Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
J Neurosci Res. 2012 Mar;90(3):597-605. doi: 10.1002/jnr.22802. Epub 2011 Dec 20.
Patients affected by peroxisomal disorders commonly present neurologic dysfunction and brain abnormalities, whose neuropathology is poorly understood. Given that high sustained concentrations of pristanic acid (Prist) are found in the brain of these patients, it is conceivable that this complex branched-chain fatty acid is neurotoxic. Therefore, the present work investigated the in vitro effects of Prist at similar concentrations found in plasma of affected patients with some peroxisomal disorders on important parameters of energy homeostasis, including respiratory parameters determined by oxygen consumption, membrane potential (ΔΨm), NAD(P)H content, and swelling in mitochondrial preparations obtained from brain of young rats using glutamate plus malate or succinate as respiratory substrates. Prist markedly increased state 4 respiration and decreased state 3 respiration, the respiratory control ratio (RCR), and the ADP/O ratio with both substrates. The mitochondrial ΔΨm and the matrix NAD(P)H content were also decreased by Prist, which was also able to provoke mitochondrial swelling. Furthermore, Prist-induced mitochondrial swelling was dependent on oxidative damage to the permeability transition pore (PTP), because cyclosporine A and the thiol-reducing agent N-acetylcysteine totally prevented mitochondrial swelling. These data suggest that Prist impairs mitochondrial homeostasis, acting as an uncoupler of oxidative phosphorylation and as a metabolic inhibitor, besides causing mitochondrial swelling probably mediated by the permeability transition pore. It is proposed that these pathomechanisms may potentially be involved in the neurological abnormalities characteristic of the peroxisomal diseases in which Prist accumulates.
患有过氧化物酶体疾病的患者通常表现出神经功能障碍和大脑异常，其神经病理学尚不清楚。由于这些患者的大脑中发现了高浓度的植烷酸（Prist），可以想象这种复杂的支链脂肪酸具有神经毒性。因此，本研究在体外研究了类似于一些过氧化物酶体疾病患者血浆中发现的 Prist 浓度对能量平衡重要参数的影响，包括通过耗氧量确定的呼吸参数、膜电位（ΔΨm）、NAD（P）H 含量和谷氨酸加苹果酸或琥珀酸作为呼吸底物从年轻大鼠大脑中获得的线粒体制剂中的肿胀。Prist 明显增加了状态 4 呼吸并降低了状态 3 呼吸、呼吸控制比（RCR）和 ADP/O 比，两种底物均如此。线粒体 ΔΨm 和基质 NAD（P）H 含量也因 Prist 而降低，Prist 还能引起线粒体肿胀。此外，Prist 诱导的线粒体肿胀依赖于氧化损伤通透性转换孔（PTP），因为环孢素 A 和硫醇还原剂 N-乙酰半胱氨酸完全阻止了线粒体肿胀。这些数据表明，Prist 破坏了线粒体的动态平衡，作为氧化磷酸化的解偶联剂和代谢抑制剂，除了引起可能由通透性转换孔介导的线粒体肿胀。据推测，这些发病机制可能潜在地涉及到过氧化物酶体疾病中 Prist 积累的神经病变。
