GSEA of mouse and human mitochondriomes reveals fatty acid oxidation in astrocytes

Abstract

The prevalent view in neuroenergetics is that glucose is the main brain fuel, with neurons being mostly oxidative and astrocytes glycolytic. Evidence supporting that astrocyte mitochondria are functional has been overlooked. Here we sought to determine what is unique about astrocyte mitochondria by performing unbiased statistical comparisons of the mitochondriome in astrocytes and neurons. Using MitoCarta, a compendium of mitochondrial proteins, together with transcriptomes of mouse neurons and astrocytes, we generated cell-specific databases of nuclear genes encoding for mitochondrion proteins, ranked according to relative expression. Standard and in-house Gene Set Enrichment Analyses (GSEA) of five mouse transcriptomes revealed that genes encoding for enzymes involved in fatty acid oxidation (FAO) and amino acid catabolism are consistently more expressed in astrocytes than in neurons. FAO and oxidative-metabolism-related genes are also up-regulated in human cortical astrocytes versus the whole cortex, and in adult astrocytes versus fetal astrocytes. We thus present the first evidence of FAO in human astrocytes. Further, as shown in vitro, FAO coexists with glycolysis in astrocytes and is inhibited by glutamate. Altogether, these analyses provide arguments against the glucose-centered view of energy metabolism in astrocytes and reveal mitochondria as specialized organelles in these cells.

Astrocyte support is important for the compensatory potential of the nigrostriatal system neurons during early neurodegeneration

“…Importantly, b‐HB is also synthesized in astrocytes, which are capable of oxidizing fatty acids in the brain (Eraso‐Pichot et al . ). In our study, degeneration of portion of astrocytes induced an increase in the b‐HB levels both in the SN and STR.…”

“…In contrast to neurons, astrocytes are enriched in transcriptomes of genes encoding for enzymes involved in fatty acid oxidation and able to utilize it for bioenergetics requirements (Eraso‐Pichot et al . ). The CPT1 family of enzymes contains astrocytic CPT1a form localized in mitochondrial membrane and neuron specific CPT1c homologue in endoplasmic reticulum.…”

“…) and are enriched in transcriptomes of genes encoding for enzymes involved in fatty acid oxidation (Eraso‐Pichot et al . ). Parkinson's disease (PD) is a slowly progressing neurodegenerative disorder that affects mostly the dopaminergic neurons in the substantia nigra (SN).…”

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

“…In the brain, FAO occurs primarily in astrocytes (Edmond et al, 1987;Auestad et al, 1991;Schonfeld and Reiser, 2013;Eraso-Pichot et al, 2018). Two recent studies comparing mitochondrial transcriptomes and proteomes between different neural cell types corroborated the increased concentration of enzymes involved in FA metabolism and transport in astrocytes compared to neurons.…”

Immunometabolic Changes in Glia – A Potential Role in the Pathophysiology of Obesity and Diabetes

“…While other areas of the brain can also produce ketones, this appears to be enriched in the hypothalamus ( Le Foll et al, 2014 ). In the brain, ketogenesis occurs predominantly in astrocytes which are also the principle oxidisers of fatty acids ( Edmond et al, 1987 , Bouyakdan et al, 2015 , Eraso-Pichot et al, 2018 , Sonnay et al, 2019 ). Both increased dietary fatty acid intake and decreased glucose availability/AMP-activated protein kinase activation can increase astrocytic ketogenesis ( Edmond et al, 1987 , Blazquez et al, 1999 , Le Foll et al, 2014 ).…”