Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Br J Cancer. 2024 Nov;131(9):1415-1424. doi: 10.1038/s41416-024-02817-1. Epub 2024 Aug 14.
"Reprogramming of energy metabolism" was first considered an emerging hallmark of cancer in 2011 by Hanahan & Weinberg and is now considered a core hallmark of cancer. Mitochondria are the hubs of metabolism, crucial for energetic functions and cellular homeostasis. The mitochondrion's bacterial origin and preservation of their own genome, which encodes proteins and RNAs essential to their function, make them unique organelles. Successful generation of mitochondrial gene products requires coordinated functioning of the mitochondrial 'central dogma,' encompassing all steps necessary for mtDNA to yield mitochondrial proteins. Each of these processes has several levels of regulation, including mtDNA accessibility and protection through mtDNA packaging and epigenetic modifications, mtDNA copy number through mitochondrial replication, mitochondrial transcription through mitochondrial transcription factors, and mitochondrial translation through mitoribosome formation. Deregulation of these mitochondrial processes in the context of cancers has only recently been appreciated, with most studies being correlative in nature. Nonetheless, numerous significant associations of the mitochondrial central dogma with pro-tumor phenotypes have been documented. Several studies have even provided mechanistic insights and further demonstrated successful pharmacologic targeting strategies. Based on the emergent importance of mitochondria for cancer biology and therapeutics, it is becoming increasingly important that we gain an understanding of the underpinning mechanisms so they can be successfully therapeutically targeted. It is expected that this mechanistic understanding will result in mitochondria-targeting approaches that balance anticancer potency with normal cell toxicity. This review will focus on current evidence for the dysregulation of mitochondrial gene expression in cancers, as well as therapeutic opportunities on the horizon.
“能量代谢重编程”于 2011 年首次被 Hanahan 和 Weinberg 认为是癌症的一个新兴标志，现在被认为是癌症的核心标志之一。线粒体是代谢的中心，对能量功能和细胞稳态至关重要。线粒体的细菌起源及其自身基因组的保留，这些基因组编码对其功能至关重要的蛋白质和 RNA，使它们成为独特的细胞器。线粒体基因产物的成功生成需要线粒体“中心法则”的协调运作，该法则涵盖了 mtDNA 产生线粒体蛋白所需的所有步骤。这些过程中的每一个都有几个调节水平，包括 mtDNA 可及性和通过 mtDNA 包装和表观遗传修饰的保护、通过线粒体复制的 mtDNA 拷贝数、通过线粒体转录因子的线粒体转录以及通过 mitoribosome 形成的线粒体翻译。最近才意识到癌症背景下这些线粒体过程的失调，大多数研究本质上都是相关性的。尽管如此，已经有许多关于线粒体中心法则与促肿瘤表型的重要关联的记录。一些研究甚至提供了机制见解，并进一步证明了成功的药物靶向策略。鉴于线粒体对癌症生物学和治疗的重要性不断增加，我们越来越需要了解潜在的机制，以便能够成功地对其进行治疗性靶向。预计这种对机制的理解将产生针对线粒体的方法，使抗癌效力与正常细胞毒性达到平衡。这篇综述将重点介绍癌症中线粒体基因表达失调的现有证据，以及即将出现的治疗机会。
