Mitochondrial responses to extreme environments: insights from metabolomics

O’Brien, Katie A.; Griffin, Julian L.; Murray, Andrew J.; Edwards, Lindsay M.

doi:10.1186/s13728-015-0026-9

Cited by 14 publications

(13 citation statements)

References 67 publications

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“…It is interesting to underline that the accumulation of succinate is one of the metabolic mitochondrial responses to extreme environments, supporting a concerted down-regulation of Kreb’s cycle and electron transport chain activity 29 . For example, in the cellular response to ischemia, succinate accumulation showed a toxic effect, which has been directly linked to mitochondrial reactive oxygen species production from Complex I (Fig.…”

Section: Discussionmentioning

confidence: 99%

Effects of microgravity on osteoblast mitochondria: a proteomic and metabolomics profile

Michaletti

Gioia

Tarantino

et al. 2017

Sci Rep

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The response of human primary osteoblasts exposed to simulated microgravity has been investigated and analysis of metabolomic and proteomic profiles demonstrated a prominent dysregulation of mitochondrion homeostasis. Gravitational unloading treatment induced a decrease in mitochondrial proteins, mainly affecting efficiency of the respiratory chain. Metabolomic analysis revealed that microgravity influenced several metabolic pathways; stimulating glycolysis and the pentose phosphate pathways, while the Krebs cycle was interrupted at succinate-fumarate transformation. Interestingly, proteomic analysis revealed that Complex II of the mitochondrial respiratory chain, which catalyses the biotransformation of this step, was under-represented by 50%. Accordingly, down-regulation of quinones 9 and 10 was measured. Complex III resulted in up-regulation by 60%, while Complex IV was down-regulated by 14%, accompanied by a reduction in proton transport synthesis of ATP. Finally, microgravity treatment induced an oxidative stress response, indicated by significant decreases in oxidised glutathione and antioxidant enzymes. Decrease in malate dehydrogenase induced a reverse in the malate-aspartate shuttle, contributing to dysregulation of ATP synthesis. Beta-oxidation of fatty acids was inhibited, promoting triglyceride production along with a reduction in the glycerol shuttle. Taken together, our findings suggest that microgravity may suppress bone cell functions, impairing mitochondrial energy potential and the energy state of the cell.

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Section: Discussionmentioning

confidence: 99%

Effects of microgravity on osteoblast mitochondria: a proteomic and metabolomics profile

Michaletti

Gioia

Tarantino

et al. 2017

Sci Rep

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“…While oxidative phosphorylation increases relative to citrate synthase activity in the soleus of hypoxic rats, the mechanisms underlying this remain unknown. More specific investigation into expression and activity levels of enzymes in the TCA cycle and electron transport chain, perhaps using high-throughput metabolomics [ 38 ] may aid our understanding of this process. Furthermore, the mechanism by which Ucp3 expression is downregulated earlier than other targets of PPARα remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Altered Oxygen Utilisation in Rat Left Ventricle and Soleus after 14 Days, but Not 2 Days, of Environmental Hypoxia

Horscroft

Burgess

et al. 2015

PLoS ONE

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The effects of environmental hypoxia on cardiac and skeletal muscle metabolism are dependent on the duration and severity of hypoxic exposure, though factors which dictate the nature of the metabolic response to hypoxia are poorly understood. We therefore set out to investigate the time-dependence of metabolic acclimatisation to hypoxia in rat cardiac and skeletal muscle. Rats were housed under normoxic conditions, or exposed to short-term (2 d) or sustained (14 d) hypoxia (10% O2), after which samples were obtained from the left ventricle of the heart and the soleus for assessment of metabolic regulation and mitochondrial function. Mass-corrected maximal oxidative phosphorylation was 20% lower in the left ventricle following sustained but not short-term hypoxia, though no change was observed in the soleus. After sustained hypoxia, the ratio of octanoyl carnitine- to pyruvate- supported respiration was 11% and 12% lower in the left ventricle and soleus, respectively, whilst hexokinase activity increased by 33% and 2.1-fold in these tissues. mRNA levels of PPARα targets fell after sustained hypoxia in both tissues, but those of PPARα remained unchanged. Despite decreased Ucp3 expression after short-term hypoxia, UCP3 protein levels and mitochondrial coupling remained unchanged. Protein carbonylation was 40% higher after short-term but not sustained hypoxic exposure in the left ventricle, but was unchanged in the soleus at both timepoints. Our findings therefore demonstrate that 14 days, but not 2 days, of hypoxia induces a loss of oxidative capacity in the left ventricle but not the soleus, and a substrate switch away from fatty acid oxidation in both tissues.

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“…Metabolomic and lipidomic analyses of biofluids measure a large number of variables of interest within the metabolic and lipid systems, thus providing a sensitive measure of functional biological phenotype (reviewed in 26 ). The power of such analyses has been demonstrated in the identification of biomarkers related to the diagnosis or prognosis of a range of diseases 27 .…”

Section: Introductionmentioning

confidence: 99%

Metabolomic and lipidomic plasma profile changes in human participants ascending to Everest Base Camp

O’Brien

Atkinson

Richardson

et al. 2019

Sci Rep

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At high altitude oxygen delivery to the tissues is impaired leading to oxygen insufficiency (hypoxia). Acclimatisation requires adjustment to tissue metabolism, the details of which remain incompletely understood. Here, metabolic responses to progressive environmental hypoxia were assessed through metabolomic and lipidomic profiling of human plasma taken from 198 human participants before and during an ascent to Everest Base Camp (5,300 m). Aqueous and lipid fractions of plasma were separated and analysed using proton (1H)-nuclear magnetic resonance spectroscopy and direct infusion mass spectrometry, respectively. Bayesian robust hierarchical regression revealed decreasing isoleucine with ascent alongside increasing lactate and decreasing glucose, which may point towards increased glycolytic rate. Changes in the lipid profile with ascent included a decrease in triglycerides (48–50 carbons) associated with de novo lipogenesis, alongside increases in circulating levels of the most abundant free fatty acids (palmitic, linoleic and oleic acids). Together, this may be indicative of fat store mobilisation. This study provides the first broad metabolomic account of progressive exposure to environmental hypobaric hypoxia in healthy humans. Decreased isoleucine is of particular interest as a potential contributor to muscle catabolism observed with exposure to hypoxia at altitude. Substantial changes in lipid metabolism may represent important metabolic responses to sub-acute exposure to environmental hypoxia.

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Mitochondrial responses to extreme environments: insights from metabolomics

Cited by 14 publications

References 67 publications

Effects of microgravity on osteoblast mitochondria: a proteomic and metabolomics profile

Effects of microgravity on osteoblast mitochondria: a proteomic and metabolomics profile

Altered Oxygen Utilisation in Rat Left Ventricle and Soleus after 14 Days, but Not 2 Days, of Environmental Hypoxia

Metabolomic and lipidomic plasma profile changes in human participants ascending to Everest Base Camp

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