Delineating the mechanisms and clinical utility of mtDNA mutagenesis in cancer

线粒体是真核细胞中负责能量产生的细胞内细胞器， 它们的独特之处在于它们含有自己的DNA（mtDNA），该DNA编码对线粒体功能重要的基因。 虽然已经确定核DNA在癌症中具有增加的总体突变负担， 我们最近发现，在人类肿瘤中，线粒体DNA随机突变的频率降低， 相对于健康的组织。此外，这些新的发现为拟议的研究提供了框架。 我们已经证明，肿瘤组织中线粒体DNA突变的低负荷与肿瘤组织中线粒体DNA突变的低负荷相关。 氧化磷酸化（OXPHOS）减少，进而活性氧减少 （ROS）介导的mtDNA损伤。这些新的发现为拟议的研究提供了动力，因为它们 这表明，与核DNA不同，mtDNA突变率的增加并不促进癌症的发生， 因此，在拟议的具体目标的指导下，我们希望 描述正常和肿瘤细胞中线粒体突变的潜在机制，并利用这些机制 用于临床。对于第一个目标，我们建议描绘代谢，活性氧， mtDNA诱变和凋亡引发，通过检验mtDNA诱变介导 凋亡反应其次，我们将确定mtDNA突变是否是治疗的预测因素。 因此，可以作为病理学反应（pCR）的特异性预后生物标志物， 局部晚期乳腺癌（LABC）的新辅助治疗。最后，我们要确定线粒体- 专注于直接增加OXPHOS的靶向癌症治疗将促进凋亡反应， 使癌细胞对化疗诱导的细胞凋亡敏感。圆满完成拟议的 本课题的目的是：（1）建立糖代谢与细胞凋亡的因果关系 （2）进一步了解mtDNA突变、细胞代谢和 癌症;（3）确定线粒体诱变作为治疗反应的预测生物标志物的效用， 早期复发和死亡;（4）探索一种新的化疗策略的效用， 线粒体呼吸;和（5）最终改善癌症的诊断和治疗，从而改善 患者的预后和生活质量。

Mitochondria are the intracellular organelles responsible for energy production in eukaryotic cells, and are unique in that they contain their own DNA (mtDNA), which encodes genes important for mitochondrial function. While it has been well-established that nuclear DNA has an increased overall burden of mutations in cancers, we recently discovered that the frequency of random mutations in mtDNA is decreased in human tumors relative to healthy tissues. Furthermore, these novel findings provide the framework for the proposed research. We have since demonstrated that the lower burden of mtDNA mutations in tumor tissue is coupled to a decrease in oxidative phosphorylation (OXPHOS) and, by extension, a reduction in reactive oxygen species (ROS)-mediated mtDNA damage. These novel findings provide the impetus for the proposed research, as they suggest that, unlike in nuclear DNA, an increased rate of mtDNA mutagenesis does not facilitate a cancer’s development; rather, it may hinder it. As such, under the direction of the proposed Specific Aims we expect to delineate the mechanisms underlying mitochondrial mutagenesis in normal and tumor cells, and exploit these for use in the clinic. For the first Aim, we propose to delineate the relationships and among metabolism, ROS, mtDNA mutagenesis, and apoptotic priming by testing the hypothesis that mtDNA mutagenesis mediates apoptotic response. Secondly, we will establish whether mtDNA mutagenesis is predictive of treatment response and thus can serve as a specific, prognostic biomarker of pathological response (pCR) to neoadjuvant treatment in locally advanced breast cancer (LABC). Lastly, we will determine if mitochondrial- targeted cancer therapeutics, focused on directly increasing OXPHOS, will promote apoptotic response and sensitize cancer cells to chemotherapeutically-induced apoptosis. Successful completion of the proposed project Aims will: (1) Establish a cause and effect relationship between glucose metabolism and apoptotic resistance; (2) Advance understanding of relationships between mtDNA mutagenesis, cell metabolism, and cancer; (3) Determine the utility of mitochondrial mutagenesis as a predictive biomarker of treatment response, early relapse, and death; (4) Explore the utility of a novel chemotherapeutic strategy that increases mitochondrial respiration; and (5) ultimately improve cancer prognostication and treatment, thereby improving patient outcomes and quality of life.