scholarly journals Expanding and validating the biomarkers for mitochondrial diseases

2020 ◽  
Vol 98 (10) ◽  
pp. 1467-1478
Author(s):  
Alessandra Maresca ◽  
◽  
Valentina Del Dotto ◽  
Martina Romagnoli ◽  
Chiara La Morgia ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Genetic Alterations ◽  
Fibroblast Growth Factor 21 ◽  
Trna Genes ◽  
The Novel ◽  
Longitudinal Assessment ◽  
Mitochondrial Translation ◽  
Monitoring Therapy

Abstract Mitochondrial diseases are highly heterogeneous metabolic disorders caused by genetic alterations in the mitochondrial DNA (mtDNA) or in the nuclear genome. In this study, we investigated a panel of blood biomarkers in a cohort of 123 mitochondrial patients, with prominent neurological and muscular manifestations. These biomarkers included creatine, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF-15), and the novel cell free circulating-mtDNA (ccf-mtDNA). All biomarkers were significantly increased in the patient group. After stratification by the specific phenotypes, ccf-mtDNA was significantly increased in the Mitochondrial Encephalomyopathy Lactic Acidosis Stroke-like episodes syndrome (MELAS) group, and FGF21 and GDF-15 were significantly elevated in patients with MELAS and Myoclonic Epilepsy Ragged Red Fibers syndrome. On the contrary, in our cohort, creatine was not associated to a specific clinical phenotype. Longitudinal assessment in four MELAS patients showed increased levels of ccf-mtDNA in relation to acute events (stroke-like episodes/status epilepticus) or progression of neurodegeneration. Our results confirm the association of FGF21 and GDF-15 with mitochondrial translation defects due to tRNA mutations. Most notably, the novel ccf-mtDNA was strongly associated with MELAS and may be used for monitoring the disease course or to evaluate the efficacy of therapies, especially in the acute phase. Key messages • FGF21/GDF15 efficiently identifies mitochondrial diseases due to mutations in tRNA genes. • The novel ccf-mtDNA is associated with MELAS and increases during acute events. • Creatine only discriminates severe mitochondrial patients. • FGF21, GDF-15, and ccf-mtDNA are possibly useful for monitoring therapy efficacy.

Posttranscriptional modifications in mitochondrial tRNA and its implication in mitochondrial translation and disease

2020 ◽  
Vol 168 (5) ◽  
pp. 435-444
Author(s):  
Tomizawa Kazuhito ◽  
Fan-Yan Wei
Keyword(s):  
Mitochondrial Diseases ◽  
Protein Translation ◽  
Fundamental Aspect ◽  
Trna Genes ◽  
Mitochondrial Translation ◽  
Mitochondrial Trna ◽  
Genes Encoding ◽  
Stability Structure ◽  
Life Threatening ◽  
Mrna Binding

Abstract A fundamental aspect of mitochondria is that they possess DNA and protein translation machinery. Mitochondrial DNA encodes 22 tRNAs that translate mitochondrial mRNAs to 13 polypeptides of respiratory complexes. Various chemical modifications have been identified in mitochondrial tRNAs via complex enzymatic processes. A growing body of evidence has demonstrated that these modifications are essential for translation by regulating tRNA stability, structure and mRNA binding, and can be dynamically regulated by the metabolic environment. Importantly, the hypomodification of mitochondrial tRNA due to pathogenic mutations in mitochondrial tRNA genes or nuclear genes encoding modifying enzymes can result in life-threatening mitochondrial diseases in humans. Thus, the mitochondrial tRNA modification is a fundamental mechanism underlying the tight regulation of mitochondrial translation and is essential for life. In this review, we focus on recent findings on the physiological roles of 5-taurinomethyl modification (herein referred as taurine modification) in mitochondrial tRNAs. We summarize the findings in human patients and animal models with a deficiency of taurine modifications and provide pathogenic links to mitochondrial diseases. We anticipate that this review will help understand the complexity of mitochondrial biology and disease.

scholarly journals Diabetic conditions induce intolerance to accumulation of pathogenic mitochondrial DNAs

2019 ◽  
Author(s):  
Emi Ogasawara ◽  
Shun Katada ◽  
Takayuki Mito ◽  
Jun-Ichi Hayashi ◽  
Kazuto Nakada
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Large Scale ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Pathogenic Mutation ◽  
Physiological Status ◽  
Trna Genes ◽  
Diabetic Mice

