Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome

Spencer, Kira A.; Mulholland, Michael; Snell, John; Howe, Miranda; James, Katerina; Hanaford, Allison R.; Morgan, Philip G.; Sedensky, Margaret; Johnson, Simon C.

doi:10.1016/j.bja.2023.08.009

Cited by 4 publications

(14 citation statements)

References 35 publications

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“…As in our prior work, the diet composition was altered gradually during the early postweaning period (Figure 1A, see Section 2). Consistent with our prior findings, 12 this regimen led to dietary ketosis in the Ndufs4 (−/−) model: in ad‐libitum fed mice at postnatal day 50 (P50), blood beta‐hydroxybutyrate was significantly elevated in animals fed the ketogenic diet compared to those control chow, while average blood glucose concentration was significantly reduced (Figure 1B,C). Blood lactate levels were not altered by dietary ketosis (Figure 1D).…”

Section: Resultssupporting

confidence: 90%

“…Accordingly, high variance in unanesthetized data and early in anesthetic exposures (when animals are not yet fully anesthetized) is expected. Nevertheless, we saw no notable changes in heart rate or SpO 2 during the three exposures, consistent with our prior findings using this paradigm in animals fed a control diet 12 . See our Data S1 tab SpO 2 and heart rate for data.…”

Section: Methodssupporting

confidence: 91%

“…Symptom onset occurs at ~P37 in Ndufs4 (−/−) animals, with progressive cachexia and visible signs of neurodegenerative changes, such as forelimb clasping, visible starting around this age. To assess anesthetic responses, animals were exposed to brief (30‐min) anesthesia with isoflurane on P50, 51, and 52 (see Section 2 and 12 ). Median and maximum survival in untreated Ndufs4 (−/−) mice is ~60 and 80 days of age.…”

Section: Methodsmentioning

confidence: 99%

“…As detailed in our prior studies, 8,12 0.4% isoflurane was used to anesthetize Ndufs4 (−/−) mice, while 1.25% isoflurane, an equipotent concentration, was used to anesthetize control animals. Note: (−)keto (−)iso data appear in, 12 as the experiments were performed concurrently to reduce overall animal use.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently shown that exposure to VAs is acutely toxic in Ndufs4 (−/−) mice at ages after the onset of disease, but not earlier in life, and that toxicity is linked to the presence of the neuroinflammatory CNS lesions characteristic of LS 11,12 . This toxicity is distinct from anesthetic hypersensitivity, as MAC changes little with disease onset.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 90%

Section: Methodssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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Stress Pathways Induced by Volatile Anesthetics and Failure of Preconditioning in a Mitochondrial Complex I Mutant

Olufs,

Wassarman,

Perouansky

2023

Anesthesiology

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Background Carriers of mutations in the mitochondrial electron transport chain (mETC) are at increased risk of anesthetic-induced neurotoxicity. To investigate the neurotoxicity mechanism and to test preconditioning as a protective strategy, we used a Drosophila melanogaster model of Leigh syndrome. Model flies carried a mutation in ND23 (ND2360114) that encodes an mETC Complex I subunit. We investigated why ND2360114 mutants become susceptible to lethal, oxygen-modulated neurotoxicity within 24 h of exposure to isoflurane but not sevoflurane. Methods We used transcriptomics and qRT-PCR to identify genes that are differentially expressed in ND2360114 but not wild type fly heads at 30 min after exposure to high versus low toxicity conditions. We also subjected ND2360114 flies to diverse stressors prior to isoflurane exposure to test whether isoflurane toxicity could be diminished by preconditioning. Results The ND2360114 mutation had a greater effect on isoflurane- than sevoflurane-mediated changes in gene expression. Isoflurane and sevoflurane did not affect expression of heat shock protein (Hsp) genes (Hsp22, Hsp27, and Hsp68) in wild type flies, but isoflurane substantially increased expression of these genes in ND2360114 mutant flies. Furthermore, isoflurane and sevoflurane induced expression of oxidative (GstD1and GstD2) and xenobiotic (Cyp6a8 and Cyp6a14) stress genes to a similar extent in wild type flies, but the effect of isoflurane was largely reduced in ND2360114 flies. In addition, activating stress response pathways by preexposure to anesthetics, heat shock, hyperoxia, hypoxia, or oxidative stress did not suppress isoflurane-induced toxicity in ND2360114 mutant flies. Conclusions Mutation of an mETC Complex I subunit generates differential effects of isoflurane and sevoflurane on gene expression that may underlie their differential effects on neurotoxicity. Additionally, the mutation produces resistance to preconditioning by stresses that protect the brain in other contexts. Therefore, Complex I activity modifies molecular and physiological effects of anesthetics in an anesthetic-specific manner.

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Evaluating the efficacy of vatiquinone in preclinical models of mitochondrial disease

Kayser,

Chen,

Mulholland

et al. 2024

Preprint

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Background Genetic mitochondrial diseases are a major challenge in modern medicine, impacting around 1:4,000 individuals. Leigh syndrome is the most common pediatric presentation of mitochondrial disease. There are currently no effective clinical treatments for mitochondrial disease. In humans, patients are often treated with antioxidants, vitamins, and strategies targeting energetics. The vitamin-E related compound vatiquinone (EPI-743, α-tocotrienol quinone) has been the subject of at least 19 clinical trials in the US since 2012, but the effects of vatiquinone on an animal model of mitochondrial disease have not yet been reported. Here, assessed the impact of vatiquinone on disease progression and in two animal models of mitochondrial disease. Methods The efficacy of vatiquinone in vitro was assessed using human fibroblasts treated with the general mitochondrial oxidative stress inducer paraquat, the GPX4 inhibitor RSL3, or the glutathione synthase inhibitor BSO in combination with excess iron. The therapeutic potential of vatiquinone in vivo was assessed using tamoxifen-induced mouse model for GPX4 deficiency and the Ndufs4 knockout mouse model of Leigh syndrome. In both models, animals were treated daily with vatiquinone or vehicle and relevant disease endpoints were assessed. Results Vatiquinone robustly prevented death in cultured cells induced by RSL3 or BSO/iron, but had no effect on paraquat induced cell death. Vatiquinone had no impact on disease onset, progression, or survival in either the tamoxifen-inducible GPX4 deficient model or the Ndufs4(-/-) mouse model, though the drug may have reduced seizure risk. Conclusions Vatiquinone provided no benefit to survival in two mouse models of disease, but may prevent seizures in the Ndufs4(-/-) model. Our findings are consistent with recent press statements regarding clinical trial results and have implications for drug trial design and reporting in patients with rare diseases.

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Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome

Cited by 4 publications

References 35 publications

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

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

Stress Pathways Induced by Volatile Anesthetics and Failure of Preconditioning in a Mitochondrial Complex I Mutant

Evaluating the efficacy of vatiquinone in preclinical models of mitochondrial disease

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