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1.
Mitochondrion ; 62: 187-204, 2022 01.
Article in English | MEDLINE | ID: mdl-34740866

ABSTRACT

Although mitochondrial dysfunction is the known cause of primary mitochondrial disease, mitochondrial dysfunction is often difficult to measure and prove, especially when biopsies of affected tissue are not available. In order to identify blood biomarkers of mitochondrial dysfunction, we reviewed studies that measured blood biomarkers in genetically, clinically or biochemically confirmed primary mitochondrial disease patients. In this way, we were certain that there was an underlying mitochondrial dysfunction which could validate the biomarker. We found biomarkers of three classes: 1) functional markers measured in blood cells, 2) biochemical markers of serum/plasma and 3) DNA markers. While none of the reviewed single biomarkers may perfectly reveal all underlying mitochondrial dysfunction, combining biomarkers that cover different aspects of mitochondrial impairment probably is a good strategy. This biomarker panel may assist in the diagnosis of primary mitochondrial disease patients. As mitochondrial dysfunction may also play a significant role in the pathophysiology of multifactorial disorders such as Alzheimer's disease and glaucoma, the panel may serve to assess mitochondrial dysfunction in complex multifactorial diseases as well and enable selection of patients who could benefit from therapies targeting mitochondria.


Subject(s)
Biomarkers/blood , Mitochondrial Diseases/blood , Mitochondrial Diseases/diagnosis , Humans , Mitochondrial Diseases/metabolism
2.
J Clin Endocrinol Metab ; 97(9): 3261-9, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22802091

ABSTRACT

CONTEXT: Conflicting data exist on mitochondrial function and physical activity in type 2 diabetes mellitus (T2DM) development. OBJECTIVE: The aim was to assess mitochondrial function at different stages during T2DM development in combination with physical exercise in longstanding T2DM patients. DESIGN AND METHODS: We performed cross-sectional analysis of skeletal muscle from 12 prediabetic 11 longstanding T2DM male subjects and 12 male controls matched by age and body mass index. INTERVENTION: One-year intrasubject controlled supervised exercise training intervention was done in longstanding T2DM patients. MAIN OUTCOME MEASUREMENTS: Extensive ex vivo analyses of mitochondrial quality, quantity, and function were collected and combined with global gene expression analysis and in vivo ATP production capacity after 1 yr of training. RESULTS: Mitochondrial density, complex I activity, and the expression of Krebs cycle and oxidative phosphorylation system-related genes were lower in longstanding T2DM subjects but not in prediabetic subjects compared with controls. This indicated a reduced capacity to generate ATP in longstanding T2DM patients only. Gene expression analysis in prediabetic subjects suggested a switch from carbohydrate toward lipid as an energy source. One year of exercise training raised in vivo skeletal muscle ATP production capacity by 21 ± 2% with an increased trend in mitochondrial density and complex I activity. In addition, expression levels of ß-oxidation, Krebs cycle, and oxidative phosphorylation system-related genes were higher after exercise training. CONCLUSIONS: Mitochondrial dysfunction is apparent only in inactive longstanding T2DM patients, which suggests that mitochondrial function and insulin resistance do not depend on each other. Prolonged exercise training can, at least partly, reverse the mitochondrial impairments associated with the longstanding diabetic state.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Mitochondria, Muscle/physiology , Mitochondrial Myopathies/metabolism , Mitochondrial Myopathies/therapy , Motor Activity/physiology , Muscle, Skeletal/metabolism , Adenosine Triphosphate/biosynthesis , Aged , Blood Pressure/physiology , Body Composition/physiology , Body Mass Index , Citric Acid Cycle/genetics , Citric Acid Cycle/physiology , Diabetes Mellitus, Type 2/therapy , Disease Progression , Female , Gene Expression/physiology , Humans , Magnetic Resonance Spectroscopy , Male , Middle Aged , Mitochondria, Muscle/metabolism , Oxidative Phosphorylation , Physical Fitness/physiology , Prediabetic State/metabolism , Real-Time Polymerase Chain Reaction
3.
Int J Obes (Lond) ; 35(9): 1154-64, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21326205

ABSTRACT

OBJECTIVE: Insulin resistance and type 2 diabetes mellitus (T2DM) are associated with increased adipocyte size, altered secretory pattern and decreased differentiation of preadipocytes. In this study, we identified the underlying molecular processes in preadipocytes of T2DM patients, a characteristic for the development of T2DM. DESIGN AND PARTICIPANTS: Preadipocyte cell cultures were prepared from subcutaneous fat biopsies of seven T2DM patients (age 53 ± 12 years; body mass index (BMI) 34 ± 5 kg m(-2)) and nine control subjects (age 51 ± 12 years; BMI 30 ± 3 kg m(-2)). Microarray analysis was used to identify altered processes between the T2DM and control preadipocytes. RESULTS: Gene expression profiling showed changed expression of transcription regulators involved in adipogenesis and in extracellular matrix remodeling, actin cytoskeleton and integrin signaling genes, which indicated decreased capacity to differentiate. Additionally, genes involved in insulin signaling and lipid metabolism were downregulated, and inflammation/apoptosis was upregulated in T2DM preadipocytes. CONCLUSION: Decreased expression of genes involved in differentiation can provide a molecular basis for the reduced adipogenesis of preadipocytes of T2DM subjects, leading to reduced formation of adipocytes in subcutaneous fat depots, and ultimately leading to ectopic fat storage.


Subject(s)
Adipocytes/pathology , Adipogenesis , Adipose Tissue/pathology , Cell Differentiation , Diabetes Mellitus, Type 2/pathology , Gene Expression Profiling , Adipogenesis/genetics , Body Mass Index , Cells, Cultured , Diabetes Mellitus, Type 2/genetics , Female , Humans , Male , Microarray Analysis , Middle Aged , Transcription, Genetic
4.
Biochem Biophys Res Commun ; 387(1): 207-11, 2009 Sep 11.
Article in English | MEDLINE | ID: mdl-19577541

ABSTRACT

Correct Wnt signaling is required for adipogenesis and alterations occur in Type 2 diabetes mellitus (T2DM). Gene expression studies showed that beta-catenin independent Wnt5b was down-regulated in T2DM preadipocytes, while its paralog Wnt5a was unchanged. Our study aimed at defining the expression profile and function of Wnt5a and Wnt5b during adipogenesis by determining their effect on aP2 and PPARgamma expression and assessing the level of beta-catenin translocation in mouse 3T3-L1 preadipocytes. Additionally, we explored the effect on adipogenic capacity by Wnt5b overexpression in combination with stimulation of the beta-catenin dependent or beta-catenin independent Wnt signaling. Expression of Wnt5b was, like Wnt5a, down-regulated upon induction of differentiation and both inhibit beta-catenin dependent Wnt signaling at the initiation of adipogenesis. Wnt5b additionally appears to be a potent enhancer of adipogenic capacity by stimulation of PPARgamma and aP2. Down-regulation of Wnt5b could therefore contribute to decreased adipogenesis observed in T2DM diabetic subjects.


Subject(s)
Adipocytes/metabolism , Adipogenesis , PPAR gamma/metabolism , Wnt Proteins/metabolism , beta Catenin/metabolism , 3T3-L1 Cells , Animals , Diabetes Mellitus, Type 2/metabolism , Humans , Mice , PPAR gamma/agonists , Signal Transduction , Wnt Proteins/genetics , Wnt-5a Protein , beta Catenin/antagonists & inhibitors
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