Mitochondrial dysfunction increases fatty acid β‐oxidation and translates into impaired neuroblast maturation

Audano, Matteo; Pedretti, Silvia; Crestani, Maurizio; Caruso, Donatella; Fabiani, Emma De; Mitro, Nico

doi:10.1002/1873-3468.13584

Cited by 17 publications

(16 citation statements)

References 49 publications

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“…These changes were associated with defective mitochondrial ultrastructure ( Figure S1B) and reduction of ETC complex subunits (Smestad et al, 2018a). This correlation is consistent with prior reports linking ETC dysfunction with increased fatty acid oxidation (FAO) (Chen et al, 2018;Vazquez et al, 2015) and accumulation of acyl-carnitines (Audano et al, 2019), and may be related to the known physical association of FAO enzymes with ETC complexes (Wang et al, 2010;Wang et al, 2019b).…”

Section: Tca Cycle Disruption Causes a Protein Pan-hyperacylation Phesupporting

confidence: 89%

Protein hyperacylation links mitochondrial dysfunction with nuclear organization

Smestad

McCauley

Amato³

et al. 2020

Preprint

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Cellular metabolism is linked to epigenetics, but the biophysical effects of metabolism on chromatin structure and implications for gene regulation remain largely unknown. Here, using a broken tricarboxylic acid (TCA) cycle and disrupted electron transport chain (ETC) exemplified by succinate dehydrogenase subunit C (SDHC) deficiency, we investigated the effects of metabolism on chromatin architecture over multiple distance scales [nucleosomes (~10^2 bp), topologically-associated domains (TADs; ~10^5 - 10^6 bp), and chromatin compartments (10^6 - 10^8 bp)]. Metabolically-driven hyperacylation of histones led to weakened nucleosome positioning in multiple types of chromatin, and we further demonstrate that lysine acylation directly destabilizes histone octamer-DNA interactions. Hyperacylation of cohesin subunits correlated with decreased mobility on interphase chromatin and increased TAD boundary strength, suggesting that cohesin is metabolically regulated. Erosion of chromatin compartment distinctions reveals metabolic regulation of chromatin liquid-liquid phase separation. The TCA cycle and ETC thus modulate chromatin structure over multiple distance scales.

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Section: Tca Cycle Disruption Causes a Protein Pan-hyperacylation Phesupporting

confidence: 89%

Protein hyperacylation links mitochondrial dysfunction with nuclear organization

Smestad

McCauley

Amato³

et al. 2020

Preprint

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“…Mitochondrial ROS production is directly dependent on mitochondrial function and an increase of this parameter has been linked to the OA pathogenesis [46]. Furthermore, it has also been suggested that mitochondrial dysfunction induces FA oxidation and oxidative stress [47][48][49]. Thus, this study may confirm the role of mitochondrial dysfunction in OA as seen by the results from OA cybrids with preference of FAs for oxidation and increased ROS production.…”

Section: Discussionsupporting

confidence: 76%

Impaired Metabolic Flexibility in the Osteoarthritis Process: A Study on Transmitochondrial Cybrids

Dalmao-Fernandez

Lund

Hermida‐Gómez

et al. 2020

Cells

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Osteoarthritis (OA) is the most frequent joint disease; however, the etiopathogenesis is still unclear. Chondrocytes rely primarily on glycolysis to meet cellular energy demand, but studies implicate impaired mitochondrial function in OA pathogenesis. The relationship between mitochondrial dysfunction and OA has been established. The aim of the study was to examine the differences in glucose and Fatty Acids (FA) metabolism, especially with regards to metabolic flexibility, in cybrids from healthy (N) or OA donors. Glucose and FA metabolism were studied using D-[14C(U)]glucose and [1-14C]oleic acid, respectively. There were no differences in glucose metabolism among the cybrids. Osteoarthritis cybrids had lower acid-soluble metabolites, reflecting incomplete FA β-oxidation but higher incorporation of oleic acid into triacylglycerol. Co-incubation with glucose and oleic acid showed that N but not OA cybrids increased their glucose metabolism. When treating with the mitochondrial inhibitor etomoxir, N cybrids still maintained higher glucose oxidation. Furthermore, OA cybrids had higher oxidative stress response. Combined, this indicated that N cybrids had higher metabolic flexibility than OA cybrids. Healthy donors maintained the glycolytic phenotype, whereas OA donors showed a preference towards oleic acid metabolism. Interestingly, the results indicated that cybrids from OA patients had mitochondrial impairments and reduced metabolic flexibility compared to N cybrids.

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“…Given the close relationship between physiological and/or pharmacological external cues and the impact on the systemic metabolic profile, this experimental approach has been extensively used in nutrition, 72,73 agricultural, 74,75 dairy, 76,77 toxicology, 78,79 preclinical, and clinical studies. In life sciences, targeted metabolomics has been mainly employed for the characterization of known metabolites and pathways (i.e., amino acids, glycolysis, Krebs cycle, and pentose phosphate pathway) in in vitro, ex vivo, and in vivo experimental settings 6,80–90 . On the other hand, untargeted metabolomics is mainly used for the identification of biomarkers in biomedical research, for instance, in pathophysiology (i.e., cancer, 91 neurodegenerative diseases, 92,93 and metabolic disorders 94 ) or epidemiology studies 95,96 .…”

Section: Main Applications Of Steady‐state Metabolomicsmentioning

confidence: 99%

Investigating metabolism by mass spectrometry: From steady state to dynamic view

et al. 2020

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Metabolism is the set of life‐sustaining reactions in organisms. These biochemical reactions are organized in metabolic pathways, in which one metabolite is converted through a series of steps catalyzed by enzymes in another chemical compound. Metabolic reactions are categorized as catabolic, the breaking down of metabolites to produce energy, and/or anabolic, the synthesis of compounds that consume energy. The balance between catabolism of the preferential fuel substrate and anabolism defines the overall metabolism of a cell or tissue. Metabolomics is a powerful tool to gain new insights contributing to the identification of complex molecular mechanisms in the field of biomedical research, both basic and translational. The enormous potential of this kind of analyses consists of two key aspects: (i) the possibility of performing so‐called targeted and untargeted experiments through which it is feasible to verify or formulate a hypothesis, respectively, and (ii) the opportunity to run either steady‐state analyses to have snapshots of the metabolome at a given time under different experimental conditions or dynamic analyses through the use of labeled tracers. In this review, we will highlight the most important practical (e.g., different sample extraction approaches) and conceptual steps to consider for metabolomic analysis, describing also the main application contexts in which it is used. In addition, we will provide some insights into the most innovative approaches and progress in the field of data analysis and processing, highlighting how this part is essential for the proper extrapolation and interpretation of data.

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Mitochondrial dysfunction increases fatty acid β‐oxidation and translates into impaired neuroblast maturation

Cited by 17 publications

References 49 publications

Protein hyperacylation links mitochondrial dysfunction with nuclear organization

Protein hyperacylation links mitochondrial dysfunction with nuclear organization

Impaired Metabolic Flexibility in the Osteoarthritis Process: A Study on Transmitochondrial Cybrids

Investigating metabolism by mass spectrometry: From steady state to dynamic view

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