Differential effects of mTOR inhibition and dietary ketosis in a mouse model of subacute necrotizing encephalomyelopathy

Bornstein, Rebecca; James, Katerina; Stokes, Julia C.; Park, Kyung Yeon; Kayser, Ernst-Bernhard; Snell, John; Bard, Angela M; Chen, Yihan; Kalume, Franck; Johnson, Simon C.

doi:10.1016/j.nbd.2021.105594

Cited by 9 publications

(28 citation statements)

References 46 publications

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“…IPI-549 also did not cause low glucose as we have observed with chronic rapamycin treatment (see ref. 17 ). In contrast, BYL719 severely impaired size, significantly more than IPI-549, while not rescuing disease ( Figure 1, B, H, I, M, and N ); these data indicate mTOR inhibition does not benefit LS through actions on insulin/insulin like growth factor 1 signaling, which is mediated by p110α ( 18 ).…”

Section: Resultsmentioning

confidence: 99%

“…To assess whether mTOR inhibition affects leukocyte/microglia proliferation in vitro, we tested the impact of ABI-009 (aka nab-rapamycin, see refs. 17 , 21 ), a water-soluble nanoparticle formulation of rapamycin (see Supplemental Methods), on Iba1 + cells in a mixed brain cell culture assay, comparing the impact with that of pexidartinib/PLX3397, a CSF1R inhibitor that blocks leukocyte survival signaling ( 22 ) ( Figure 2A ). ABI-009 and pexidartinib both reduced the fraction of Iba1 + cells in mixed neonatal brain cell cultures in a dose-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

“…The rotarod assay provided a mild epileptogenic stimulus in the Ndufs4 (KO) model: seizures occurred in approximately 30% of untreated Ndufs4 (KO) mice, but were not observed in control animals, during rotarod at age P30 ( 17 ) ( Figure 3F and Supplemental Methods). We performed rotorod assay on control and pexidartinib-treated Ndufs4 (KO) mice to assess whether targeting leukocytes impacts seizures.…”

Section: Resultsmentioning

confidence: 99%

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Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Stokes¹,

Bornstein²,

James³

et al. 2022

JCI Insight

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: Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of LS. Depleting leukocytes with a colony-stimulating factor 1 receptor inhibitor disrupts disease progression, including suppression of CNS lesion formation and a substantial extension of survival. Leukocyte depletion rescues diverse symptoms including seizures, respiratory center function, hyperlactemia, and neurologic sequelae. These data reveal a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement is causal in disease. This work has significant implications for the mechanisms of mitochondrial disease and may lead to novel therapeutic strategies. One-Sentence Summary: Leukocyte depletion prevents CNS lesions, neurological disease, and metabolic dysfunction in the Ndufs4(KO) model of Leigh syndrome.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Stokes¹,

Bornstein²,

James³

et al. 2022

JCI Insight

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“…Blood lactate levels were not altered by dietary ketosis (Figure 1D). On the ketogenic diet regimen, control animals show a milder ketosis compared to Ndufs4 (−/−) mice and a slight increase in blood glucose at baseline 12,15 (Figure 1E–G).…”

Section: Resultsmentioning

confidence: 98%

“…13,14 Dietary ketosis also appears to reduce seizure incidence in the Ndufs4(−/−) mouse model of Leigh syndrome. 15 However, studies to date do not seem to support the notion that overall disease progression is altered by a ketogenic diet in either the Ndufs4(−/−) model or patients, suggesting that benefits may be limited to seizure control. 14,15 While a ketogenic diet is being used for clinical care of mitochondrial disease patients, potential interactions between VAs and a ketogenic diet in the setting of genetic mitochondrial disease have not been tested.…”

Section: Introductionmentioning

confidence: 99%

Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome

Spencer,

Howe,

Mulholland

et al. 2024

Pediatric Anesthesia

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BackgroundGenetic mitochondrial diseases impact over 1 in 4000 individuals, most often presenting in infancy or early childhood. Seizures are major clinical sequelae in some mitochondrial diseases including Leigh syndrome, the most common pediatric presentation of mitochondrial disease. Dietary ketosis has been used to manage seizures in mitochondrial disease patients. Mitochondrial disease patients often require surgical interventions, leading to anesthetic exposures. Anesthetics have been shown to be toxic in the setting of mitochondrial disease, but the impact of a ketogenic diet on anesthetic toxicities in this setting has not been studied.AimsOur aim in this study was to determine whether dietary ketosis impacts volatile anesthetic toxicities in the setting of genetic mitochondrial disease.MethodsThe impact of dietary ketosis on toxicities of volatile anesthetic exposure in mitochondrial disease was studied by exposing young Ndufs4(−/−) mice fed ketogenic or control diet to isoflurane anesthesia. Blood metabolites were measured before and at the end of exposures, and survival and weight were monitored.ResultsCompared to a regular diet, the ketogenic diet exacerbated hyperlactatemia resulting from isoflurane exposure (control vs. ketogenic diet in anesthesia mean difference 1.96 mM, Tukey's multiple comparison adjusted p = .0271) and was associated with a significant increase in mortality during and immediately after exposures (27% vs. 87.5% mortality in the control and ketogenic diet groups, respectively, during the exposure period, Fisher's exact test p = .0121). Our data indicate that dietary ketosis and volatile anesthesia interact negatively in the setting of mitochondrial disease.ConclusionsOur findings suggest that extra caution should be taken in the anesthetic management of mitochondrial disease patients in dietary ketosis.

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Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome

Spencer,

Mulholland,

Snell

et al. 2023

British Journal of Anaesthesia

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Differential effects of mTOR inhibition and dietary ketosis in a mouse model of subacute necrotizing encephalomyelopathy

Cited by 9 publications

References 46 publications

Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome

Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome

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