Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Nat Cancer. 2020 Oct;1(10):976-989. doi: 10.1038/s43018-020-00112-5. Epub 2020 Sep 21.
Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.
氧化磷酸化（OXPHOS）缺陷是由体细胞线粒体 DNA（mtDNA）突变引起的，随着年龄的增长在人类结直肠上皮中逐渐增加，并且在结直肠肿瘤中很常见，但它们是否会积极促进肿瘤发生仍不清楚。在这里，我们证明了导致 OXPHOS 缺陷的 mtDNA 突变在人类腺瘤/癌序列中富集，这表明它们可能赋予代谢优势。为了验证这一点，我们在小鼠的 OXPHOS 缺陷性肠干细胞中删除了肿瘤抑制因子 Apc。由于细胞增殖加速和细胞凋亡减少，导致产生的肿瘤比对照小鼠更大。我们表明，正常隐窝和肿瘤都会通过上调丝氨酸合成途径（SSP）来响应 OXPHOS 缺陷进行代谢重排。此外，正常的人结肠隐窝在发生肿瘤之前会响应 OXPHOS 缺陷而上调 SSP。我们的数据表明，与年龄相关的 OXPHOS 缺陷会导致代谢重排，从而可以为加速肠道癌症发展提供功能贡献。