AbstractMarked accumulation of mitochondrial DNA (mtDNA) with a particular pathogenic mutation is necessary for the mutant mtDNA to express its pathogenicity as mitochondrial respiration defects. However, the nuclear genome background, or the physiological status, or both, might also be important for the pathogenic regulation of mutant mtDNAs, because most mitochondrial function is controlled by polypeptides encoded in the nuclear genome. To test this, we generated diabetic mice carrying pathogenic mtDNA with a large-scale deletion (ΔmtDNA) that loses six tRNA genes and seven structural genes essential for mitochondrial respiration. Compared with non-diabetic mice carrying ΔmtDNA, diabetic mice carrying ΔmtDNA showed a decrease in mitochondrial biogenesis regulated by nuclear-encoded genes, and mitochondrial respiration defects and the resultant mitochondrial disease phenotypes were induced even in the case of low loads of ΔmtDNA. In addition, diabetic culture conditions intensified the pathogenicity of human mtDNA with an A3243G point mutation in the tRNALue (UUR) gene. Our results indicated that the diabetic conditions are a modifier that exacerbates mitochondrial respiration defects due to mutant mtDNAs. The finding suggests the possibility that recovery from diabetic conditions might be an effective treatment strategy for some disorders involving both mutant mtDNAs and diabetic signs.Author SummaryIt has been reported that accumulation of pathogenic mutant mitochondrial DNA (mtDNA) and the resultant mitochondrial metabolic dysfunction are associated with a wide variety of disorders, such as mitochondrial diseases, diabetes, neuo-degenerative disorders, and cancers. Considering that most mitochondrial function is regulated by nuclear-genome-encoded polypeptides, it is very important to focus on cooperation between mutant mtDNA, nuclear genetic background, and vital conditions for understanding precise pathogeneses of mtDNA-mediated disorders. By using model cells and mice carrying pathogenic mtDNAs, we report here that diabetic conditions are a modifier for the pathogenic regulation of mutant mtDNAs. Because the onset and progression of diabetes are often associated with aging, our finding suggests that some age-associated disorders with mutant mtDNAs and diabetic complications might be induced partly by enhancement of the pathogenicity of mutant mtDNAs by diabetic conditions.

scholarly journals Mitochondrial Syndromes Revisited

2021 ◽  
Vol 10 (6) ◽  
pp. 1249
Author(s):  
Daniele Orsucci ◽  
Elena Caldarazzo Ienco ◽  
Andrea Rossi ◽  
Gabriele Siciliano ◽  
Michelangelo Mancuso
Keyword(s):  
Clinical Trials ◽  
Genetic Basis ◽  
Phenotypic Variability ◽  
Mitochondrial Diseases ◽  
Genetic Alterations ◽  
Mitochondrial Disorders ◽  
Single Mutation ◽  
Multicenter Studies ◽  
Future Studies ◽  
Clinical Syndromes

In the last ten years, the knowledge of the genetic basis of mitochondrial diseases has significantly advanced. However, the vast phenotypic variability linked to mitochondrial disorders and the peculiar characteristics of their genetics make mitochondrial disorders a complex group of disorders. Although specific genetic alterations have been associated with some syndromic presentations, the genotype–phenotype relationship in mitochondrial disorders is complex (a single mutation can cause several clinical syndromes, while different genetic alterations can cause similar phenotypes). This review will revisit the most common syndromic pictures of mitochondrial disorders, from a clinical rather than a molecular perspective. We believe that the new phenotype definitions implemented by recent large multicenter studies, and revised here, may contribute to a more homogeneous patient categorization, which will be useful in future studies on natural history and clinical trials.

Altered adipokines in obese adolescents: A cross-sectional and longitudinal analysis across the spectrum of glycemia

2021 ◽  
Author(s):  
Risa M Wolf ◽  
Andrew E Jaffe ◽  
Susana Rodriguez ◽  
Xia Lei ◽  
Dylan C. Sarver ◽  
...  
Keyword(s):  
Fibroblast Growth Factor 21 ◽  
Oral Glucose ◽  
The Novel ◽  
Cross Sectional ◽  
Obese Adolescents ◽  
Obese Youth ◽  
Glucose Tolerance Tests ◽  
Inflammatory Milieu ◽  
Related Proteins

