They became symptomatic at an older age (ranging from childhood to adulthood), with the exception of defects associated with Leigh or Leigh-like phenotype. The clinical course was more gradual and relatively less severe; four of the 26 patients died, one in his second year, another in her second decade and two in their sixth decade. There are differences in age at onset, severity of clinical course, outcome, and intrafamilial variability in patients affected of an OXPHOS defect due to nuclear or mtDNA mutations. Patients with nuclear mutations become symptomatic at a young age, and have a severe clinical course. Patients with mtDNA mutations show a wider clinical spectrum of age at onset and severity. These differences may be of importance regarding the choice of which genome to study in affected patients as well as with respect to genetic counseling.

Adolescent↗
PubMed2001

Mitochondria and degenerative disorders.

In mammalian cells, mitochondria provide energy from aerobic metabolism. They play an important regulatory role in apoptosis, produce and detoxify free radicals, and serve as a cellular calcium buffer. Neurodegenerative disorders involving mitochondria can be divided into those caused by oxidative phosphorylation (OXPHOS) abnormalities either due to mitochondrial DNA (mtDNA) abnormalities, e.g., chronic external ophthalmoplegia, or due to nuclear mutations of OXPHOS proteins, e.g., complex I and II associated with Leigh syndrome. There are diseases caused by nuclear genes encoding non-OXPHOS mitochondrial proteins, such as frataxin in Friedreich ataxia (which is likely to play an important role in mitochondrial-cytosolic iron cycling), paraplegin (possibly a mitochondrial ATP-dependent zinc metalloprotease of the AAA-ATPases in hereditary spastic paraparesis), and possibly Wilson disease protein (an abnormal copper transporting ATP-dependent P-type ATPase associated with Wilson disease). Huntingon disease is an example of diseases with OXPHOS defects associated with mutations of nuclear genes encoding non-mitochondrial proteins such as huntingtin. There are also disorders with evidence of mitochondrial involvement that cannot as yet be assigned. These include Parkinson disease (where a complex I defect is described and free radicals are generated from dopamine metabolism), amyotrophic lateral sclerosis, and Alzheimer disease, where there is evidence to suggest mitochondrial involvement perhaps secondary to other abnormalities.

Adenosine Triphosphatases↗
PubMed1994

Chronic progressive external ophthalmoplegia is associated with a novel mutation in the mitochondrial tRNA(Asn) gene.

Chronic progressive external ophthalmoplegia (CPEO) is caused by a decreased oxidative phosphorylation (OXPHOS) activity due to large-scale deletions of the mitochondrial genome in 50% of the patients. The deletions encompass structural OXPHOS genes as well as tRNA genes, required for their expression so that the pathogenesis could be due to the deleted OXPHOS subunits or to an impaired mitochondrial translation. We have analyzed the mitochondrial genome of a patient presenting with CPEO for single base substitutions and discovered a novel heteroplasmic mutation in the tRNA(Asn) gene at position 5692 that converts a highly conserved adenine into a guanine. This mutation is unique because it is located at the transition of the anticodon loop to the anticodon stem and it leads to an additional base pair, thus reducing the number of loop-forming nucleotides from seven to five. Our findings suggest that CPEO can be caused by a single base substitution in a mitochondrial tRNA gene so that the mitochondrial protein synthesis becomes the rate limiting step in OXPHOS fidelity.

Base Sequence↗
PubMed1999

Regulation of energy metabolism in human cells in aging and diabetes: FoF(1), mtDNA, UCP, and ROS.

