bims-ecasc1 2024-10-13 papers

bims-ecasc1

Biomed News

on Enoyl Coenzyme A hydratase, short chain, 1

Issue of 2024–10–13
seven papers selected by
Bill Suzor, Cure Mito Foundation

Increased ketone levels as a key magnetic resonance spectroscopic findings during acute exacerbation in ECHS1-related Leigh syndrome.
Disease models of Leigh syndrome: From yeast to organoids.
Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in Italy.
Crosstalk between macrophages and immunometabolism and their potential roles in tissue repair and regeneration.
Rab8a Is a Key Target That Melatonin Prevents Lipid Disorder from Atrazine.
Exploring the role of mitochondrial uncoupling protein 4 in brain metabolism: implications for Alzheimer's disease.
Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases.

Radiol Case Rep. 2024 Dec;19(12): 6292-6296

Increased ketone levels as a key magnetic resonance spectroscopic findings during acute exacerbation in ECHS1-related Leigh syndrome.

Yuka Murofushi, Kenta Ochiai, Madoka Yasukochi, Kentaro Sano, Keiko Ichimoto, Kei Murayama, Yasushi Okazaki, Taku Omata, Jun-Ichi Takanashi.

  Short-chain enoyl-CoA hydratase, encoded by ECHS1, plays a major role in the valine catabolic pathway and mitochondrial fatty acid β-oxidation. Deficiency of this enzyme causes Leigh syndrome. Herein, we report a case of ECHS1-related Leigh syndrome with a prominent ketone body spectrum on magnetic resonance spectroscopy during acute exacerbation. A 6-month-old boy with mild motor developmental delay presented with disturbances of consciousness and hypercapnia without prior infection or feeding failure. Upon admission, investigations revealed prominent ketosis and elevated 2,3-dihydroxy-2-methylbutyric acid excretion. Brain magnetic resonance imaging revealed symmetrical T2 prolongation with restricted diffusion in the basal ganglia. Magnetic resonance spectroscopy showed a prominent ketone body spectrum in the cerebral white matter, and prominent ketone bodies, elevated lactate and markedly decreased N-acetylaspartate levels in the basal ganglia. Genetic analysis identified compound heterozygous variants of ECHS1. Short-chain enoyl-CoA hydratase deficiency is a disease for which a valine-restricted diet is reported to be beneficial, and early diagnosis is desirable. Severe ketosis and the ketone body magnetic resonance spectroscopy spectrum during acute exacerbation may aid in the diagnosis of this disease.

Keywords:  ECHS1; Ketosis; Leigh syndrome; Magnetic resonance spectroscopy; Metabolic encephalopathies

DOI:  https://doi.org/10.1016/j.radcr.2024.08.164
J Inherit Metab Dis. 2024 Oct 09.

Disease models of Leigh syndrome: From yeast to organoids.

Marie-Thérèse Henke, Alessandro Prigione, Markus Schuelke.

  Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS-causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used Ndufs4 knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans-mitochondrial cybrids to more recent model systems such as patient-derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three-dimensional organoids. These latter models open the possibility of developing high-throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.

Keywords:  Leigh syndrome; animal models; disease modeling; mitochondrial diseases; organoids; phenotyping; pluripotent stem cells

DOI:  https://doi.org/10.1002/jimd.12804
Ital J Pediatr. 2024 Oct 07. 50(1): 204

Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in Italy.

Francesco Porta, Arianna Maiorana, Vincenza Gragnaniello, Elena Procopio, Serena Gasperini, Roberta Taurisano, Marco Spada, Carlo Dionisi-Vici, Alberto Burlina.

   BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) are rare and potentially life-threatening diseases that cause deficient energy production and accumulation of toxic metabolites. Despite dietary management, adherence to maximum fasting guidelines, restricted long-chain triglyceride intake and supplementation with medium-chain triglyceride (MCT) oil (current standard of care), most patients experience recurrent decompensation episodes that can require hospitalisation. Herein, we analysed the effectiveness and safety of triheptanoin (a highly purified, synthetic medium odd-chain triglyceride) treatment in a cohort of Italian patients with LC-FAOD.
METHODS: This retrospective, nationwide study included nine patients with LC-FAOD who switched from standard therapy with MCT oil to triheptanoin oral liquid. Data were collected between 2018 and 2022. Clinical outcome measures were the number and duration of intercurrent catabolic episodes and number and duration of metabolic decompensation episodes requiring hospitalisation. Creatine kinase (CK) levels and treatment-related adverse effects were also reported.
RESULTS: Patients were provided a mean ± standard deviation (SD) triheptanoin dose of 1.5 ± 0.9 g/kg/day in four divided administrations, which accounted for 23.9 ± 8.9% of patients' total daily caloric intake. Triheptanoin treatment was started between 2.7 and 16 years of age and was continued for 2.2 ± 0.9 years. The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014), and annualised hospitalisation rates and duration. Mean CK levels (outside metabolic decompensation episodes) were lower with triheptanoin treatment versus MCT oil for seven patients. No intensive care unit admissions were required during triheptanoin treatment. Epigastric pain and diarrhoea were recorded as adverse effects during both MCT and triheptanoin treatment.
CONCLUSIONS: The significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD. Triheptanoin was well tolerated and decreased the number of intercurrent catabolic episodes, metabolic decompensation episodes requiring hospitalisation, and the annualised rate and duration of hospitalisations.

Keywords:  Inherited metabolic disorders; Long-chain fatty acid oxidation disorders; Medium-chain triglyceride oil; Triheptanoin

DOI:  https://doi.org/10.1186/s13052-024-01782-y
Heliyon. 2024 Sep 30. 10(18): e38018

Crosstalk between macrophages and immunometabolism and their potential roles in tissue repair and regeneration.

Hongbo Ma, Limei Gao, Rong Chang, Lihong Zhai, Yanli Zhao.

  Immune metabolism is a result of many specific metabolic reactions, such as glycolysis, the tricarboxylic acid (TCA) pathway, the pentose phosphate pathway (PPP), mitochondrial oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), fatty acid biosynthesis (FAs) and amino acid pathways, which promote cell proliferation and maintenance with structural and pathological energy to regulate cellular signaling. The metabolism of macrophages produces many metabolic intermediates that play important regulatory roles in tissue repair and regeneration. The metabolic activity of proinflammatory macrophages (M1) mainly depends on glycolysis and the TCA cycle system, but anti-inflammatory macrophages (M2) have intact functions of the TCA cycle, which enhances FAO and is dependent on OXPHOS. However, the metabolic mechanisms of macrophages in tissue repair and regeneration have not been well investigated. Thus, we review how three main metabolic mechanisms of macrophages, glucose metabolism, lipid metabolism, and amino acid metabolism, regulate tissue repair and regeneration.

Keywords:  Amino acid metabolism; Glucose metabolism; Lipid metabolism; Macrophages; Tissue repair and regeneration

DOI:  https://doi.org/10.1016/j.heliyon.2024.e38018
J Agric Food Chem. 2024 Oct 09.

Rab8a Is a Key Target That Melatonin Prevents Lipid Disorder from Atrazine.

Tian-Ning Yang, Yu-Xiang Wang, Ping-An Jian, Xiang-Yu Ma, Yi-Fei Ren, Ning-Ning Huang, Xue-Nan Li, Jin-Long Li.

  Atrazine (ATZ), a widely used herbicide, disrupts mitochondrial function and lipid metabolism in the liver. Melatonin (MLT), a naturally synthesized hormone, combats mitochondrial dysfunction and alleviates lipid toxicity. However, the mechanisms behind ATZ-induced lipid metabolism toxicity and the protective effects of MLT remain unexplored. Mice were randomly assigned to four groups: control (Con), 5 mg/kg MLT, 170 mg/kg ATZ, and a cotreatment group receiving 170 mg/kg ATZ with 5 mg/kg MLT (ATZ+MLT). Additionally, we analyzed the effects of MLT and Rab8a on mRNA and proteins related to mitochondrial function and lipid metabolism disrupted by ATZ in AML12 cells. In conclusion, ATZ induced mitochondrial stress and disrupted fatty acid metabolism in mouse hepatocytes and AML12 cells. Exogenous MLT restores Rab8a levels, regulating fatty acid utilization in mitochondria and mitochondrial function. Notably, targeting Rab8a does not significantly affect mitochondrial function but prevents ATZ-induced lipid metabolism disorders in hepatocytes.

