Brain energy metabolism-neurotoxicity, neuroprotection

• Autorzy: Reiser G.
• Języki publikacji: EN

Abstrakty

EN

Paradigms of cerebral metabolism claim that mitochondrial β-oxidation of activated fatty acids(FA) has only minor importance for brain energy homeostasis. In contrast to other organs with high energy demand, longchain FA (LCFA) play minor roles as hydrogen source in brain. There are clear disadvantages of the use of free fatty acids as brain fuel. These shortcomings could have exerted evolutionary pressure to lower expression in brain of β-oxidation enzymes in brain mitochondria to favor glucose oxidation. Otherwise, accumulated fatty acids exert detrimental activities on mitochondria, to trigger mitochondrial route of apoptosis. Pathological tissue accumulation of LCFA impairs mitochondrial physiology, ATP regeneration, and sensitizes mitochondria for permeability transition and stimulates oxidative stress. In contrast to LCFA, mitochondria do not degrade branched-chain phytanic acid (PA) and very long chain fatty acids (VLCFA). Elevated serum levels are biochemical hallmarks of inherited neurodegenerative diseases, (i) of PAfor the adult form of the Refsum disease and, (ii) of VLCFA for X-linked adrenoleukodystrophy (X-ALD). The severe neurodegenerative disorder X-ALD results from defective ABCD1 transporter protein. Clinical symptoms are manifested in neural tissues and adrenal gland. VLCFA increase the vulnerability of Abcd1−/− astrocytes more than that of astrocytes from wild-type mice. In VLCFA-exposed Abcd1−/− astrocytes, the reduction of a tetrazolium electron acceptor was severely diminished. Exposure of isolated mitochondria to PA impairs the inner membrane integrity and energy-dependent functions, electron transport in the respiratory chain and cellular physiology of hippocampal astrocytes. Activation of an intracellular Ca2+ signaling pathway by PA and pristanic acid suggests that a membrane receptor coupled to intracellular Ca2+ release might be involved. We propose that inhibition of β-oxidation does not seem to be a promising therapeutically helpful strategy to lower cerebral oxidative stress, as shown by ROS measurements in brain mitochondria or in-situ in astrocytes. They contradict proposals to cure consequences of oxidative stress in cerebral tissue by β-oxidation inhibition. For fatty acids physiology, we also consider the 3 PPAR isoforms (α, β/δ and γ), which represent a tightly interconnected array of ligand-activated transcription factors, for which we coined the term PPAR triad.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2015
• Tom: 75
• Numer: Supl.
• Opis fizyczny: p.S13

Twórcy

autor

Reiser G.

• Institute of Inflammation and Neurodegeneration, Faculty of Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany