Juhász László, Spisák Krisztina, Szolnoki Boglárka Zsuzsa, Nászai Anna, Szabó Ágnes, Rutai Attila, Tallósy Szabolcs Péter, Szabó Andrea, Toldi József, Tanaka Masaru, Takeda Keiko, Ozaki Kinuyo, Inoue Hiromi, Yamamoto Sayo, Ono Etsuro, Boros Mihály, Kaszaki József, Vécsei László
Institute of Surgical Research, University of Szeged, Albert Szent-Györgyi Medical School, Szeged, Hungary.
Department of Neurology, University of Szeged, Albert Szent-Györgyi Medical School, Szeged, Hungary.
J Neurochem. 2025 May;169(5):e70075. doi: 10.1111/jnc.70075.
Numerous illnesses, including neurological and mental disorders, have been associated with mitochondrial dysfunction. Disruptions in mitochondrial respiration and energy production have been linked to dysmetabolism of the tryptophan (Trp)-kynurenine (KYN) pathway, which produces a diverse array of bioactive metabolites. Kynurenic acid (KYNA) is a putative neuroprotectant. The exact mechanisms through which Trp-KYN metabolic dysregulation affects mitochondrial function remain largely unclear. This study investigates the impact of the genetic deletion of kynurenine aminotransferase (KAT) enzymes, which are responsible for KYNA synthesis, on mitochondrial function, specifically mitochondrial respiration and ATP synthesis, and its potential role in neuropsychiatric pathology. CRISPR/Cas9-induced knockout mouse strains kat1, kat2, and kat3 were generated. Eight-to-ten-week-old male mice were used, and cerebral and hepatic respiration, complex I- and II-linked oxidative phosphorylation (CI and CII OXPHOS), and complex IV (CIV) activity were measured using high-resolution respirometry. Mitochondrial membrane potential changes were measured with Fluorescence-Sensor Blue and safranin dye. KAT knockout mice exhibited significantly lower cerebellar respiration (CI OXPHOS, CII OXPHOS, and CIV activity) compared to wild-type mice. Lower baseline respiration and attenuated OXPHOS activities were observed in the hippocampus and striatum, particularly in kat2 and kat3 mice. Non-neuronal tissues showed reduced CIV activity, while ADP-stimulated CI and CII OXPHOS remained unchanged. The deletion of the KAT genes significantly impairs mitochondrial respiration and ATP synthesis, potentially contributing to pathogenesis. This study highlights the importance of KYNA in mitochondrial function, offering new insights into potential therapeutic targets for various disorders. Targeting the KYN pathway could mitigate mitochondrial dysfunction in a variety of diseased conditions.
包括神经和精神障碍在内的众多疾病都与线粒体功能障碍有关。线粒体呼吸和能量产生的紊乱与色氨酸（Trp）-犬尿氨酸（KYN）途径的代谢异常有关，该途径会产生多种生物活性代谢产物。犬尿喹啉酸（KYNA）是一种假定的神经保护剂。Trp-KYN代谢失调影响线粒体功能的确切机制在很大程度上仍不清楚。本研究调查了负责KYNA合成的犬尿氨酸转氨酶（KAT）酶基因缺失对线粒体功能的影响，特别是线粒体呼吸和ATP合成，以及其在神经精神病理学中的潜在作用。生成了CRISPR/Cas9诱导的kat1、kat2和kat3基因敲除小鼠品系。使用8至10周龄的雄性小鼠，通过高分辨率呼吸测定法测量脑和肝呼吸、复合体I和II相关的氧化磷酸化（CI和CII OXPHOS）以及复合体IV（CIV）活性。用荧光传感器蓝和番红染料测量线粒体膜电位变化。与野生型小鼠相比，KAT基因敲除小鼠的小脑呼吸（CI OXPHOS、CII OXPHOS和CIV活性）显著降低。在海马体和纹状体中观察到较低的基础呼吸和减弱的OXPHOS活性，特别是在kat2和kat3小鼠中。非神经组织的CIV活性降低，而ADP刺激的CI和CII OXPHOS保持不变。KAT基因的缺失显著损害线粒体呼吸和ATP合成，可能导致发病机制。本研究强调了KYNA在线粒体功能中的重要性，为各种疾病的潜在治疗靶点提供了新的见解。针对KYN途径可能减轻多种疾病状态下的线粒体功能障碍。
