scholarly journals Impaired Mitochondrial Bioenergetics Function in Pediatric Chronic Overlapping Pain Conditions with Functional Gastrointestinal Disorders

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Gisela Chelimsky ◽  
Pippa Simpson ◽  
Liyun Zhang ◽  
Doug Bierer ◽  
Steve Komas ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Respiratory Chain ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Functional Disability ◽  
Functional Gastrointestinal Disorders ◽  
Energy Generation ◽  
Proton Leak ◽  
Gastrointestinal Disorders ◽  
Reserve Capacity

Background. Fatigue is often the primary complaint of children with functional gastrointestinal disorders (FGDI) and other chronic overlapping pain disorders (COPC). The basis for this symptom remains unknown. We evaluated mitochondrial function in the white blood cells of these patients. Methods. This prospective Children’s Wisconsin IRB approved study recruited subjects aging 10–18 years from pediatric neurogastroenterology clinics and healthy comparison subjects (HC). Environmental and oxidative stressors can damage the mitochondrial respiratory chain. The known low-grade inflammation in COPC could, therefore, impact the respiratory chain and theoretically account for the disabling fatigue so often voiced by patients. Mitochondrial energy generation can be easily measured in peripheral mononuclear cells (PMC) as a general marker by the Seahorse XF96 Extracellular Flux Analyzer. We measured 5 parameters of oxygen consumption using this methodology: basal respiration (BR), ATP linked oxygen consumption (ATP-LC), maximal oxygen consumption rate (max R), spare respiratory capacity (SRC), and extracellular acidification rate (ECAR), which reflect non-electron chain energy generation through glycolysis. In health, we expect high ATP linked respiration, high reserve capacity, low proton leak, and low non-mitochondrial respiration. In disease, the proton leak typically increases, ATP demand increases, and there is decreased reserve capacity with increased non-mitochondrial respiration. Findings and clinical data were compared to healthy control subjects using a Mann–Whitney test for skewed variables, Fisher’s exact test for dichotomous variables, and regression tree for association with functional outcome (functional disability inventory, FDI). Results. 19 HC and 31 COPC showed no statistically significant difference in age. FGID, orthostatic intolerance, migraine, sleep disturbance, and chronic fatigue were present in the majority of COPC subjects. BR, ECAR, and ATP-LC rates were lower in the COPC group. The low BR and ATP-LC suggest that mitochondria are stressed with decreased ability to produce ATP. Tree analysis selected SRC as the best predictor of functional disability: patients with SRC >150 had a greater FDI (more disability) compared to patients with SRC <=150, p -value = 0.021. Conclusion. Subjects with COPC have reduced mitochondrial capacity to produce ATP. Predisposing genetic factors or reversible acquired changes may be responsible. A higher SRC best predicts disability. Since a higher SRC is typically associated with more mitochondrial reserve, the SRC may indicate an underutilized available energy supply related to inactivity, or a “brake” on mitochondrial function. Prospective longitudinal studies can likely discern whether these findings represent deconditioning, true mitochondrial dysfunction, or both.

Functional disability in children with functional gastrointestinal disorders (FGDs)

2003 ◽  
Vol 124 (4) ◽  
pp. A395
Author(s):  
Jennifer V. Schurman ◽  
Caroline E. Danda ◽  
Teri Comninellis ◽  
Craig A. Friesen ◽  
Elly Welchert ◽  
...  
Keyword(s):  
Functional Disability ◽  
Functional Gastrointestinal Disorders ◽  
Gastrointestinal Disorders

Effect of hyperthermia and acidosis on equine skeletal muscle mitochondrial oxygen consumption

2020 ◽  
pp. 1-10
Author(s):  
M.S. Davis ◽  
M.R. Fulton ◽  
A. Popken
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Oxidative Phosphorylation ◽  
Muscle Fatigue ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Complex I ◽  
Mitochondrial Oxygen Consumption ◽  
Biochemical Basis ◽  
Complex Ii

The skeletal muscle of exercising horses develops pronounced hyperthermia and acidosis during strenuous or prolonged exercise, with very high tissue temperature and low pH associated with muscle fatigue or damage. The purpose of this study was to evaluate the individual effects of physiologically relevant hyperthermia and acidosis on equine skeletal muscle mitochondrial function, using ex vivo measurement of oxygen consumption to assess the function of different mitochondrial elements. Fresh triceps muscle biopsies from 6 healthy unfit Thoroughbred geldings were permeabilised to permit diffusion of small molecular weight substrates through the sarcolemma and analysed in a high resolution respirometer at 38, 40, 42, and 44 °C, and pH=7.1, 6.5, and 6.1. Oxygen consumption was measured under conditions of non-phosphorylating (leak) respiration and phosphorylating respiration through Complex I and Complex II. Data were analysed using a one-way repeated measures ANOVA and data are expressed as mean ± standard deviation. Leak respiration was ~3-fold higher at 44 °C compared to 38 °C regardless of electron source (Complex I: 22.88±3.05 vs 8.08±1.92 pmol O2/mg/s), P=0.002; Complex II: 79.14±23.72 vs 21.43±11.08 pmol O2/mg/s, P=0.022), resulting in a decrease in efficiency of oxidative phosphorylation. Acidosis had minimal effect on mitochondrial respiration at pH=6.5, but pH=6.1 resulted in a 50% decrease in mitochondrial oxygen consumption. These results suggest that skeletal muscle hyperthermia decreases the efficiency of oxidative phosphorylation through increased leak respiration, thus providing a specific biochemical basis for hyperthermia-induced muscle fatigue. The effect of myocellular acidosis on mitochondrial respiration was minimal under typical levels of acidosis, but atypically severe acidosis can lead to impairment of mitochondrial function.

AML Cells Have Increased Mitochondrial Mass but Less Reserve in Their Respiratory Chain Complexes Leading to Heightened Sensitivity to Inhibition of Mitochondrial Protein Translation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3585-3585
Author(s):  
Shrivani Sriskanthadevan ◽  
Skrtic Marko ◽  
Bozhena Livak ◽  
Yulia Jitkova ◽  
Rose Hurren ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Respiratory Chain ◽  
Mitochondrial Biogenesis ◽  
Complex Iii ◽  
Reserve Capacity ◽  
Mitochondrial Translation ◽  
Respiratory Chain Complexes ◽  
Mitochondrial Mass ◽  
Respiratory Complexes ◽  
Chain Complexes

Abstract Abstract 3585 Recent studies suggest that dysregulated mitochondrial oxygen consumption promotes the growth of AML cells. Therefore, we characterized the structure and metabolic function of the mitochondria in AML and normal G-CSF-mobilized hematopoietic mononuclear cells (PBSCs). Compared to PBSCs, 1o AML cells had increased mitochondrial mass as demonstrated by an increased mitochondrial DNA copy number and increased activity of matrix enzyme citrate synthase. The increased mitochondrial mass observed in 1o AML cells may represent larger mitochondria and/or more numerous mitochondria. Therefore, we evaluated the mitochondria of 1o AML and normal CD34+ hematopoietic cells by electron microscopy. The mitochondria in 1o AML cells were larger in area, but fewer in number compared to normal CD34+ cells. Mitochondria contain the respiratory chain complexes that promote oxidative phosphorylation. Given the dysregulated mitochondrial biogenesis in 1o AML cells, we examined the levels and capacity of the respiratory complexes in 1o AML and normal PBSCs. When normalized for mitochondrial mass, 1o AML cells (n = 12) had reduced activity of respiratory complexes III and IV compared to PBSCs (n = 10) (Mean complex III activity AML vs PBSC: 0.32 ± 0.04 RU vs 0.66 ± 0.11 RU p = 0.0063; Mean complex IV activity AML vs PBSC: 0.13 ± 0.01 RU vs 0.24 ± 0.02 RU, p= 0.0003). We evaluated the capacity of the respiratory complexes in AML cells and PBSCs by treating with increasing concentrations of the complex III inhibitor antimycin, and measuring the changes in oxygen consumption. AML cells displayed heightened sensitivity to the complex III inhibitor and less reserve capacity in the respiratory complex compared to PBSCs (mean concentration of antimycin required to reduce oxygen consumption by 50%: AML (n = 11) vs PBSC (n = 3): 13.7 ± 1.6 nM vs 29.0 ± 2.4 nM; p = 0.0007). AML cell lines were similar to 1o AML cells with decreased basal respiratory complex activity and reserve capacity compared to PBSCs. Given the reduced levels and reserve in the respiratory chain complexes in AML cells, we evaluated the effects of inhibiting mitochondrial protein translation in AML cells and PBSCs. Chemical (tigecycline, and chloramphenicol) and genetic (RNAi knockdown of the EF-Tu) inhibition of mitochondrial translation reduced the levels and function of the respiratory complexes that contain proteins encoded by mitochondrial DNA. Consistent with the reduced reserve capacity, inhibiting mitochondrial translation preferentially reduced oxygen consumption and viability of 1o AML cells and AML cell lines over PBSCs and normal CD34+ cells. To understand the molecular basis for the abnormal mitochondrial biogenesis in 1o AML cells, we measured levels of the NRF-1, TFAM and EF-Tu, genes known to positively regulate mitochondrial biogenesis. Compared to PBSCs, AML samples showed at least a 3-fold increase in mRNA expression of these genes. Myc is a positive regulator of NRF-1, TFAM and EF-Tu. Therefore, we measured levels of myc in 1o AML cells and PBSCs by Q-RT-PCR. Compared to PBSCs, myc was increased in 1o AML cells and positively correlated with expression of NRF-1, TFAM and EF-Tu as well as with mitochondrial mass. To determine whether increased myc expression is functionally related to the increased mitochondrial biogenesis and decreased reserve in respiratory capacity, we employed P493 Burkitt's cells with inducible myc knockdown. P493 cells expressing myc had increased mitochondrial mass, larger mitochondria, and increased basal oxygen consumption compared to the myc knockdown cells. When normalized for mitochondrial mass, myc expressing cells had reduced activity of respiratory complexes III and IV compared to myc knockdown cells. In addition, myc expressing cells had less reserve in respiratory complex III (concentration of antimycin required to reduce oxygen consumption by 50% –+ myc P493 vs –myc P493: 6.580 ± 0.393 nM vs 12.87 ± 1.97 nM p =0.0352). Thus, compared to normal hematopoietic cells, AML cells have greater mitochondrial mass but reduced reserve in their respiratory complexes. As a result of this decreased reserve, AML cells have a heightened sensitivity to inhibition of mitochondrial translation which reduces respiratory chain complex levels and activity. Genetically, the abnormal mitochondrial structure and function appears related to dysregulated myc and its influence on genes promoting increased mitochondrial biogenesis. Disclosures: No relevant conflicts of interest to declare.

AML Cells Have Altered Mitochondrial Biogenesis and Low Spare Reserve Capacity in Their Respiratory Chain That Renders Them Susceptible to Oxidative Metabolic Stress.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2581-2581
Author(s):  
Shrivani Sriskanthadevan ◽  
Timothy E Chung ◽  
Marko Skrtic ◽  
Bozhena Jhas ◽  
Rose Hurren ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Respiratory Chain ◽  
Mitochondrial Biogenesis ◽  
Hematopoietic Cells ◽  
Atp Synthesis ◽  
Reserve Capacity ◽  
Complex Activity ◽  
Normal Cells ◽  
Mitochondrial Mass ◽  
Respiratory Complexes

Abstract Abstract 2581 Oxidative metabolism generates intracellular energy and metabolic intermediates necessary to promote the growth of AML cells. Recently, we demonstrated that AML cells are uniquely sensitive to inhibition of mitochondrial translation. Therefore, we characterized the structure and metabolic function of the mitochondria in AML and normal hematopoietic cells. Compared to normal cells (n = 10), 1° AML cells (n = 12) had increased mitochondrial mass and increased levels of the NRF-1, TFAM, EF-Tu and Myc, genes that positively regulate mitochondrial biogenesis. By transmission electron microscopy, we demonstrated that the mitochondria in 1°AML cells were larger in area, but fewer in number compared to normal CD34+ cells. Given the dysregulated mitochondrial biogenesis in 1° AML cells, we examined the activity and reserve capacity of the respiratory complexes in 1° AML and normal cells. When normalized for mitochondrial mass, 1°AML cells (n = 12) had reduced activity of respiratory complexes III, IV and V compared to normal cells (n = 10). Thus, despite the increased mitochondrial mass in AML, respiratory chain complex activity did not increase proportionately. Next, we evaluated the spare reserve capacity in AML cell lines, 1° AML samples, and normal cells. Spare reserve capacity reflects the difference between basal and maximal respiratory rate and was determined by measuring oxygen consumption after treatment with oligomycin to block ATP synthesis and FCCP to uncouple ATP synthesis from the electron transport chain. The spare reserve capacity in AML cells and 1o samples was lower than normal hematopoietic cells. In order to determine the reserve capacity in individual respiratory complexes, we evaluated the rate of oxygen consumption in 1°AML and normal cells by treating the cells with increasing concentrations of the complex I, III IV, and V inhibitors, rotenone, antimycin, sodium azide, and oligomycin, respectively, and measuring changes in oxygen consumption. AML cells displayed less reserve capacity in the individual complexes compared to normal hematopoietic cells, and the differences were most striking for complexes III and IV. Consistent with the reduced reserve capacity, AML cells were more sensitive to respiratory chain inhibitors. We then employed a genetic approach to investigate the relationship between mitochondrial mass and spare reserve capacity using P493 Burkitt's cells with inducible myc as we and others have previously shown that myc regulates mitochondrial mass. Compared to myc knockdown cells, myc +P493 cells had increased mitochondrial mass, larger mitochondria, increased basal oxygen consumption, but reduced activity of respiratory complexes III, IV and V when normalized for mitochondrial mass, compared to myc - cells. In addition, myc expressing cells had less spare reserve capacity in their respiratory chain. Thus, in this isogenic cell line, increased mitochondrial mass was not accompanied by a proportionate increase in respiratory chain activity resulting in decreased spare reserve capacity. Given the reduced reserve capacity in AML cells, we evaluated the effects of increasing electron flux through respiratory chain. We speculated that the low spare reserve capacity would render AML cells more vulnerable to oxidative stress. To test this strategy AML cells and 1° samples as well as normal cells were treated increasing concentrations of the fatty acid substrate palmitate or the TCA cycle substrate dimethyl succinate. Consistent with our hypothesis, treatment with palmitate or dimethyl succinate transiently increased oxygen consumption and decreased spare reserve capacity in AML but not normal cells. Subsequently these treatments, increased reactive oxygen and induced cell death preferentially in AML cells and 1° samples compare to normal hematopoietic cells. Moreover, this treatment preferentially reduced the clonogenic growth of 1° AML cells over normal cells and reduced the engraftment of 1°AML but not normal cells into immune deficient mice. In summary, compared to normal hematopoietic cells, AML cells have greater mitochondrial mass but respiratory chain activity does not increase proportionately. The lack of proportionate rise in respiratory complex activity results in reduced spare reserve capacity in the respiratory complexes and greater sensitivity to oxidative stress. These data highlight a unique metabolic vulnerability in AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Mitochondrial Protease, Neurolysin (NLN), Regulates Respiratory Chain Complex and Supercomplex Formation and Is Necessary for AML Viability

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 729-729
Author(s):  
Sara Mirali ◽  
Botham Aaron ◽  
Veronique Voisin ◽  
Changjiang Xu ◽  
Jonathan St-Germain ◽  
...  
Keyword(s):  
Stem Cells ◽  
Oxygen Consumption ◽  
Respiratory Chain ◽  
Mitochondrial Function ◽  
Oxidative Metabolism ◽  
Research Funding ◽  
Hematopoietic Cells ◽  
Chain Complex ◽  
Respiratory Chain Complex ◽  
Complex Assembly

Acute myeloid leukemia (AML) cells and stem cells have unique mitochondrial characteristics with an increased reliance on oxidative phosphorylation (OXPHOS). To identify new biological vulnerabilities in the mitochondrial proteome of AML cells, we conducted an shRNA screen and identified neurolysin (NLN), a zinc metalloprotease whose mitochondrial function is not well understood and whose role in AML has not been previously reported. To begin our investigation into the role of NLN in AML, we analyzed NLN gene expression in a database of 536 AML and 73 normal bone marrow samples. NLN was overexpressed in 41% of AML samples. Overexpression of NLN in primary AML cells compared to normal hematopoietic cells was confirmed by immunoblotting. To validate the results of the screen and to determine whether NLN is required for AML growth and viability, we knocked down NLN in the leukemia cell lines OCI-AML2, MV4-11, NB4, and TEX with shRNA. NLN knockdown reduced leukemia growth and viability by 50-70%. Moreover, knockdown of NLN in AML cells reduced the clonogenic growth of leukemic cells in vitro and the engraftment of AML cells into mouse marrow after five weeks by up to 80% and 85%, respectively. The mitochondrial function of NLN is largely unknown, so we identified NLN's mitochondrial protein interactors in T-REx HEK293 cells using proximity-dependent biotin labeling (BioID) coupled with mass spectrometry (MS). This screen identified 73 mitochondrial proteins that preferentially interacted with NLN and were enriched for functions including respiratory chain complex assembly, respiratory electron transport, and mitochondrion organization. Therefore, we assessed the effects of NLN knockdown on OXPHOS. NLN knockdown reduced basal and maximal oxygen consumption, but there were no changes in the levels of individual respiratory chain complex subunits. To understand how NLN influences OXPHOS, we examined the formation of respiratory chain supercomplexes (RCS). Respiratory chain complexes I, III, and IV assemble into higher order quaternary structures called RCS, which promote efficient oxidative metabolism. NLN knockdown significantly impaired RCS formation in T-REx HEK293, OCI-AML2, and NB4 cells, which was rescued by overexpressing wild-type shRNA-resistant NLN. RCS have not been previously studied in leukemia. Therefore, we analyzed their levels in primary AML patient samples and normal hematopoietic cells. RCS assembly was increased in a subset of AML patient samples and positively correlated with NLN protein expression (R2 = 0.83, p &lt; 0.05), suggesting that NLN mediates RCS assembly in AML. To investigate how NLN may be regulating RCS assembly, we analyzed our BioID results to identify NLN interactors that are known regulators of supercomplex formation. Among the top interactors was the known RCS regulator, LETM1. Knockdown of NLN in AML cells impaired LETM1 assembly. Of note, knockdown of LETM1 also reduced growth and oxygen consumption of AML cells. As a chemical approach to evaluate the effects of NLN inhibition on AML cells, we used the allosteric NLN inhibitor R2, (3-[(2S)-1-[(3R)-3-(2-Chlorophenyl)-2-(2-fluorophenyl)pyrazolidin-1-yl]-1-oxopropan-2-yl]-1-(adamantan-2-yl)urea), whose anti-cancer effects have not been previously reported. R2 reduced viability of AML cells, as well as two primary AML culture models, 8227 and 130578. R2 impaired RCS formation in OCI-AML2, NB4, 8227, and primary AML cells. Moreover, R2 reduced the CD34+CD38- stem cell enriched population in 8227 cells, reduced LETM1 complex assembly, and impaired OXPHOS in OCI-AML2 and 8227 cells. Finally, we assessed the effects of inhibiting NLN in mice engrafted with primary AML and normal hematopoietic cells in vivo. Treatment of mice with R2 reduced the leukemic burden in these mice without toxicity. Moreover, inhibiting NLN targeted the AML stem cells as evidenced by reduced engraftment in secondary experiments. In contrast, inhibiting NLN did not reduce the engraftment of normal hematopoietic cells. Collectively, these results demonstrate that inhibition of NLN preferentially targets AML cells and stem cells as compared to normal hematopoietic cells. In summary, we defined a novel role for NLN in RCS formation. We show that RCS are necessary for oxidative metabolism in AML and highlight NLN inhibition as a potential therapeutic strategy. Disclosures Minden: Trillium Therapetuics: Other: licensing agreement. Chan:Agios: Honoraria; AbbVie Pharmaceuticals: Research Funding; Celgene: Honoraria, Research Funding. Schimmer:Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy.