Keywords:  Rab8a; atrazine; fatty acid; hepatocytes; melatonin

DOI:  https://doi.org/10.1021/acs.jafc.4c07006
Front Neurosci. 2024 ;18 1483708

Exploring the role of mitochondrial uncoupling protein 4 in brain metabolism: implications for Alzheimer's disease.

Simone M Crivelli, Aisylu Gaifullina, Jean-Yves Chatton.

  The brain's high demand for energy necessitates tightly regulated metabolic pathways to sustain physiological activity. Glucose, the primary energy substrate, undergoes complex metabolic transformations, with mitochondria playing a central role in ATP production via oxidative phosphorylation. Dysregulation of this metabolic interplay is implicated in Alzheimer's disease (AD), where compromised glucose metabolism, oxidative stress, and mitochondrial dysfunction contribute to disease progression. This review explores the intricate bioenergetic crosstalk between astrocytes and neurons, highlighting the function of mitochondrial uncoupling proteins (UCPs), particularly UCP4, as important regulators of brain metabolism and neuronal function. Predominantly expressed in the brain, UCP4 reduces the membrane potential in the inner mitochondrial membrane, thereby potentially decreasing the generation of reactive oxygen species. Furthermore, UCP4 mitigates mitochondrial calcium overload and sustains cellular ATP levels through a metabolic shift from mitochondrial respiration to glycolysis. Interestingly, the levels of the neuronal UCPs, UCP2, 4 and 5 are significantly reduced in AD brain tissue and a specific UCP4 variant has been associated to an increased risk of developing AD. Few studies modulating the expression of UCP4 in astrocytes or neurons have highlighted protective effects against neurodegeneration and aging, suggesting that pharmacological strategies aimed at activating UCPs, such as protonophoric uncouplers, hold promise for therapeutic interventions in AD and other neurodegenerative diseases. Despite significant advances, our understanding of UCPs in brain metabolism remains in its early stages, emphasizing the need for further research to unravel their biological functions in the brain and their therapeutic potential.

Keywords:  Alzheimer’s disease; UCP4; astrocytes; mitochondria; neurons; uncoupling agent; uncoupling protein

DOI:  https://doi.org/10.3389/fnins.2024.1483708
Ageing Res Rev. 2024 Oct 05. pii: S1568-1637(24)00340-4. [Epub ahead of print]101 102522

Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases.

Roberto Iorio, Sabrina Petricca, Giovanna Di Emidio, Stefano Falone, Carla Tatone.

  Mitochondria are metabolic and signalling hubs that integrate a plethora of interconnected processes to maintain cell homeostasis. They are also dormant mediators of inflammation and cell death, and with aging damages affecting mitochondria gradually accumulate, resulting in the manifestation of age-associated disorders. In addition to coordinate multiple intracellular functions, mitochondria mediate intercellular and inter-organ cross talk in different physiological and stress conditions. To fulfil this task, mitochondrial signalling has evolved distinct and complex conventional and unconventional routes of horizontal/vertical mitochondrial transfer. In this regard, great interest has been focused on the ability of extracellular vesicles (EVs), such as exosomes and microvesicles, to carry selected mitochondrial cargoes to target cells, in response to internal and external cues. Over the past years, the field of mitochondrial EVs (mitoEVs) has grown exponentially, revealing unexpected heterogeneity of these structures associated with an ever-expanding mitochondrial function, though the full extent of the underlying mechanisms is far from being elucidated. Therefore, emerging subsets of EVs encompass exophers, migrasomes, mitophers, mitovesicles, and mitolysosomes that can act locally or over long-distances to restore mitochondrial homeostasis and cell functionality, or to amplify disease. This review provides a comprehensive overview of our current understanding of the biology and trafficking of MitoEVs in different physiological and pathological conditions. Additionally, a specific focus on the role of mitoEVs in aging and the onset and progression of different age-related diseases is discussed.

Keywords:  Age-related diseases; Bioenergetic remodelling; Cancer; Intercellular communication; Mitochondria-specific ectocytosis; Mitochondrial derived vesicles (MDVs); Mitochondrial extracellular vesicles (mitoEVs); Mitochondrial quality control (MQC)

DOI:  https://doi.org/10.1016/j.arr.2024.102522