Recent advances in bioenergetics consist of discoveries related to rotational coupling in ATP synthase (FoF(1)), uncoupling proteins (UCP), reactive oxygen species (ROS) and mitochondrial DNA (mtDNA). As shown in cloned sheep, mammalian genomes are composed of both nuclear DNA (nDNA) and maternal mtDNA. Oxidative phosphorylation (oxphos) varies greatly depending on cellular activities, and is regulated by both gene expression and the electrochemical potential difference of H(+) (Delta muH(+)). The expression of both mtDNA (by mtTFA) and nDNA for oxphos and UCP (by NRFs, etc.) is coordinated by a factor called PGC-1. The Delta muH(+) rotates an axis in FoF(1) that is regulated by inhibitors and ATP-sensitive K(+)-channels. We cultured human rho(o) cells (cells without mtDNA) in synthetic media and elucidated relationships among mtDNA, nDNA, Delta muH(+), UCPs, ROS, and apoptosis. These cells lack oxphos-dependent ROS formation and survive under conditions of high O(2). Cells cultured in the absence of ROS scavengers have proliferated for 40 years. UCPs lower Delta muH(+) and prevent ROS formation and resulting apoptosis. These results were applied to diabetology and gerontology. The pancreatic rho(o) cells did not secrete insulin, and mtDNA mutations caused diabetes, owing to the deficient Delta muH(+). Insulin resistance was closely related to UCPs and other energy regulators. The resulting high-glucose environment caused glycation of proteins and ROS-mediated apoptosis in vascular cells involved in diabetic complications. Telomeres, oxphos, and ROS are determinants in cellular aging. Cell division and ROS shortened telomeres and accelerated aging. In aged cells, Delta muH(+) was reduced by the slow respiration, and this change induced apoptosis. Cybrids made from aged cytoplasts and rho(o) cells showed that both decreased expression of nDNA, and somatic mutations of mtDNA are involved in the slowing of respiration in aged cells.

Aging↗
PubMed2000

Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene.

Combined OXPHOS-system enzyme deficiencies are observed in approximately 25% of all OXPHOS-system disturbances. Of these, combined complex I and III deficiency is relatively scarce. So far, only mtDNA and thymidine phosphorylase (TP) mutations have been associated with combined OXPHOS-system disturbances. In this report we show, for the first time, that a nuclear gene mutation in a structural, nuclear encoded complex I gene is associated with combined complex I and III deficiency. After our initial report we describe mutations in the NDUFS4 gene of complex I in two additional patients. The first mutation is a deletion of G at position 289 or 290. Amino acid 96 changes from a tryptophan to a stop codon. The mutation was found homozygous in the patient; both parents are heterozygous for the mutation. The second mutation is a transition from C to T at cDNA position 316. Codon is changed from CGA (arginine) to TGA (stop). The patient is homozygous for the mutation; both parents are heterozygous. Both mutations in the NDUFS4 gene led to a premature stop in Leigh-like patients with an early lethal phenotype. We hypothesise that the structural integrity of the OXPHOS system, in mammal supermolecular structures, may be responsible for the observed biochemical features.

Base Sequence↗
PubMed1996

Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer's disease.

In vivo imaging of patients with Alzheimer's disease using positron emission tomography (PET) demonstrates progressive reductions in brain glucose metabolism and blood flow in relation to dementia severity, more so in association than primary cortical regions. These reductions likely follow regional synaptic loss or dysfunction and reflect physiological down-regulation of gene expression for glucose delivery, oxidative phosphorylation (OXPHOS), and energy consumption in brain. Indeed, the pattern of down-regulation of expression for both mitochondrial and nuclear genes coding for subunits of OXPHOS enzymes in the Alzheimer brain resembles the pattern of down-regulation in normal brain caused by chronic sensory deprivation. In both cases, down-regulation likely is mediated by changes in transcriptional and posttranscriptional regulatory factors. Physiological down-regulation of OXPHOS gene expression in Alzheimer's is consistent with PET evidence that cognitive or psychophysical activation of mildly to moderately demented Alzheimer's patients can augment brain-blood flow and glucose metabolism to the same extent as in control subjects. If the primary neuronal defect that leads to reduced brain energy demand in Alzheimer's disease could be prevented or treated, brain glucose transport and OXPHOS enzyme activities might recover to normal levels.

Alzheimer Disease↗