scholarly journals The mitochondrial function of the cerebral vasculature in insulin-resistant Zucker obese rats

2016 ◽  
Vol 310 (7) ◽  
pp. H830-H838 ◽  
Author(s):  
Ivan Merdzo ◽  
Ibolya Rutkai ◽  
Tunde Tokes ◽  
Venkata N. L. R. Sure ◽  
Prasad V. G. Katakam ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Cerebral Arteries ◽  
Proton Leak ◽  
Mitochondrial Morphology ◽  
Cerebral Vasculature ◽  
Cerebral Microvessels ◽  
Oxide Synthase

Little is known about mitochondrial functioning in the cerebral vasculature during insulin resistance (IR). We examined mitochondrial respiration in isolated cerebral arteries of male Zucker obese (ZO) rats and phenotypically normal Zucker lean (ZL) rats using the Seahorse XFe24 analyzer. We investigated mitochondrial morphology in cerebral blood vessels as well as mitochondrial and nonmitochondrial protein expression levels in cerebral arteries and microvessels. We also measured reactive oxygen species (ROS) levels in cerebral microvessels. Under basal conditions, the mitochondrial respiration components (nonmitochondrial respiration, basal respiration, ATP production, proton leak, and spare respiratory capacity) showed similar levels among the ZL and ZO groups with the exception of maximal respiration, which was higher in the ZO group. We examined the role of nitric oxide by measuring mitochondrial respiration following inhibition of nitric oxide synthase with Nω-nitro-l-arginine methyl ester (l-NAME) and mitochondrial activation after administration of diazoxide (DZ). Both ZL and ZO groups showed similar responses to these stimuli with minor variations. l-NAME significantly increased the proton leak, and DZ decreased nonmitochondrial respiration in the ZL group. Other components were not affected. Mitochondrial morphology and distribution within vascular smooth muscle and endothelium as well as mitochondrial protein levels were similar in the arteries and microvessels of both groups. Endothelial nitric oxide synthase (eNOS) and ROS levels were increased in cerebral microvessels of the ZO. Our study suggests that mitochondrial function is not significantly altered in the cerebral vasculature of young ZO rats, but increased ROS production might be due to increased eNOS in the cerebral microcirculation during IR.

scholarly journals Relationship between Liver Mitochondrial Respiration and Proton Leak in Low and High RFI Steers from Two Lineages of RFI Angus Bulls

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
G. Acetoze ◽  
K. L. Weber ◽  
J. J. Ramsey ◽  
H. A. Rossow
Keyword(s):  
Body Weight ◽  
Oxygen Consumption ◽  
Mitochondrial Respiration ◽  
Dry Matter ◽  
Genetic Test ◽  
Bodyweight Gain ◽  
Dry Matter Intake ◽  
Proton Leak ◽  
Adaptation Period ◽  
Mitochondrial Oxygen Consumption

The objective of this research is to evaluate liver mitochondrial oxygen consumption and proton leak kinetics in progeny from two lineages of Angus bulls with high and low residual feed intake (RFI). Two Angus bulls were selected based on results from a genetic test for RFI and were used as sires. Eight offspring at 10-11 months of age from each sire were housed in individual pens for 70–105 days following a diet adaptation period of 14 days. Progeny of the low RFI sire had 0.57 kg/d (P=0.05) lower average RFI than progeny of the high RFI sire. There was no difference in dry matter intake between low and high RFI steers, but low RFI steers gained more body weight (P=0.02) and tended to have higher average daily gains (P=0.07). State 3 and State 4 respiration, RCR, and proton leak did not differ between high and low RFI steers (P=0.96, P=0.81, P=0.93, and P=0.88, resp.). Therefore, the increase in bodyweight gain which distinguished the low RFI steers from the high RFI steers may be associated with other metabolic mechanisms that are not associated with liver mitochondrial respiration and proton leak kinetics.

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