Dataset Information

Altered Mitochondrial Function, Mitochondrial DNA and Reduced Metabolic Flexibility in Patients With Diabetic Nephropathy.

ABSTRACT: The purpose of this study was to determine if mitochondrial dysfunction plays a role in diabetic nephropathy (DN), a kidney disease which affects > 100 million people worldwide and is a leading cause of renal failure despite therapy. A cross-sectional study comparing DN with diabetes patients without kidney disease (DC) and healthy controls (HCs); and renal mesangial cells (HMCs) grown in normal and high glucose, was carried out. Patients with diabetes (DC) had increased circulating mitochondrial DNA (MtDNA), and HMCs increased their MtDNA within 24 h of hyperglycaemia. The increased MtDNA content in DCs and HMCs was not functional as transcription was unaltered/down-regulated, and MtDNA damage was present. MtDNA was increased in DC compared to HC, conversely, patients with DN had lower MtDNA than DC. Hyperglycaemic HMCs had fragmented mitochondria and TLR9 pathway activation, and in diabetic patients, mitophagy was reduced. Despite MtDNA content and integrity changing within 4 days, hyperglycaemic HMCs had a normal bio-energetic profile until 8 days, after which mitochondrial metabolism was progressively impaired. Peripheral blood mononuclear cells (PBMCs) from DN patients had reduced reserve capacity and maximal respiration, loss of metabolic flexibility and reduced Bioenergetic Health Index (BHI) compared to DC. Our data show that MtDNA changes precede bioenergetic dysfunction and that patients with DN have impaired mitochondrial metabolism compared to DC, leading us to propose that systemic mitochondrial dysfunction initiated by glucose induced MtDNA damage may be involved in the development of DN. Longitudinal studies are needed to define a potential cause-effect relationship between changes in MtDNA and bioenergetics in DN.

SUBMITTER: Czajka A

PROVIDER: S-EPMC4534759 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Altered Mitochondrial Function, Mitochondrial DNA and Reduced Metabolic Flexibility in Patients With Diabetic Nephropathy.

Czajka Anna A Ajaz Saima S Gnudi Luigi L Parsade Chandani Kiran CK Jones Peter P Reid Fiona F Malik Afshan N AN

EBioMedicine 20150411 6

The purpose of this study was to determine if mitochondrial dysfunction plays a role in diabetic nephropathy (DN), a kidney disease which affects > 100 million people worldwide and is a leading cause of renal failure despite therapy. A cross-sectional study comparing DN with diabetes patients without kidney disease (DC) and healthy controls (HCs); and renal mesangial cells (HMCs) grown in normal and high glucose, was carried out. Patients with diabetes (DC) had increased circulating mitochondria ...[more]

PMID: 26288815

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Project description:ObjectiveThe prevalence of obesity is growing globally. Adiposity increases the risk for metabolic syndrome, type 2 diabetes and cardiovascular disease. Adipose tissue distribution influences systemic metabolism and impacts metabolic disease risk. The link between sexual dimorphisms of adiposity and metabolism is poorly defined. We hypothesise that depot-specific adipose tissue mitochondrial function contributes to the sexual dimorphism of metabolic flexibility in obesity.MethodsMale and female mice fed high fat diet (HFD) or standard diet (STD) from 8-18 weeks of age underwent whole animal calorimetry and high-resolution mitochondrial respirometry analysis on adipose tissue depots. To determine translatability we used RT-qPCR to examine key brown adipocyte-associated gene expression: peroxisome proliferator-activated receptor co-activator 1α, Uncoupling protein 1 and cell death inducing DFFA like effector a in brown adipose tissue (BAT) and subcutaneous adipose tissue (sWAT) of 18-week-old mice and sWAT from human volunteers.ResultsMale mice exhibited greater weight gain compared to female mice when challenged with HFD. Relative to increased body mass, the adipose to body weight ratio for BAT and sWAT depots was increased in HFD-fed males compared to female HFD-fed mice. Oxygen consumption, energy expenditure, respiratory exchange ratio and food consumption did not differ between males and females fed HFD. BAT mitochondria from obese females showed increased Complex I & II respiration and maximal respiration compared to lean females whereas obese males did not exhibit adaptive mitochondrial BAT respiration. Sexual dimorphism in BAT-associated gene expression in sWAT was also associated with Body Mass Index in humans.ConclusionsWe show that sexual dimorphism of weight gain is reflected in mitochondrial respiration analysis. Female mice have increased metabolic flexibility to adapt to changes in energy intake by regulating energy expenditure through increased complex II and maximal mitochondrial respiration within BAT when HFD challenged and increased proton leak in sWAT mitochondria.

Project description:Diet may be modified seasonally or by biogeographic, demographic or cultural shifts. It can differentially influence mitochondrial bioenergetics, retrograde signalling to the nuclear genome, and anterograde signalling to mitochondria. All these interactions have the potential to alter the frequencies of mtDNA haplotypes (mitotypes) in nature and may impact human health. In a model laboratory system, we fed four diets varying in Protein: Carbohydrate (P:C) ratio (1:2, 1:4, 1:8 and 1:16 P:C) to four homoplasmic Drosophila melanogaster mitotypes (nuclear genome standardised) and assayed their frequency in population cages. When fed a high protein 1:2 P:C diet, the frequency of flies harbouring Alstonville mtDNA increased. In contrast, when fed the high carbohydrate 1:16 P:C food the incidence of flies harbouring Dahomey mtDNA increased. This result, driven by differences in larval development, was generalisable to the replacement of the laboratory diet with fruits having high and low P:C ratios, perturbation of the nuclear genome and changes to the microbiome. Structural modelling and cellular assays suggested a V161L mutation in the ND4 subunit of complex I of Dahomey mtDNA was mildly deleterious, reduced mitochondrial functions, increased oxidative stress and resulted in an increase in larval development time on the 1:2 P:C diet. The 1:16 P:C diet triggered a cascade of changes in both mitotypes. In Dahomey larvae, increased feeding fuelled increased β-oxidation and the partial bypass of the complex I mutation. Conversely, Alstonville larvae upregulated genes involved with oxidative phosphorylation, increased glycogen metabolism and they were more physically active. We hypothesise that the increased physical activity diverted energy from growth and cell division and thereby slowed development. These data further question the use of mtDNA as an assumed neutral marker in evolutionary and population genetic studies. Moreover, if humans respond similarly, we posit that individuals with specific mtDNA variations may differentially metabolise carbohydrates, which has implications for a variety of diseases including cardiovascular disease, obesity, and perhaps Parkinson's Disease.

Dataset Information

Altered Mitochondrial Function, Mitochondrial DNA and Reduced Metabolic Flexibility in Patients With Diabetic Nephropathy.

Publications

Altered Mitochondrial Function, Mitochondrial DNA and Reduced Metabolic Flexibility in Patients With Diabetic Nephropathy.

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