| 1. |
- Abhyankar, Avinash, et al.
(författare)
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Comparative sequence analysis of the non-protein-coding mitochondrial DNA of inbred rat strains.
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:12
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Tidskriftsartikel (refereegranskat)abstract
- The proper function of mammalian mitochondria necessitates a coordinated expression of both nuclear and mitochondrial genes, most likely due to the co-evolution of nuclear and mitochondrial genomes. The non-protein coding regions of mitochondrial DNA (mtDNA) including the D-loop, tRNA and rRNA genes form a major component of this regulated expression unit. Here we present comparative analyses of the non-protein-coding regions from 27 Rattus norvegicus mtDNA sequences. There were two variable positions in 12S rRNA, 20 in 16S rRNA, eight within the tRNA genes and 13 in the D-loop. Only one of the three neutrality tests used demonstrated statistically significant evidence for selection in 16S rRNA and tRNA-Cys. Based on our analyses of conserved sequences, we propose that some of the variable nucleotide positions identified in 16S rRNA and tRNA-Cys, and the D-loop might be important for mitochondrial function and its regulation.
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| 2. |
- Abhyankar, Avinash
(författare)
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Mitochondrial and chromosomal genomics in type 2 diabetes
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Understanding the mechanisms of complex polygenic diseases like type 2 diabetes (T2D) is as complex as their nature. Cellular processes involved in glucose homeostasis need high and reliable energy supply. Mitochondria are the major energy producers in mammalian cells. Since majority of the mitochondrial genes are encoded by the nuclear genome, a tightly regulated and coordinated nuclear-mitochondrial crosstalk needs to be ensured. Perturbation of this communication will attenuate the cellular response to variable energy demands. To understand the role of nuclear-mitochondrial interactions in T2D, we setup a reciprocal cross between the diabetic GK and the normoglycaemic F344 rats. This reciprocal cross consisted of two individual crosses that shared identical nuclear DNA haplotypes while they differed in the mtDNA haplotypes at 110 nucleotide positions. We performed cross-separated linkage analysis to map QTLs segregating only in the presence of specific mtDNA genotype, which is a first-line indication for the interactions between nuclear QTL and mtDNA. Two genomic loci were found linked to three traits depending on the mtDNA haplotype. Within these loci we were able to identify forty nuclear-encoded mitochondrial genes. One of the identified loci, Niddm71, was dissected further using a congenic rat, C9B. Characterization of the C9B rat revealed that the Niddm71 locus encodes for a defect in insulin secretion and a defect in mitochondrial function. With a combination of bioinformatics and experimental methods we identified several genes and non-coding sequences within Niddm71 that likely play a role in insulin secretion and mitochondrial function. To investigate the role of mtDNA variants on the susceptibility of T2D we sequenced complete mitochondrial genomes of the diabetic GK and normoglycemic F344 rats and identified 110 variable nucleotide positions. To prioritize functionally important nucleotide variants, we further sequenced mitochondrial genomes of 12 commonly used inbred laboratory rat strains. Using different phylogenetic methods we identified several genes and sites in the mtDNA that might be important for mitochondrial function. In this study we have identified nuclear loci which are modulated by the mitochondrial genotype and identified mitochondrial loci that might be of vital importance for its function. The results of our study will provide additional stimulus for further research in understanding nuclear-mitochondrial interactions and their role in metabolic diseases like T2D.
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| 3. |
- Mezhybovska, Maryna, et al.
(författare)
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Beta-catenin is involved in alterations in mitochondrial activity in non-transformed intestinal epithelial and colon cancer cells.
- 2009
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 101:9, s. 1596-1605
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alteration in respiratory activity and mitochondrial DNA (mtDNA) transcription seems to be an important feature of cancer cells. Leukotriene D(4) (LTD(4)) is a proinflammatory mediator implicated in the pathology of chronic inflammation and cancer. We have shown earlier that LTD(4) causes translocation of beta-catenin both to the mitochondria, in which it associates with the survival protein Bcl-2 identifying a novel role for beta-catenin in cell survival, and to the nucleus in which it activates the TCF/LEF transcription machinery. METHODS: Here we have used non-transformed intestinal epithelial Int 407 cells and Caco-2 colon cancer cells, transfected or not with wild type and mutated (S33Y) beta-catenin to analyse its effect on mitochondria activity. We have measured the ATP/ADP ratio, and transcription of the mtDNA genes ND2, ND6 and 16 s in these cells stimulated or not with LTD(4). RESULTS: We have shown for the first time that LTD(4) triggers a cellular increase in NADPH dehydrogenase activity and ATP/ADP ratio. In addition, LTD(4) significantly increased the transcription of mtDNA genes. Overexpression of wild-type beta-catenin or a constitutively active beta-catenin mutant mimicked the effect of LTD(4) on ATP/ADP ratio and mtDNA transcription. These elevations in mitochondrial activity resulted in increased reactive oxygen species levels and subsequent activations of the p65 subunit of NF-kappaB. CONCLUSIONS: The present novel data show that LTD(4), presumably through beta-catenin accumulation in the mitochondria, affects mitochondrial activity, lending further credence to the idea that inflammatory signalling pathways are intrinsically linked with potential oncogenic signals.
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| 4. |
- Nicolas, Aude, et al.
(författare)
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- 2018
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Ingår i: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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| 5. |
- Nosadini, R, et al.
