Targeting mitochondrial oxidative phosphorylation (OXPHOS) to treat cancer has been hampered due to serious side-effects potentially arising from the inability to discriminate between non-cancerous and cancerous mitochondria. Herein, comprehensive mitochondrial phenotyping was leveraged to define both the composition and function of OXPHOS across various murine cancers and compared to both matched normal tissues and other organs. When compared to both matched normal tissues, as well as high OXPHOS reliant organs like heart, intrinsic expression of the OXPHOS complexes, as well as OXPHOS flux were discovered to be consistently lower across distinct cancer types. Assuming intrinsic OXPHOS expression/function predicts OXPHOS reliance in vivo, these data suggest that pharmacologic blockade of mitochondrial OXPHOS likely compromises bioenergetic homeostasis in healthy oxidative organs prior to impacting tumor mitochondrial flux in a clinically meaningful way. Although these data caution against the use of indiscriminate mitochondrial inhibitors for cancer treatment, considerable heterogeneity was observed across cancer types with respect to both mitochondrial proteome composition and substrate-specific flux, highlighting the possibility for targeting discrete mitochondrial proteins or pathways unique to a given cancer type.

由于无法区分非癌性线粒体和癌性线粒体，可能会产生严重的副作用，因此靶向线粒体氧化磷酸化（OXPHOS）来治疗癌症一直受到阻碍。在此，利用全面的线粒体表型分析来定义各种小鼠癌症中 OXPHOS 的组成和功能，并与匹配的正常组织和其他器官进行比较。与匹配的正常组织以及高度依赖 OXPHOS 的器官（如心脏）相比，发现 OXPHOS 复合物的内在表达以及 OXPHOS 通量在不同的癌症类型中始终较低。假设内在的 OXPHOS 表达/功能预测体内 OXPHOS 的依赖性，这些数据表明，在以有临床意义的方式影响肿瘤线粒体通量之前，对线粒体 OXPHOS 的药理学阻断可能会损害健康氧化器官的生物能稳态。尽管这些数据警告不要不加选择地使用线粒体抑制剂来治疗癌症，但在线粒体蛋白质组组成和底物特异性通量方面，不同癌症类型之间观察到相当大的异质性，这凸显了针对特定癌症特有的离散线粒体蛋白或途径的可能性类型。