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Mitochondrial - nuclear genetic interaction modulates whole body metabolism, adiposity and gene expression in vivo.

ABSTRACT: We hypothesized that changes in the mitochondrial DNA (mtDNA) would significantly influence whole body metabolism, adiposity and gene expression in response to diet. Because it is not feasible to directly test these predictions in humans we used Mitochondrial-Nuclear eXchange mice, which have reciprocally exchanged nuclear and mitochondrial genomes between different Mus musculus strains. Results demonstrate that nuclear-mitochondrial genetic background combination significantly alters metabolic efficiency and body composition. Comparative RNA sequencing analysis in adipose tissues also showed a clear influence of the mtDNA on regulating nuclear gene expression on the same nuclear background (up to a 10-fold change in the number of differentially expressed genes), revealing that neither Mendelian nor mitochondrial genetics unilaterally control gene expression. Additional analyses indicate that nuclear-mitochondrial genome combination modulates gene expression in a manner heretofore not described. These findings provide a new framework for understanding complex genetic disease susceptibility.

SUBMITTER: Dunham-Snary KJ

PROVIDER: S-EPMC6197375 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Mitochondrial - nuclear genetic interaction modulates whole body metabolism, adiposity and gene expression in vivo.

Dunham-Snary Kimberly J KJ Sandel Michael W MW Sammy Melissa J MJ Westbrook David G DG Xiao Rui R McMonigle Ryan J RJ Ratcliffe William F WF Penn Arthur A Young Martin E ME Ballinger Scott W SW

EBioMedicine 20180916

We hypothesized that changes in the mitochondrial DNA (mtDNA) would significantly influence whole body metabolism, adiposity and gene expression in response to diet. Because it is not feasible to directly test these predictions in humans we used Mitochondrial-Nuclear eXchange mice, which have reciprocally exchanged nuclear and mitochondrial genomes between different Mus musculus strains. Results demonstrate that nuclear-mitochondrial genetic background combination significantly alters metabolic ...[more]

PMID: 30232024

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Project description:BackgroundThe PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to mitochondria in the myocardium. Mouse models of diabetes exhibit impaired mitochondrial AKT signaling but the implications of this on cardiac structure and function is unknown. We hypothesized that loss of mitochondrial AKT signaling is a critical step in cardiomyopathy and reduces cardiac oxidative phosphorylation.MethodsTo focus our investigation on the pathophysiological consequences of this mitochondrial signaling pathway, we generated transgenic mouse models of cardiac-specific, mitochondria-targeting, dominant negative AKT1 (CAMDAKT) and constitutively active AKT1 expression (CAMCAKT). Myocardial structure and function were examined using echocardiography, histology, and biochemical assays. We further investigated the underlying effects of mitochondrial AKT1 on mitochondrial structure and function, its interaction with ATP synthase, and explored in vivo metabolism beyond the heart.ResultsUpon induction of dominant negative mitochondrial AKT1, CAMDAKT mice developed cardiac fibrosis accompanied by left ventricular hypertrophy and dysfunction. Cardiac mitochondrial oxidative phosphorylation efficiency and ATP content were reduced, mitochondrial cristae structure was lost, and ATP synthase structure was compromised. Conversely, CAMCAKT mice were protected against development of diabetic cardiomyopathy when challenged with a high calorie diet. Activation of mitochondrial AKT1 protected cardiac function and increased fatty acid uptake in myocardium. In addition, total energy expenditure was increased in CAMCAKT mice, accompanied by reduced adiposity and reduced development of fatty liver.ConclusionCAMDAKT mice modeled the effects of impaired mitochondrial signaling which occurs in the diabetic myocardium. Disruption of this pathway is a key step in the development of cardiomyopathy. Activation of mitochondrial AKT1 in CAMCAKT had a protective role against diabetic cardiomyopathy as well as improved metabolism beyond the heart.

Project description:Abstract Background: Friedreich’s Ataxia (FA) is a neurodegenerative disease caused by disruptions in the gene encoding frataxin, a protein involved in formation of the iron-sulfur clusters needed for mitochondrial oxidative phosphorylation (OXPHOS). FA confers an increased risk for diabetes mellitus, but the mechanisms underlying this propensity are not well understood. Design: Cross-sectional study (clinicaltrials.gov: NCT02920671) Methods: Participants were non-diabetic individuals with FA (ages 18y-<65y) and healthy controls with a similar distribution of age, sex, BMI, and ancestry. OXPHOS capacity of calf muscle was assessed using a non-invasive, exercise-based MRI technique, creatine chemical exchange saturation transfer (CrCEST); results for lateral gastrocnemius (LG), the most consistently exercised muscle, are shown. After an overnight fast, a stable isotope tracer-enhanced oral glucose tolerance test was done. Body composition was assessed using dual energy x-ray absorptiometry. Linear regression analyses of the entire sample tested the association between outcomes and covariates (results are shown as standardized coefficient β). Results: This interim analysis has n=34 participants (11 FA, 23 control). Participants with FA were 61% male, median age 27y (IQI, 23-39), median BMI 26.9 kg/m2 (IQI, 24.1-29.4), and median visceral fat mass 0.50 kg (IQI, 0.35-0.70). Controls were 61% male, median age 29y (IQI, 26-38), median BMI 24.6 kg/m2 (IQI, 21.7-28.5), and median visceral fat mass 0.45 kg (IQI, 0.27-0.64). Fasting glucose was higher in FA (91 vs. 82 mg/dL, p=0.006). Lactate was similar at baseline and increased after oral glucose in both, but remained higher after 180min in FA (at 210min, 1.13 vs. 0.88 mmol/L, p=0.01). Post-exercise CrCEST recovery time constant (τCr) was increased 2.2-fold in FA (p=0.02), consistent with decreased OXPHOS capacity. In univariate analyses, whole body insulin sensitivity (WBISI) was decreased in FA (β -1.14, p=0.003), decreased with longer τCr, (β -0.48, p=0.01), and decreased with higher visceral fat (β -0.55, p=0.004). In multivariate analyses, these associations were attenuated when FA diagnosis (β -0.85, p=0.06) and τCr (β -0.25, p=0.25) were included in the same model, but were persistent when FA diagnosis (β -0.93, p=0.008) and visceral fat (β -0.43, p=0.01) were included in the same model. In univariate analyses, lactate area under the curve (AUC) was nominally increased in FA (β 0.67, p=0.11), and significantly positively associated with longer τCr (β 0.51, p=0.008). Conclusions: Individuals with a genetic mitochondrial disorder conferring increased diabetes risk have decreased whole body insulin sensitivity that may be mediated by decreased skeletal muscle OXPHOS capacity. Studies in rare disorders may provide insights into the role of skeletal muscle metabolism in the pathogenesis of Type 2 diabetes. Funding: NIH/NIDDK Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Dataset Information

Mitochondrial - nuclear genetic interaction modulates whole body metabolism, adiposity and gene expression in vivo.

Publications

Mitochondrial - nuclear genetic interaction modulates whole body metabolism, adiposity and gene expression in vivo.

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