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Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure.

ABSTRACT: (1) Background: The development of mitochondrial medicine has been severely impeded by a lack of effective therapies. (2) Methods: To better understand Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-like episodes (MELAS) syndrome, neuronal cybrid cells carrying different mutation loads of the m.3243A > G mitochondrial DNA variant were analysed using a multi-omic approach. (3) Results: Specific metabolomic signatures revealed that the glutamate pathway was significantly increased in MELAS cells with a direct correlation between glutamate concentration and the m.3243A > G heteroplasmy level. Transcriptomic analysis in mutant cells further revealed alterations in specific gene clusters, including those of the glutamate, gamma-aminobutyric acid pathways, and tricarboxylic acid (TCA) cycle. These results were supported by post-mortem brain tissue analysis from a MELAS patient, confirming the glutamate dysregulation. Exposure of MELAS cells to ketone bodies significantly reduced the glutamate level and improved mitochondrial functions, reducing the accumulation of several intermediate metabolites of the TCA cycle and alleviating the NADH-redox imbalance. (4) Conclusions: Thus, a multi-omic integrated approach to MELAS cells revealed glutamate as a promising disease biomarker, while also indicating that a ketogenic diet should be tested in MELAS patients.

SUBMITTER: Belal S

PROVIDER: S-EPMC9312837 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVE:We previously showed that MELAS patients have decreased cerebrovascular reactivity (CVR) (p? 0.002) and increased cerebral blood flow (CBF) (p<0.0026); changes correlated with disease severity and % mutant mtDNA (inversely for CVR; directly for CBF). We ran a prospective pilot in 3 MELAS sibs (m.3243A>G tRNALeu(UUR)) with variable % mutant blood mtDNA to assess effects of L-Arginine (L-Arg) (single dose and 6-wk steady-state trial) on regional CBF, arterial CVR and neurovascular coupling. METHODS:Patients were studied with 3T MRI using arterial spin labeling (ASL) to measure CBF and changes in % Blood Oxygen Level Dependent (BOLD) signal to changes in arterial partial pressure of CO2 to measure CVR. Task fMRI consisted of an alternating black and white checkerboard to evaluate visual cortex response in MELAS and controls. RESULTS:Following L-Arg, there was restoration of serum Arg (76-230 ?M) in MELAS sibs and a trend towards increasing CVR in frontal and corresponding decrease in occipital cortex; CVR was unchanged globally. There was a 29-37% reduction in baseline CBF in one patient following 6 wks of L-Arg. Pre-treatment fMRI activation in response to visual cortex stimulus was markedly decreased in the same patient compared to controls in primary visual striate cortex V1 and extrastriate regions V2 to V5 with a marked increase toward control values following a single dose and 6 wks of L-Arg. CONCLUSION:Proposed "healing" effect may be due to more efficient utilization of energy substrates with increased cellular energy balances and ensuing reduction in signalling pathways that augment flow in the untreated state. CLASSIFICATION OF EVIDENCE:This prospective pilot study provides Class III evidence that oral L-Arginine (100 mg/kg single dose or 100 mg/kg three times daily po X 6 weeks) normalizes resting blood flow from elevated pre-treatment levels in patients with MELAS syndrome, selectively increases their CVR from reduced pre-treatment levels in regions most impaired at the expense of less abnormal regions, and normalizes reduced BOLD fMRI activation in response to visual cortex stimulus. CLINICAL TRIALS.GOV (NIH):NCT01603446.

Project description:Background and objectivesStroke management in the context of primary mitochondrial disease is clinically challenging, and the best treatment options for patients with stroke-like episodes remain uncertain. We sought to perform a systematic review of the safety and efficacy of l-arginine use in the acute and prophylactic management of stroke-like episodes in patients with mitochondrial disease.MethodsThe systematic review was registered in PROSPERO (CRD42020181230). We searched 6 databases from inception to January 15, 2021: MEDLINE, Embase, Scopus, Web of Science, CINAHL, and ClinicalTrials.gov. Original articles and registered trials available, in English, reporting l-arginine use in the acute or prophylactic management of stroke-like episodes in patients with genetically confirmed mitochondrial disease were eligible for inclusion. Data on safety and treatment response were extracted and summarized by multiple observers. Risk of bias was assessed by the methodologic quality of case reports, case series, and a risk-of-bias checklist for nonrandomized studies. Quality of evidence was synthesized with the Oxford Centre for Evidence-Based Medicine Levels of Evidence and Grade of Recommendations. The predetermined main outcome measures were clinical response to l-arginine treatment, adverse events, withdrawals, and deaths (on treatment and/or during follow-up), as defined by the author.ResultsThirty-seven articles met inclusion criteria (0 randomized controlled trials; 3 open-label; 1 retrospective cohort; 33 case reports/case series) (N = 91 patients; 86% m.3243A>G). In the case reports, 54% of patients reported a positive clinical response to acute l-arginine, of which 40% were concomitantly treated with antiepileptic drugs. Improved headache at 24 hours was the greatest reported benefit in response to IV l-arginine in the open-label trials (31 of 39, 79%). In 15 of 48 patients (31%) who positively responded to prophylactic l-arginine, antiepileptic drugs were either used (7 of 15) or unreported (8 of 15). Moderate adverse events were reported in the follow-up of both IV and oral l-arginine treatment, and 11 patients (12%) died during follow-up or while on prophylactic treatment.DiscussionThe available evidence is of poor methodologic quality and classified as Level 5. IV and oral l-arginine confers no demonstrable clinical benefit in either the acute or prophylactic treatment of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, with more robust controlled trials required to assess its efficacy and safety profile.

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Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure.

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