Department of Biomedical Sciences, University of Padova, Padova, Italy.
Department of Biochemistry and Molecular Biology, Semmelweis University, Budapest, Hungary; Oroboros Instruments, Schöpfstr. 18, 6020 Innsbruck, Austria.
Biochim Biophys Acta Mol Basis Dis. 2024 Mar;1870(3):167033. doi: 10.1016/j.bbadis.2024.167033. Epub 2024 Jan 26.
Mitochondrial disorders are hallmarked by the dysfunction of oxidative phosphorylation (OXPHOS) yet are highly heterogeneous at the clinical and genetic levels. Striking tissue-specific pathological manifestations are a poorly understood feature of these conditions, even if the disease-causing genes are ubiquitously expressed. To investigate the functional basis of this phenomenon, we analyzed several OXPHOS-related bioenergetic parameters, including oxygen consumption rates, electron transfer system (ETS)-related coenzyme Q (mtCoQ) redox state and production of reactive oxygen species (ROS) in mouse brain and liver mitochondria fueled by different substrates. In addition, we determined how these functional parameters are affected by ETS impairment in a tissue-specific manner using pathologically relevant mouse models lacking either Ndufs4 or Ttc19, leading to Complex I (CI) or Complex III (CIII) deficiency, respectively. Detailed OXPHOS analysis revealed striking differences between brain and liver mitochondria in the capacity of the different metabolic substrates to fuel the ETS, reduce the ETS-related mtCoQ, and to induce ROS production. In addition, ETS deficiency due to either CI or CIII dysfunction had a much greater impact on the intrinsic bioenergetic parameters of brain compared with liver mitochondria. These findings are discussed in terms of the still rather mysterious tissue-specific manifestations of mitochondrial disease.
线粒体疾病的特征是氧化磷酸化（OXPHOS）功能障碍，但在临床和遗传水平上具有高度异质性。这些疾病的一个特点是组织特异性的病理表现明显，但人们对此知之甚少，即使致病基因普遍表达。为了研究这种现象的功能基础，我们分析了几种与 OXPHOS 相关的生物能量学参数，包括不同底物供能时小鼠脑和肝线粒体的耗氧量、电子传递系统（ETS）相关辅酶 Q（mtCoQ）氧化还原状态和活性氧（ROS）的产生。此外，我们使用与病理相关的缺乏 Ndufs4 或 Ttc19 的小鼠模型，以组织特异性的方式确定这些功能参数如何受到 ETS 损伤的影响，分别导致复合物 I（CI）或复合物 III（CIII）缺陷。详细的 OXPHOS 分析显示，不同代谢底物为 ETS 供能、还原 ETS 相关的 mtCoQ 和诱导 ROS 产生的能力在脑和肝线粒体之间存在显著差异。此外，由于 CI 或 CIII 功能障碍导致的 ETS 缺陷对脑线粒体的内在生物能量学参数的影响比对肝线粒体的影响大得多。这些发现将从线粒体疾病的组织特异性表现仍然相当神秘的角度进行讨论。