(författare)
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Altered transcapillary escape of albumin and microalbuminuria reflects two different pathogenetic mechanisms
- 2005
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Ingår i: Diabetes. - 1939-327X. ; 54:1, s. 228-233
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Tidskriftsartikel (refereegranskat)abstract
- We studied the following in normo- and microalbuminuric hypertensive type 2 diabetic patients: 1) transcapillary escape rate of albumin (TERalb) and 2) expression of mRNA slit diaphragm and podocyte proteins in renal biopsies. Normoalbuminuric subjects had renal cancer, and kidney biopsy was performed during surgery. TERalb was evaluated by clearance of I-125- albumin. Real-time PCR of mRNA slit diaphragm was measured in kidney specimens. Albumin excretion rate (AER) was by definition lower in normoalbuminuric subjects than in microalbuminuric subjects with typical diabetic glomerulopathy (group 1), in microalbuminuric subjects with normal or near-normal glomerular structure (group 2), and in microalbuminuric subjects with atypical diabetic nephropathy (group 3). This classification was based on light microscopy analysis of renal tissue. TERalb (%/h) was similar in normoalbuminuric and microalbuminuric group 1, 2, and 3 diabetic patients (medians: 14.1 vs. 14.4 vs. 15.7 vs. 14.9, respectively) (ANOVA, NS). mRNA expression of slit diaphragm proteins CD2AP, FAT, Actn 4, NPHS1, and NPHS2 was higher in normoalbuminuric patients than in microalbuminuric patients (groups 1, 2, and 3) (ANOVA, P < 0.001). All diabetic patients had greater carotid artery intimal thickness than normal control subjects using ultrasound technique (ANOVA, P < 0.01). In conclusion, the present study suggests that microalbuminuria identifies a subgroup of hypertensive type 2 diabetic patients who have altered mRNA expression of slit diaphragm and podocyte proteins, even before glomerular structure shows abnormalities using light microscopy analysis. On the contrary, altered TERalb and increased carotid artery intimal thickness are shown by all hypertensive type 2 diabetic patients, both with normal and altered patterns of AER.
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| 6. |
- Nosadini, R, et al.
(författare)
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Increased renal arterial resistance predicts the course of renal function in type 2 diabetes with microalbuminuria
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:1, s. 234-239
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetic patients often die because of end-stage renal failure, but no definitive reliable factor predicting long-term renal outcome has been identified. We tested whether a renal arterial resistance index (R/I) >= 80, using Doppler ultrasound technique, was predictive of worsening renal function. The primary end points of the study were 1) the course of glomerular filtration rate (GFR) and 2) the albumin excretion rate in 157 microalbuminuric, hypertensive, type 2 diabetic patients after a 7.8-year follow-up period (range 7.1-9.2). Kaplan-Meier curves for the primary end point (decrease of GFR 3.0 ml/min per 1.73 in per year) was two to three times more frequently observed in patients with R/I >= 80. Four- to fivefold fewer patients showed a regression to normoalbuminuria during the follow-up period from baseline microalbuminuria in the cohort with R/I >= 80. Overt proteinuria did develop in 24% of patients with R/I >= 80 and in 5% of patients with R/I <80 (P < 0.01). In conclusion, intrarenal arterial resistance appears to play a nontrivial role in deteriorating renal function in type 2 diabetic patients. R/I is a noninvasive diagnostic procedure, which strongly predicts the outcome of renal function in type 2 diabetic patients, even when GFR patterns are still normal.
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| 7. |
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| 8. |
- Tonolo, G., et al.
(författare)
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Simvastatin maintains steady patterns of GFR and improves AER and expression of slit diaphragm proteins in type II diabetes
- 2006
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Ingår i: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 70:1, s. 177-186
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Tidskriftsartikel (refereegranskat)abstract
- The factors determining the course of glomerular fitration rate (GFR) and albumin excretion rate (AER) and the expression of mRNA of slit diaphragm (SD) and podocyte proteins in microalbuminuric, hypertensive type II diabetic patients are not fully understood. GFR, AER, and SD protein mRNA were studied in 86 microalbuminuric, hypertensive, type II diabetics at baseline and after 4-year random double-blind treatment either with 40 mg simvastatin (Group 1) or with 30 g cholestyramine (Group 2) per day. Both groups had at baseline a GFR decay per year in the previous 2-4 years of 3 ml/min/1.73 m(2). Both Groups 1 and 2 showed a significant decrease of low-density lipoprotein cholesterol levels after simvastatin and cholestyramine treatment (P < 0.01). No change from base line values was observed as for hs-C-reactive protein and interleukin-6. A significant decrease of 8-hydroxydeoxyguanosine urinary excretion was observed after simvastatin treatment. GFR did not change from baseline with simvstatin, whereas a decrease was observed with cholestyramine treatment ( simvastatin vs cholestyramine: -0.21 vs -2.75 ml/min/ 1.73 m(2), P < 0.01). AER decreased in Group 1 (P < 0.01), but not in Group 2 patients. Real-time polymerase chain reaction measurement of mRNA SD proteins (CD2AP, FAT, Actn 4, NPHS1, and NPHS2) significantly increased in kidney biopsy specimens after simvastatin, but not cholestyramine treatment. Simvastatin, but not cholestyramine, 4-year treatment maintains steady patterns of GFR, and improves AER and expression of SD proteins in type II diabetes, despite similar hypocholesterolemic effects in circulation.
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