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Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.

ABSTRACT: Having direct access to brain vasculature, astrocytes can take up available blood nutrients and metabolize them to fulfil their own energy needs and deliver metabolic intermediates to local synapses^1,2. These glial cells should be, therefore, metabolically adaptable to swap different substrates. However, in vitro and in vivo studies consistently show that astrocytes are primarily glycolytic^3-7, suggesting glucose is their main metabolic precursor. Notably, transcriptomic data^8,9 and in vitro¹⁰ studies reveal that mouse astrocytes are capable of mitochondrially oxidizing fatty acids and that they can detoxify excess neuronal-derived fatty acids in disease models^11,12. Still, the factual metabolic advantage of fatty acid use by astrocytes and its physiological impact on higher-order cerebral functions remain unknown. Here, we show that knockout of carnitine-palmitoyl transferase-1A (CPT1A)-a key enzyme of mitochondrial fatty acid oxidation-in adult mouse astrocytes causes cognitive impairment. Mechanistically, decreased fatty acid oxidation rewired astrocytic pyruvate metabolism to facilitate electron flux through a super-assembled mitochondrial respiratory chain, resulting in attenuation of reactive oxygen species formation. Thus, astrocytes naturally metabolize fatty acids to preserve the mitochondrial respiratory chain in an energetically inefficient disassembled conformation that secures signalling reactive oxygen species and sustains cognitive performance.

SUBMITTER: Morant-Ferrando B

PROVIDER: S-EPMC10447235 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.

Morant-Ferrando Brenda B Jimenez-Blasco Daniel D Alonso-Batan Paula P Agulla Jesús J Lapresa Rebeca R Garcia-Rodriguez Dario D Yunta-Sanchez Sara S Lopez-Fabuel Irene I Fernandez Emilio E Carmeliet Peter P Almeida Angeles A Garcia-Macia Marina M Bolaños Juan P JP

Nature metabolism 20230717 8

Having direct access to brain vasculature, astrocytes can take up available blood nutrients and metabolize them to fulfil their own energy needs and deliver metabolic intermediates to local synapses<sup>1,2</sup>. These glial cells should be, therefore, metabolically adaptable to swap different substrates. However, in vitro and in vivo studies consistently show that astrocytes are primarily glycolytic<sup>3-7</sup>, suggesting glucose is their main metabolic precursor. Notably, transcriptomic da ...[more]

PMID: 37460843

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Project description:BackgroundThe oxidation of fatty acids in mitochondria plays an important role in energy metabolism and genetic disorders of this pathway may cause metabolic diseases. Enzyme deficiencies can block the metabolism at defined reactions in the mitochondrion and lead to accumulation of specific substrates causing severe clinical manifestations. Ten of the disorders directly affecting mitochondrial fatty acid oxidation have been well-defined, implicating episodic hypoketotic hypoglycemia provoked by catabolic stress, multiple organ failure, muscle weakness, or hypertrophic cardiomyopathy. Additionally, syndromes of severe maternal illness (HELLP syndrome and AFLP) have been associated with pregnancies carrying a fetus affected by fatty acid oxidation deficiencies. However, little is known about fatty acids kinetics, especially during fasting or exercise when the demand for fatty acid oxidation is increased (catabolic stress).ResultsA computational kinetic network of 64 reactions with 91 compounds and 301 parameters was constructed to study dynamic properties of mitochondrial fatty acid beta-oxidation. Various deficiencies of acyl-CoA dehydrogenase were simulated and verified with measured concentrations of indicative metabolites of screened newborns in Middle Europe and South Australia. The simulated accumulation of specific acyl-CoAs according to the investigated enzyme deficiencies are in agreement with experimental data and findings in literature. Investigation of the dynamic properties of the fatty acid beta-oxidation reveals that the formation of acetyl-CoA - substrate for energy production - is highly impaired within the first hours of fasting corresponding to the rapid progress to coma within 1-2 hours. LCAD deficiency exhibits the highest accumulation of fatty acids along with marked increase of these substrates during catabolic stress and the lowest production rate of acetyl-CoA. These findings might confirm gestational loss to be the explanation that no human cases of LCAD deficiency have been described.ConclusionIn summary, this work provides a detailed kinetic model of mitochondrial metabolism with specific focus on fatty acid beta-oxidation to simulate and predict the dynamic response of that metabolic network in the context of human disease. Our findings offer insight into the disease process (e.g. rapid progress to coma) and might confirm new explanations (no human cases of LCAD deficiency), which can hardly be obtained from experimental data alone.

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Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.

Publications

Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.

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