Cellular Specificity and Inter-cellular Coordination in the Brain Bioenergetic System: Implications for Aging and Neurodegeneration

Abstract

As an organ with a highly heterogenous cellular composition, the brain has a bioenergetic system that is more complex than peripheral tissues. Such complexities are not only due to the diverse bioenergetic phenotypes of a variety of cell types that differentially contribute to the metabolic profile of the brain, but also originate from the bidirectional metabolic communications and coupling across cell types. While brain energy metabolism and mitochondrial function have been extensively investigated in aging and age-associated neurodegenerative disorders, the role of various cell types and their inter-cellular communications in regulating brain metabolic and synaptic functions remains elusive. In this review, we summarize recent advances in differentiating bioenergetic phenotypes of neurons, astrocytes, and microglia in the context of their functional specificity, and their metabolic shifts upon aging and pathological conditions. Moreover, the metabolic coordination between the two most abundant cell populations in brain, neurons and astrocytes, is discussed regarding how they jointly establish a dynamic and responsive system to maintain brain bioenergetic homeostasis and to combat against threats such as oxidative stress, lipid toxicity, and neuroinflammation. Elucidating the mechanisms by which brain cells with distinctive bioenergetic phenotypes individually and collectively shape the bioenergetic system of the brain will provide rationale for spatiotemporally precise interventions to sustain a metabolic equilibrium that is resilient against synaptic dysfunction in aging and neurodegeneration.

Keywords: astrocyte; brain aging; metabolic coupling; metabolic shift; microglia; mitochondria; neurodegenerative diseases; neuron.

Figure 1

Diverse metabolic phenotypes of brain cells. Neurons produce ATP primarily via mitochondrial oxidative phosphorylation (OXPHOS), but their glycolytic rate is less active than that of astrocytes due to suppressed PFK activity. Both lactate and ketone bodies can enter neurons via monocarboxylate transporter 2 (MCT2). Astrocytes are highly active in glycolysis to produce lactate but less dependent on OXPHOS due to low pyruvate dehydrogenase (PDH) activity. Lactate is generated by lactate dehydrogenase 5 (LDH5) in astrocytes and exported by MCT1 and MCT4. Astrocytes are capable to metabolize fatty acids through β-oxidation. Fatty acids transport into mitochondria is facilitated by carnitine and carnitine palmitoyltransferases (CPTs). Ketone bodies can be generated in astrocytic mitochondria via ketogenesis. Excessive astrocytic glucose can be stored as glycogen, which can be converted back to glucose. Resting microglia have high rate of OXPHOS and low production of reactive oxygen species (ROS), whereas activated microglia produce large amount of ROS and undergo a metabolic reprogramming from OXPHOS toward glycolysis and lactate production.

Figure 2

Neuron-astrocyte metabolic coordination. Astrocyte-synthesized cholesterols are packaged in APOE-associated lipoproteins and exported by ATP-binding cassette transporter A1 (ABCA1); released lipoproteins bind to neuronal LDL receptors and are internalized for neuronal use or conversion to 24-hydroxycholesterol (24-OHC) by cholesterol 24-hydroxylase (CYP46). 24-OHC produced by neurons can activate astrocytic live X receptor (LXR) to induce the expression of APOE and ABCA1. Hyperactive neurons release excessive free fatty acids (FFAs) in APOE-associated lipid particles to astrocytes where FFAs are targeted to lipid droplets for subsequent degradation by mitochondrial β-oxidation. High glycolytic rate in astrocytes produces lactate that can be transported to neurons by MCTs and used for ATP production. Neurotransmitter glutamate released by neurons is uptaken by astrocytes through glutamate transporter 1 (GLT1) and converted to glutamine for recycle to neurons and the re-generation of glutamate. Neurons can transfer damaged axonal mitochondria to astrocytes for autophagic degradation (mitophagy) whereas astrocytes can transfer healthy mitochondria to adjacent neurons as a neuroprotective and neurorecovery mechanism after stroke.