Mitochondrial dna-related disorders: Emphasis on mechanisms and heterogeneity

Mitochondrial diseases are a heterogeneous group of disorders that are currently the focus of intense research. The many cell functions performed by mitochondria include ATP production, calcium homeostasis, and apoptosis. One of the unique properties of mitochondria is the existence of a separate mitochondrial genome (mitochondrial DNA, mtDNA) found in varying copy numbers and containing 37 genes, 13 of them encoding proteins. All 13 mitochondrially encoded proteins form part of oxidative phosphorylation complexes through combination with approximately 100 nuclear DNA-encoded proteins. Coregulation of nDNA and mtDNA is therefore essential for mitochondrial function, and this coregulation contributes to the heterogeneity and complexity observed in mitochondrial disorders. In recent times, significant advances have been made in our understanding of mtDNA-related disorders. A comprehensive review of these studies will benefit both current and new researchers and clinicians involved in the field. This review examines the major types of mtDNA-related defects and their pathogenic mechanisms, with a special emphasis on the heterogeneity of mitochondrial disorders. Potential treatment strategies specialized for each of the disorders, including the hormone melatonin and the recent advances in gene therapy, related to their potential applications for the management of the primary mtDNA disorders are also discussed

Specific increase of a mitochondrial RNA transcript in chronic ethanol-fed rats

AbstractAn in vitro transcription system utilizing isolated mitochondria has been used to study the effect of chronic ethanol consumption on liver mitochondrial DNA transcription. The results obtained showed an overall increase of RNA synthesis and a dramatic accumulation of a discrete polyadenylated RNA species. This effect is a consequence of the chronic ethanol consumption since these changes do not occur when isolated control mitochondria are incubated in the presence of ethanol

Genetics of obesity.

OBJECTIVE: The aim was to review and update advances in genetics of obesity. DESIGN: Analysis and interpretation of recent investigations about regulating the energy balance as well as about gene-nutrient interactions and current nutri-genomic research methods. BACKGROUND AND MAIN STATEMENTS: Obesity results from a long-term positive energy balance. However, its rising prevalence in developed and developing societies must reflect lifestyle changes, since genetic susceptibility remains stable over many generations. Like most complex diseases, obesity derives from a failure of adequate homoeostasis within the physiological system controlling body weight. The identification of genes that are involved in syndromic, monogenic and polygenic obesity has seriously improved our knowledge of body weight regulation. This disorder may arise from a deregulation at the genetic level (e.g. gene transcription or altered protein function) or environmental exposure (e.g. diet, physical activity, etc.). CONCLUSIONS: In practice, obesity involves the interaction between genetic and environmental factors

Adjusting MtDNA quantification in whole blood for peripheral blood platelet and leukocyte counts

Alterations of mitochondrial DNA copy number (mtDNAcn) in the blood (mitochondrial to nuclear DNA ratio) appear associated with several systemic diseases, including primary mitochondrial disorders, carcinogenesis, and hematologic diseases. Measuring mtDNAcn in DNA extracted from whole blood (WB) instead of from peripheral blood mononuclear cells or buffy coat may yield different results due to mitochondrial DNA present in platelets. The aim of this work is to quantify the contribution of platelets to mtDNAcn in whole blood mtDNAcn(WB)] and to propose a correction formula to estimate leukocytes'' mtDNAcn mtDNAcn(L)] from mtDNAcn(WB). Blood samples from 10 healthy adults were combined with platelet-enriched plasma and saline solution to produce artificial blood preparations. Aliquots of each sample were combined with five different platelet concentrations. In 46 of these blood preparations, mtDNAcn was measured by qPCR. MtDNAcn(WB) increased 1.07 (95%CI 0.86, 1.29; p<0.001) per 1000 platelets present in the preparation. We proved that leukocyte count should also be taken into account as mtDNAcn(WB) was inversely associated with leukocyte count; it increased 1.10 (95%CI 0.95, 1.25, p<0.001) per unit increase of the ratio between platelet and leukocyte counts. If hematological measurements are available, subtracting 1.10 the platelets/leukocyte ratio from mtDNAcn(WB) may serve as an estimation for mtDNAcn(L). Both platelet and leukocyte counts in the sample are important sources of variation if comparing mtDNAcn among groups of patients when mtDNAcn is measured in DNA extracted from whole blood. Not taking the platelet/leukocyte ratio into account in whole blood measurements, may lead to overestimation and misclassification if interpreted as leukocytes'' mtDNAcn

The State of Self-Organized Criticality of the Sun During the Last 3 Solar Cycles. I. Observations

We analyze the occurrence frequency distributions of peak fluxes $P$, total fluxes $E$, and durations $T$ of solar flares over the last three solar cycles (during 1980--2010) from hard X-ray data of HXRBS/SMM, BATSE/CGRO, and RHESSI. From the synthesized data we find powerlaw slopes with mean values of $\alpha_P=1.72\pm0.08$ for the peak flux, $\alpha_E=1.60\pm0.14$ for the total flux, and $\alpha_T=1.98\pm0.35$ for flare durations. We find a systematic anti-correlation of the powerlaw slope of peak fluxes as a function of the solar cycle, varying with an approximate sinusoidal variation $\alpha_P(t)=\alpha_0+\Delta \alpha \cos{[2\pi (t-t_0)/T_{cycle}]}$, with a mean of $\alpha_0=1.73$, a variation of $\Delta \alpha =0.14$, a solar cycle period $T_{cycle}=12.6$ yrs, and a cycle minimum time $t_0=1984.1$. The powerlaw slope is flattest during the maximum of a solar cycle, which indicates a higher magnetic complexity of the solar corona that leads to an overproportional rate of powerful flares.Comment: subm. to Solar Physic

Role of Mitochondrial Complex IV in Age-Dependent Obesity

Aging is associated with progressive white adipose tissue (WAT) enlargement initiated early in life, but the molecular mechanisms involved remain unknown. Here we show that mitochondrial complex IV (CIV) activity and assembly are already repressed in white adipocytes of middle-aged mice and involve a HIF1A-dependent decline of essential CIV components such as COX5B. At the molecular level, HIF1A binds to the Cox5b proximal promoter and represses its expression. Silencing of Cox5b decreased fatty acid oxidation and promoted intracellular lipid accumulation. Moreover, local in vivo Cox5b silencing in WAT of young mice increased the size of adipocytes, whereas restoration of COX5B expression in aging mice counteracted adipocyte enlargement. An age-dependent reduction in COX5B gene expression was also found in human visceral adipose tissue. Collectively, our findings establish a pivotal role for CIV dysfunction in progressive white adipocyte enlargement during aging, which can be restored to alleviate age-dependent WAT expansion

Noncommutative solitons on Kahler manifolds

We construct a new class of scalar noncommutative multi-solitons on an arbitrary Kahler manifold by using Berezin's geometric approach to quantization and its generalization to deformation quantization. We analyze the stability condition which arises from the leading 1/hbar correction to the soliton energy and for homogeneous Kahler manifolds obtain that the stable solitons are given in terms of generalized coherent states. We apply this general formalism to a number of examples, which include the sphere, hyperbolic plane, torus and general symmetric bounded domains. As a general feature we notice that on homogeneous manifolds of positive curvature, solitons tend to attract each other, while if the curvature is negative they will repel each other. Applications of these results are discussed.Comment: 26 pages, 3 figures, harvmac; references adde

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD

OBJECTIVE: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. METHODS: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. RESULTS: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. CONCLUSION: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD