Decreased Bioenergetic Health Index in monocytes isolated from the pericardial fluid and blood of post-operative cardiac surgery patients

Kramer, Philip; Chacko, Balu K.; George, David J.; Zhi, Degui; Wei, Chih‐Chang; Dell’Italia, Louis J.; Melby, Spencer J.; George, James F.; Darley‐Usmar, Victor

doi:10.1042/bsr20150161

Cited by 46 publications

(47 citation statements)

References 28 publications

(49 reference statements)

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“…Finally, we found that sex does not significantly associate with OCR levels (Fig. S2), in agreement with (34).…”

Section: Resultssupporting

confidence: 87%

OCR-Stats: Robust estimation and statistical testing of mitochondrial respiration activities using Seahorse XF Analyzer

Kremer

Iuso

et al. 2017

Preprint

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Accurate quantification of cellular and mitochondrial bioenergetic activity is of great interest in medicine and biology. Mitochondrial stress tests performed with Seahorse Bioscience XF Analyzers allow estimating different bioenergetic measures by monitoring oxygen consumption rates (OCR) of living cells in multi-well plates. However, studies of statistical best practices for determining OCR measurements and comparisons have been lacking so far. Therefore, we performed mitochondrial stress tests in 126 96-well plates involving 203 fibroblast cell lines to understand how OCR behaves across different biosamples, wells, and plates. We show that the noise of OCR is multiplicative, that outlier data points can concern individual measurements or all measurements of a well, and that the inter-plate variation is greater than intra-plate variation. Based on these insights, we developed a novel statistical method, OCR-Stats, that: i) robustly estimates OCR levels modeling multiplicative noise and automatically identifying outlier data points and outlier wells; and ii) performs statistical testing between samples, taking into account the different magnitudes of the between- and within-plates variations. This led to a significant reduction of the coefficient of variation across plates of basal respiration by 36% and of maximal respiration by 32%. Moreover, using positive and negative controls, we show that our statistical test outperforms existing methods, which either suffer from an excess of false positives (within-plates methods), or of false negatives (between-plates methods). Altogether, the aim of this study is to propose statistical good practices to support experimentalists in designing, analyzing, testing and reporting results of mitochondrial stress tests using this high throughput platform.

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“…Finally, we found that sex does not significantly associate with OCR levels (Fig. S2), in agreement with (34).…”

Section: Resultssupporting

confidence: 87%

OCR-Stats: Robust estimation and statistical testing of mitochondrial respiration activities using Seahorse XF Analyzer

Kremer

Iuso

et al. 2017

Preprint

View full text Add to dashboard Cite

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“…The strength of this study lies in the evaluation and utility of PBMCs as a surrogate for insulin-sensitive tissues, the procurement of which is difficult or prohibitive, especially in children. Similar mitochondrial studies are being done with monocytes from patients procured postoperatively after cardiac surgery [23]. Collectively, findings from this study set the foundation to further characterize mitochondrial molecular underpinnings as mechanisms of metabolic disease with minimal invasiveness.…”

Section: Discussionmentioning

confidence: 53%

Insulin resistance in HIV-infected youth is associated with decreased mitochondrial respiration

Takemoto

Miller

Wang

et al. 2017

Aids

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Objective:To identify relationships between insulin resistance (IR) and mitochondrial respiration in perinatally HIV-infected youth.Design:Case–control study.Methods:Mitochondrial respiration was assessed in perinatally HIV-infected youth in Tanner stages 2–5, 25 youth with IR (IR+) and 50 without IR (IR−) who were enrolled in the Pediatric HIV/AIDS Cohort Study. IR was defined as a homeostatic model of assessment for IR value at least 4.0. A novel, high-throughput oximetry method was used to evaluate cellular respiration in peripheral blood mononuclear cells. Unadjusted and adjusted differences in mitochondrial respiration markers between IR+ and IR− were evaluated, as were correlations between mitochondrial respiration markers and biochemical measurements.Results:IR+ and IR− youth were similar on age, sex, and race/ethnicity. Mean age was 16.5 and 15.6 years in IR+ and IR−, respectively. The IR+ group had significantly higher mean BMI and metabolic analytes (fasting glucose, insulin, cholesterol, triglycerides, and venous lactate and pyruvate) compared with the IR−. Mitochondrial respiration markers were, on average, lower in the IR+ compared with IR−, including basal respiration (417.5 vs. 597.5 pmol, P = 0.074), ATP production (11 513 vs. 15 202 pmol, P = 0.078), proton leak (584.6 vs. 790.0 pmol, P = 0.033), maximal respiration (1815 vs. 2399 pmol, P = 0.025), and spare respiration capacity (1162 vs. 2017 pmol, P = 0.032). Nonmitochondrial respiration did not differ by IR status. The results did not change when adjusted for age.Conclusion:HIV-infected youth with IR have lower mitochondrial respiration markers when compared to youth without IR. Disordered mitochondrial respiration may be a potential mechanism for IR in this population.

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“…The index represents the mitochondrial energy production corrected for oxygen consumption by sources which do not produce energy. The BHI has been developed using the Seahorse platform to measure mitochondrial function in peripheral immune cells 34 and is proposed as a biomarker of bioenergetic health 35–38

BHI = (reserve capacity \times ATP-linked respiration) / (proton-leak respiration \times non-mitochondrial OCR)

Proton efflux rate : A measure of proton flux corrected for important assay factors.…”

Section: Methodsmentioning

confidence: 99%

Developmental regression and mitochondrial function in children with autism

Singh

Diggins

et al. 2020

Ann Clin Transl Neurol

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Background: Developmental regression (DR) occurs in about one-third of children with Autism Spectrum Disorder (ASD) yet it is poorly understood. Current evidence suggests that mitochondrial function in not normal in many children with ASD. However, the relationship between mitochondrial function and DR has not been well-studied in ASD. Methods: This cross-sectional study of 32 children, 2 to 8 years old with ASD, with (n = 11) and without (n = 12) DR, and non-ASD controls (n = 9) compared mitochondrial respiration and mtDNA damage and copy number between groups and their relation to standardized measures of ASD severity. Results: Individuals with ASD demonstrated lower ND1, ND4, and CYTB copy number (Ps < 0.01) as compared to controls. Children with ASD and DR had higher maximal oxygen consumption rate (Ps < 0.02), maximal respiratory capacity (P < 0.05), and reserve capacity (P = 0.01) than those with ASD without DR. Coupling Efficiency and Maximal Respiratory Capacity were associated with disruptive behaviors but these relationships were different for those with and without DR. Higher ND1 copy number was associated with better behavior. Conclusions: This study suggests that individuals with ASD and DR may represent a unique metabolic endophenotype with distinct abnormalities in respiratory function that may put their mitochondria in a state of vulnerability. This may allow physiological stress to trigger mitochondrial decompensation as is seen clinically as DR. Since mitochondrial function was found to be related to ASD symptoms, the mitochondria could be a potential target for novel therapeutics. Additionally, identifying those with vulnerable mitochondrial before DR could result in prevention of ASD.

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Decreased Bioenergetic Health Index in monocytes isolated from the pericardial fluid and blood of post-operative cardiac surgery patients

Cited by 46 publications

References 28 publications

OCR-Stats: Robust estimation and statistical testing of mitochondrial respiration activities using Seahorse XF Analyzer

OCR-Stats: Robust estimation and statistical testing of mitochondrial respiration activities using Seahorse XF Analyzer

Insulin resistance in HIV-infected youth is associated with decreased mitochondrial respiration

Developmental regression and mitochondrial function in children with autism

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