Neuroinflammation Group, Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences (FMHS), Macquarie University, 2, Technology Place, North Ryde, NSW, 2109, Australia.
Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences (FMHS), Macquarie University, North Ryde, NSW, 2109, Australia.
Neurotox Res. 2019 Apr;35(3):530-541. doi: 10.1007/s12640-019-9997-4. Epub 2019 Jan 21.
Upregulation of the kynurenine pathway (KP) of tryptophan metabolism is commonly observed in neurodegenerative disease. When activated, L-kynurenine (KYN) increases in the periphery and central nervous system where it is further metabolised to other neuroactive metabolites including 3-hydroxykynurenine (3-HK), kynurenic acid (KYNA) and quinolinic acid (QUIN). Particularly biologically relevant metabolites are 3-HK and QUIN, formed downstream of the enzyme kynurenine 3-monooxygenase (KMO) which plays a pivotal role in maintaining KP homeostasis. Indeed, excessive production of 3-HK and QUIN has been described in neurodegenerative disease including Alzheimer's disease and Huntington's disease. In this study, we characterise KMO activity in human primary neurons and identified new mechanisms by which KMO activation mediates neurotoxicity. We show that while transient activation of the KP promotes synthesis of the essential co-enzyme nicotinamide adenine dinucleotide (NAD), allowing cells to meet short-term increased energy demands, chronic KMO activation induces production of reactive oxygen species (ROS), mitochondrial damage and decreases spare-respiratory capacity (SRC). We further found that these events generate a vicious-cycle, as mitochondrial dysfunction further shunts the KP towards the KMO branch of the KP to presumably enhance QUIN production. These mechanisms may be especially relevant in neurodegenerative disease as neurons are highly sensitive to oxidative stress and mitochondrial impairment.
色氨酸代谢的犬尿氨酸途径（KP）上调在神经退行性疾病中很常见。当被激活时，L-犬尿氨酸（KYN）在周围和中枢神经系统中增加，在那里它进一步代谢为其他神经活性代谢物，包括 3-羟基犬尿氨酸（3-HK）、犬尿氨酸酸（KYNA）和喹啉酸（QUIN）。特别具有生物学相关性的代谢物是 3-HK 和 QUIN，它们是在犬尿氨酸 3-单加氧酶（KMO）酶的下游形成的，KMO 酶在维持 KP 内稳态中起着关键作用。事实上，在包括阿尔茨海默病和亨廷顿病在内的神经退行性疾病中，已经描述了 3-HK 和 QUIN 的过度产生。在这项研究中，我们在人原代神经元中表征了 KMO 的活性，并确定了 KMO 激活介导神经毒性的新机制。我们表明，虽然 KP 的短暂激活促进了必需辅酶烟酰胺腺嘌呤二核苷酸（NAD）的合成，使细胞能够满足短期增加的能量需求，但慢性 KMO 激活会诱导活性氧（ROS）的产生、线粒体损伤和减少备用呼吸能力（SRC）。我们进一步发现，这些事件产生了一个恶性循环，因为线粒体功能障碍进一步将 KP 转移到 KP 的 KMO 分支，大概是为了增强 QUIN 的产生。这些机制在神经退行性疾病中可能特别相关，因为神经元对氧化应激和线粒体损伤非常敏感。