Obesity and type 2 diabetes is rapidly increasing in the adolescent population. We sought to determine whether adipokines, specifically leptin, C1q/TNF-related proteins 1 (CTRP1) and CTRP9, and the hepatokine fibroblast growth factor 21 (FGF-21), are associated with obesity and insulin resistance in a cohort of lean and obese adolescents, across the spectrum of glycemia. In an observational, longitudinal study of lean and obese adolescents, we measured fasting labs, oral glucose tolerance tests, and adipokines including: Leptin, CTRP1, CTRP9, and FGF-21. Participants completed baseline and 2-year follow-up study visits, and were categorized as lean (n=30), obese normoglycemic (ONG) (n=61), and obese hyperglycemic (OHG) (n=31) adolescents at baseline, and lean (n=8), ONG (n=18), and OHG (n=4) at follow-up. Results showed that at baseline, leptin was higher in all obese groups (p<0.001) compared to LC. FGF-21 was higher in OHG participants compared to LC (p<0.001) and ONG (p<0.001), and positively associated with fasting glucose (p<0.001), fasting insulin (p<0.001), HOMA-IR (p<0.001), and HbA1c (p=0.01). CTRP1 was higher in OHG compared to ONG (p=0.03). CTRP9 was not associated with obesity or hyperglycemia in this pediatric cohort. At 2 years, leptin decreased in ONG (p=0.003) and FGF21 increased in OHG (p=0.02), relative to lean controls. Altered adipokine levels are associated with the inflammatory milieu in obese youth with and without hyperglycemia. In adolescence, the novel adipokine CTRP1 was elevated with hyperglycemia, while CTRP9 was unchanged in this cohort.

Genetic Disease and Therapy

2021 ◽  
Vol 16 (1) ◽  
pp. 145-166
Author(s):  
Theodore L. Roth ◽  
Alexander Marson
Keyword(s):  
Dna Sequences ◽  
Current Practice ◽  
Genetic Diseases ◽  
Genetic Material ◽  
Nuclear Genome ◽  
Genetic Alterations ◽  
Genetic Diagnostics ◽  
Gene Therapies ◽  
Disease Risks ◽  
Diagnosis Therapy

Genetic diseases cause numerous complex and intractable pathologies. DNA sequences encoding each human's complexity and many disease risks are contained in the mitochondrial genome, nuclear genome, and microbial metagenome. Diagnosis of these diseases has unified around applications of next-generation DNA sequencing. However, translating specific genetic diagnoses into targeted genetic therapies remains a central goal. To date, genetic therapies have fallen into three broad categories: bulk replacement of affected genetic compartments with a new exogenous genome, nontargeted addition of exogenous genetic material to compensate for genetic errors, and most recently, direct correction of causative genetic alterations using gene editing. Generalized methods of diagnosis, therapy, and reagent delivery into each genetic compartment will accelerate the next generations of curative genetic therapies. We discuss the structure and variability of the mitochondrial, nuclear, and microbial metagenomic compartments, as well as the historical development and current practice of genetic diagnostics and gene therapies targeting each compartment.

FIBROBLAST GROWTH FACTOR 21 FROM THE PERSPECTIVE OF A PROMISING MARKER OF METABOLIC DISORDERS AND PREMATURE AGING IN POLYMORBID CARDIOVASCULAR PATHOLOGY IN YOUNG AND MIDDLE-AGED PEOPLE

2020 ◽  
Vol 4 (2) ◽  
pp. 1002-1005
Author(s):  
G.A. Proshchai ◽  
◽  
S.V. Dudarenko ◽  
A.S. Partcerniak ◽  
E.Yu. Zagarskikh ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Disorders ◽  
Premature Aging ◽  
Fibroblast Growth Factor 21 ◽  
Control Group ◽  
Middle Aged ◽  
Cardiovascular Pathology ◽  
Aged People ◽  
Carbohydrate And Lipid Metabolism

Objective: To evaluate the possibility of using fibroblast growth factor 21 (FGF 21) as a marker of metabolic disorders and premature aging in polymorbid cardiovascular pathology. Research methods: 199 men aged 35-55 years who were stratified into 3 groups were examined: group A - 117 patients with type 2 diabetes mellitus (type 2 diabetes), polymorbid cardiovascular disease (PCVD), obesity, androgen deficiency and anxiety-depressive disorders (ADD); group B - 55 patients with PCVD, obesity and ADD; group C - control group (n = 27). The examination of patients included a laboratory study of the level of FGF 21, indicators of carbohydrate and lipid metabolism, hormonal status, as well as daily monitoring of blood pressure and ECG. Results and conclusions. When compared with the control group, the level of FGF 21 was 3 times higher in the presence of type 2 diabetes. The most intense increase in FGF 21 levels was observed in groups of patients with several diseases. An increase in the level of FGF 21 in young and middle-aged people is probably due to a compensatory reaction to the existing androgen deficiency, disorders of carbohydrate and lipid metabolism. Strong correlations between FGF 21 and glucose, HDL cholesterol, total testosterone, ALT, and SBP during the day allow FGF 21 to be considered an early marker of cardiovascular disease and premature aging (PA) in young and middle-aged people

scholarly journals Measuring Food Anticipation in Mice

2018 ◽  
Vol 1 (1) ◽  
pp. 65-74
Author(s):  
Tomaz Martini ◽  
Jürgen Ripperger ◽  
Urs Albrecht
Keyword(s):  
Body Temperature ◽  
Gene Function ◽  
Metabolic Disorders ◽  
Genetic Alterations ◽  
Circadian System ◽  
Physiological Adaptation ◽  
Pharmacological Intervention ◽  
Feeding Time ◽  
Evolutionary Advantage ◽  
Internal Body

The interplay between the circadian system and metabolism may give animals an evolutionary advantage by allowing them to anticipate food availability at specific times of the day. Physiological adaptation to feeding time allows investigation of animal parameters and comparison of food anticipation between groups of animals with genetic alterations and/or post pharmacological intervention. Such an approach is vital for understanding gene function and mechanisms underlying the temporal patterns of both food anticipation and feeding. Exploring these mechanisms will allow better understanding of metabolic disorders and might reveal potential new targets for pharmacological intervention. Changes that can be easily monitored and that represent food anticipation on the level of the whole organism are a temporarily restricted increase of activity and internal body temperature.

scholarly journals Alterations in vitamin A/retinoic acid homeostasis in diet-induced obesity and insulin resistance

2017 ◽  
Vol 76 (4) ◽  
pp. 597-602 ◽  
Author(s):  
Nimesh Mody
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Biological Activities ◽  
Parent Compound ◽  
Genetic Alterations ◽  
Fibroblast Growth Factor 21 ◽  
Glucose Levels ◽  
Disease States ◽  
Diet Induced Obesity ◽  
Blood Glucose Levels

Vitamin A is an essential micronutrient for life and the phytochemical β-carotene, also known as pro-vitamin A, is an important dietary source of this vitamin. Vitamin A (retinol) is the parent compound of all bioactive retinoids but it is retinoic acid (RA) that is the active metabolite of vitamin A. The plasma concentration of retinol is maintained in a narrow range and its normal biological activities strictly regulated since excessive intake can lead to toxicity and thus also be detrimental to life. The present review will give an overview of how vitamin A homeostasis is maintained and move on to focus on the link between circulating vitamin A and metabolic disease states. Finally, we will examine how pharmacological or genetic alterations in vitamin A homeostasis and RA-signalling can influence body fat and blood glucose levels including a novel link to the liver secreted hormone fibroblast growth factor 21, an important metabolic regulator.

scholarly journals Mitochondrial DNA transcription and translation: clinical syndromes

2018 ◽  
Vol 62 (3) ◽  
pp. 321-340 ◽  
Author(s):  
Veronika Boczonadi ◽  
Giulia Ricci ◽  
Rita Horvath
Keyword(s):  
Mitochondrial Protein ◽  
Clinical Manifestations ◽  
Mitochondrial Diseases ◽  
Mitochondrial Translation ◽  
Tissue Specific ◽  
Functional Studies ◽  
Whole Exome ◽  
Clinical Syndromes ◽  
Chain Defects ◽  
Nuclear Mutations

Diagnosing primary mitochondrial diseases is challenging in clinical practice. Although, defective oxidative phosphorylation (OXPHOS) is the common final pathway, it is unknown why different mtDNA or nuclear mutations result in largely heterogeneous and often tissue -specific clinical presentations. Mitochondrial tRNA (mt-tRNA) mutations are frequent causes of mitochondrial diseases both in children and adults. However numerous nuclear mutations involved in mitochondrial protein synthesis affecting ubiquitously expressed genes have been reported in association with very tissue specific clinical manifestations suggesting that there are so far unknown factors determining the tissue specificity in mitochondrial translation. Most of these gene defects result in histological abnormalities and multiple respiratory chain defects in the affected organs. The clinical phenotypes are usually early-onset, severe, and often fatal, implying the importance of mitochondrial translation from birth. However, some rare, reversible infantile mitochondrial diseases are caused by very specific defects of mitochondrial translation. An unbiased genetic approach (whole exome sequencing, RNA sequencing) combined with proteomics and functional studies revealed novel factors involved in mitochondrial translation which contribute to the clinical manifestation and recovery in these rare reversible mitochondrial conditions.

scholarly journals Identification of highly-disrupted tRNA genes in nuclear genome of the red alga, Cyanidioschyzon merolae 10D

2013 ◽  
Vol 3 (1) ◽  
Author(s):  
Akiko Soma ◽  
Junichi Sugahara ◽  
Akinori Onodera ◽  
Nozomu Yachie ◽  
Akio Kanai ◽  
...  
Keyword(s):  
Nuclear Genome ◽  
Red Alga ◽  
Cyanidioschyzon Merolae ◽  
Trna Genes
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