Absence of the mitochondrial translocator protein 18 kDa in mice does not affect body weight or food intake responses to altered energy availability

Morrissey, Nicole A.; Beall, Craig; Ellacott, Kate L. J.

doi:10.1111/jne.13027

Cited by 3 publications

(4 citation statements)

References 39 publications

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“…As detailed in Morrissey et al. (2021), mating pairs of TSPO heterozygote ( +/− ) (Tspo tm1b(EUCOMM)Wtsi ) mice were used to produce the homozygote knockout (TSPO −/− ) and wildtype (TSPO +/+ ) littermate neonates from which TSPO +/+ and TSPO −/− primary astrocytes were isolated for use in these studies. Mice were crossed >7 generations onto a C57BL/6J background.…”

Section: Methodsmentioning

confidence: 99%

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Regulation of astrocyte metabolism by mitochondrial translocator protein 18 kDa

Firth,

Robb,

Stewart

et al. 2024

Journal of Neurochemistry

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The mitochondrial translocator protein 18 kDa (TSPO) has been linked to functions from steroidogenesis to regulation of cellular metabolism and is an attractive therapeutic target for chronic CNS inflammation. Studies in Leydig cells and microglia indicate that TSPO function may vary between cells depending on their specialized roles. Astrocytes are critical for providing trophic and metabolic support in the brain. Recent work has highlighted that TSPO expression increases in astrocytes under inflamed conditions and may drive astrocyte reactivity. Relatively little is known about the role TSPO plays in regulating astrocyte metabolism and whether this protein is involved in immunometabolic processes in these cells. Using TSPO‐deficient (TSPO−/−) mouse primary astrocytes in vitro (MPAs) and a human astrocytoma cell line (U373 cells), we performed extracellular metabolic flux analyses. We found that TSPO deficiency reduced basal cellular respiration and attenuated the bioenergetic response to glucopenia. Fatty acid oxidation was increased, and lactate production was reduced in TSPO−/− MPAs and U373 cells. Co‐immunoprecipitation studies revealed that TSPO forms a complex with carnitine palmitoyltransferase 1a in U373 and MPAs, presenting a mechanism wherein TSPO may regulate FAO in these cells. Compared to TSPO+/+ cells, in TSPO−/− MPAs we observed attenuated tumor necrosis factor release following 3 h lipopolysaccharide (LPS) stimulation, which was enhanced at 24 h post‐LPS stimulation. Together these data suggest that while TSPO acts as a regulator of metabolic flexibility, TSPO deficiency does not appear to modulate the metabolic response of MPAs to inflammation, at least in response to the model used in this study.

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Section: Methodsmentioning

confidence: 99%

“…TSPO genotypes ( +/+ , +/− , −/− ) of breeder mice and mouse primary astrocytes (MPAs) were determined by PCR as reported previously in Morrissey et al. (2021) (Figure S1).…”

Section: Methodsmentioning

confidence: 99%

Regulation of astrocyte metabolism by mitochondrial translocator protein 18 kDa

Firth,

Robb,

Stewart

et al. 2024

Journal of Neurochemistry

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“…As detailed in Morrissey et al . 2021 39 , mating pairs of TSPO heterozygote ( +/- ) (Tspo tm1b (EUCOMM) Wtsi ) mice were used to produce the homozygote knockout (TSPO -/- ) and wildtype (TSPO +/+ ) littermate mice used in these studies. Mice were crossed >7 generations onto a C57BL/6J background.…”

Section: Methodsmentioning

confidence: 99%

“…TSPO genotypes ( +/+ , +/- , -/- ) of breeder mice and mouse primary astrocytes (MPAs) were determined by PCR as reported previously in Morrissey et al . 2021 39 (Supplementary Figure 1).…”

Section: Methodsmentioning

confidence: 99%

Regulation of astrocyte metabolism by mitochondrial translocator protein 18kDa

Firth,

Robb,

Stewart

et al. 2023

Preprint

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The mitochondrial translocator protein 18kDa (TSPO) has been linked to a variety of functions from steroidogenesis to regulation of cellular metabolism and is an attractive therapeutic target for chronic CNS inflammation. Studies in the periphery using Leydig cells and hepatocytes, as well as work in microglia, indicate that the function of TSPO may vary between cells depending on their specialised roles. Astrocytes are critical for providing trophic and metabolic support in the brain as part of their role in maintaining brain homeostasis. Recent work has highlighted that TSPO expression increases in astrocytes under inflamed conditions and may drive astrocyte reactivity. However, relatively little is known about the role TSPO plays in regulating astrocyte metabolism and whether this protein is involved in immunometabolic processes in these cells. Using TSPO-deficient (TSPO-/-) mouse primary astrocytesin vitro(MPAs) and a human astrocytoma cell line (U373 cells), we performed metabolic flux analyses. We found that loss of TSPO reduced basal astrocyte respiration and increased the bioenergetic response to glucose reintroduction following glucopenia, while increasing fatty acid oxidation (FAO). Lactate production was significantly reduced in TSPO-/-astrocytes. Co-immunoprecipitation studies in U373 cells revealed that TSPO forms a complex with carnitine palmitoyltransferase 1a, which presents a mechanism wherein TSPO may regulate FAO in astrocytes. Compared to TSPO+/+cells, inflammation induced by 3h lipopolysaccharide (LPS) stimulation of TSPO-/-MPAs revealed attenuated tumour necrosis factor release, which was enhanced in TSPO-/-MPAs at 24h LPS stimulation. Together these data suggest that while TSPO acts as a regulator of metabolic flexibility in astrocytes, loss of TSPO does not appear to modulate the metabolic response of astrocytes to inflammation, at least in response to the stimulus/time course used in this study.

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