Effects of mid-respiratory chain inhibition on mitochondrial function <i>in vitro</i> and <i>in vivo</i>

Broom, Ashley; Ambroso, Jeffrey L.; Brunori, Gino; Burns, Angie; Armitage, James R.; Francis, Ian; Gandhi, Mitul; Peterson, Richard A.; Gant, Timothy W.; Boobis, Alan R.; Lyon, Jonathan J.

doi:10.1039/c5tx00197h

Cited by 9 publications

(14 citation statements)

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“…1A , see Methods). GSK932121A binds to the Qi site of CIII [ 23 ] and inhibits CIII catalytic activity in rodents [ 21 ] Prior work has demonstrated its toxic effects upon mitochondrial function in female Crl:CD(SD) rats when administered at a dose of 50 mg kg −1 i.p [ 21 ]. The dose used here is below that shown to invoke overt hepatotoxicity, with the aim being to exert mild CIII inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…Liver fibrosis associated with mitochondrial dysfunction has been shown to coincide with raised circulating lactate [ 27 – 29 ]; however, no rise in plasma lactate was observed here following hypoxic exposure or GSK932121A administration, either alone or in combination (Additional File 1 : Figure S1E). Administration of GSK932121A at 50 mg kg −1 has been associated with hepatic glycogen depletion [ 21 ], yet no change in hepatic glycogen storage was observed (Additional File 1 : Figure S1F). Together, this suggests that whilst 2 days of hypoxic exposure in combination with GSK932121A administration invoked hepatic stress, the dose used did not result in overt hepatotoxicity.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we investigated the metabolic response of rat liver to short-term (2 days) and prolonged (14 days) exposure to inhalation hypoxia (10% O 2 ). The role of the mitochondrial ETS in this response, and so the importance of altered respiratory capacity, was probed through the mild inhibition of CIII [ 21 ]. To assess the consequences for hepatic and systemic metabolic regulation, metabolomic profiles were examined in liver and plasma, with a particular focus on alterations in lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress

et al. 2021

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Background Tissue hypoxia is a key feature of several endemic hepatic diseases, including alcoholic and non-alcoholic fatty liver disease, and organ failure. Hypoxia imposes a severe metabolic challenge on the liver, potentially disrupting its capacity to carry out essential functions including fuel storage and the integration of lipid metabolism at the whole-body level. Mitochondrial respiratory function is understood to be critical in mediating the hepatic hypoxic response, yet the time-dependent nature of this response and the role of the respiratory chain in this remain unclear. Results Here, we report that hepatic respiratory capacity is enhanced following short-term exposure to hypoxia (2 days, 10% O2) and is associated with increased abundance of the respiratory chain supercomplex III2+IV and increased cardiolipin levels. Suppression of this enhanced respiratory capacity, achieved via mild inhibition of mitochondrial complex III, disrupted metabolic homeostasis. Hypoxic exposure for 2 days led to accumulation of plasma and hepatic long chain acyl-carnitines. This was observed alongside depletion of hepatic triacylglycerol species with total chain lengths of 39-53 carbons, containing palmitic, palmitoleic, stearic, and oleic acids, which are associated with de novo lipogenesis. The changes to hepatic respiratory capacity and lipid metabolism following 2 days hypoxic exposure were transient, becoming resolved after 14 days in line with systemic acclimation to hypoxia and elevated circulating haemoglobin concentrations. Conclusions The liver maintains metabolic homeostasis in response to shorter term hypoxic exposure through transient enhancement of respiratory chain capacity and alterations to lipid metabolism. These findings may have implications in understanding and treating hepatic pathologies associated with hypoxia.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress

et al. 2021

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“…Drugs targeting the mitochondrial respiratory chain (MRC) are relatively well tolerated in normal tissues (Blecha et al 2017 ). Many in vitro studies may also be insensitive to mitochondrial toxicants as cells are kept in supra-physiological (e.g., 3–5 times higher than normal plasma levels) glucose concentrations (Blomme and Will 2016 ; Broom et al 2016 ; Perron et al 2013 ; Tilmant et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors

et al. 2021

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Inhibition of complex I of the mitochondrial respiratory chain (cI) by rotenone and methyl-phenylpyridinium (MPP +) leads to the degeneration of dopaminergic neurons in man and rodents. To formally describe this mechanism of toxicity, an adverse outcome pathway (AOP:3) has been developed that implies that any inhibitor of cI, or possibly of other parts of the respiratory chain, would have the potential to trigger parkinsonian motor deficits. We used here 21 pesticides, all of which are described in the literature as mitochondrial inhibitors, to study the general applicability of AOP:3 or of in vitro assays that are assessing its activation. Five cI, three complex II (cII), and five complex III (cIII) inhibitors were characterized in detail in human dopaminergic neuronal cell cultures. The NeuriTox assay, examining neurite damage in LUHMES cells, was used as in vitro proxy of the adverse outcome (AO), i.e., of dopaminergic neurodegeneration. This test provided data on whether test compounds were unspecific cytotoxicants or specifically neurotoxic, and it yielded potency data with respect to neurite degeneration. The pesticide panel was also examined in assays for the sequential key events (KE) leading to the AO, i.e., mitochondrial respiratory chain inhibition, mitochondrial dysfunction, and disturbed proteostasis. Data from KE assays were compared to the NeuriTox data (AO). The cII-inhibitory pesticides tested here did not appear to trigger the AOP:3 at all. Some of the cI/cIII inhibitors showed a consistent AOP activation response in all assays, while others did not. In general, there was a clear hierarchy of assay sensitivity: changes of gene expression (biomarker of neuronal stress) correlated well with NeuriTox data; mitochondrial failure (measured both by a mitochondrial membrane potential-sensitive dye and a respirometric assay) was about 10–260 times more sensitive than neurite damage (AO); cI/cIII activity was sometimes affected at > 1000 times lower concentrations than the neurites. These data suggest that the use of AOP:3 for hazard assessment has a number of caveats: (i) specific parkinsonian neurodegeneration cannot be easily predicted from assays of mitochondrial dysfunction; (ii) deriving a point-of-departure for risk assessment from early KE assays may overestimate toxicant potency.

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“…This in vivo effect was suggested to have resulted from the initial insult in combination with compensatory changes made by the tissue in order to maintain energy production. 35 Fan et al reported that a short-term incubation of mitochondria in vitro with the organic arsenical MOPIMP promoted the inhibition of respiratory chain complexes I, II, III and IV, and with damage to the respiration process. 19 The activity of complex IV, the terminal complex of the electron transport chain, was significantly destroyed even when treated with MOPIMP at a low concentration level.…”

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confidence: 99%

Targeting of the respiratory chain by toxicants: beyond the toxicities to mitochondrial morphology

Zhou

Huang

2018

Toxicology Research

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Effects of mid-respiratory chain inhibition on mitochondrial function in vitro and in vivo

Abstract: Schematic showing the toxicological and adaptive effects of drug-induced respiratory chain inhibition in vivo; also highlighting unanticipated differences from observations made in vitro (in red).

Cited by 9 publications

References 42 publications

Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress

Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress

Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors

Targeting of the respiratory chain by toxicants: beyond the toxicities to mitochondrial morphology

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