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.

线粒体疾病的特点是氧化磷酸化(OXPHOS)功能障碍，但在临床和遗传水平上具有高度异质性。尽管致病基因普遍表达，但人们对这些疾病的显着组织特异性病理表现仍知之甚少。为了研究这种现象的功能基础，我们分析了几种与 OXPHOS 相关的生物能参数，包括耗氧率、电子转移系统 (ETS) 相关的辅酶 Q (mtCoQ) 氧化还原态和小鼠大脑中活性氧 (ROS)和由不同底物提供燃料的肝线粒体。此外，我们使用缺乏Ndufs4或Ttc19的病理相关小鼠模型，确定了这些功能参数如何以组织特异性方式受到 ETS 损伤的影响，从而分别导致复合物 I (CI) 或复合物 III (CIII) 缺陷。详细的 OXPHOS 分析揭示了大脑和肝脏线粒体在不同代谢底物为 ETS 提供燃料、减少 ETS 相关 mtCoQ 以及诱导 ROS 产生的能力方面存在显着差异。此外，与肝线粒体相比，CI 或 CIII 功能障碍导致的 ETS 缺乏对大脑内在生物能参数的影响更大。这些发现是根据线粒体疾病仍然相当神秘的组织特异性表现进行讨论的。