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Review
. 2013 Oct;33(10):1493-9.
doi: 10.1038/jcbfm.2013.128. Epub 2013 Aug 7.

Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain

Peter Schönfeld  1 , Georg Reiser
Affiliations
Review

Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain

Peter Schönfeld et al. J Cereb Blood Flow Metab. 2013 Oct.

Abstract

It is puzzling that hydrogen-rich fatty acids are used only poorly as fuel in the brain. The long-standing belief that a slow passage of fatty acids across the blood-brain barrier might be the reason. However, this has been corrected by experimental results. Otherwise, accumulated nonesterified fatty acids or their activated derivatives could exert detrimental activities on mitochondria, which might trigger the mitochondrial route of apoptosis. Here, we draw attention to three particular problems: (1) ATP generation linked to β-oxidation of fatty acids demands more oxygen than glucose, thereby enhancing the risk for neurons to become hypoxic; (2) β-oxidation of fatty acids generates superoxide, which, taken together with the poor anti-oxidative defense in neurons, causes severe oxidative stress; (3) the rate of ATP generation based on adipose tissue-derived fatty acids is slower than that using blood glucose as fuel. Thus, in periods of extended continuous and rapid neuronal firing, fatty acid oxidation cannot guarantee rapid ATP generation in neurons. We conjecture that the disadvantages connected with using fatty acids as fuel have created evolutionary pressure on lowering the expression of the β-oxidation enzyme equipment in brain mitochondria to avoid extensive fatty acid oxidation and to favor glucose oxidation in brain.

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Figures

Figure 1
Figure 1
Route of nonesterified fatty acids from blood to the mitochondrial degradation in the brain. After dissociation of albumin-bound nonesterified fatty acids (NEFA) from albumin (indicated in yellow), NEFA migrate across the blood–brain-barrier (BBB). Thereafter, NEFA enter neural cells and are activated to acyl-CoA-derivatives in the cytosolic compartment. In the activated form, NEFA support either the biosynthesis of membrane lipids or the re-acylation of lysophospholipids. Alternatively, β-oxidation of acyl-CoA-derivatives in the mitochondria delivers the reducing equivalents nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) for fueling the electron transport chain, which generates the electrochemical proton gradient, the driving force for energy-dependent ATP synthesis. CO2 and H2O are formed as degradation products of the β-oxidation of acyl-CoA-derivatives.
Figure 2
Figure 2
Nonesterified fatty acids (NEFA) impair the mitochondrial physiology. Being natural protonophores, nonesterified fatty acids partly decrease the membrane potential at the inner mitochondrial membrane. This depolarization causes a collapse of the electrochemical proton gradient (Δp), thereby uncoupling the oxidative phosphorylation (oxPhos) and reducing the Ca2+ retention capacity (CRC). Binding of NEFA to electron transport chain (ETC) complexes interferes with the electron transport, thereby stimulating the generation of superoxide as by-product of the ETC. Superoxide is the source of other reactive oxygen species, such as hydrogen peroxide, hydroxyl radical, and peroxynitrite. Moreover, both depolarization and binding of NEFA to proteins of the permeability transition pore (PTP) sensitized the opening of the PTP. In the open state, PTP conducts the release of Ca2+ from the mitochondrial matrix and of proapoptotic factors (e.g., cytochrome c, AIF, Smac-Diablo). OM, outer membrane; IM, inner membrane.
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