TSGA10, a multifunctional protein critical for mitochondrial coupling and metabolic regulation, plays a paradoxical role in cancer progression and carcinogenesis. Here, we outline a potential mechanism by which TSGA10 mediates metabolism in oncogenesis and thermal modulation. Initially identified in spermatogenesis, TSGA10 interacts with mitochondrial Complex III: it directly binds cytochrome c1 (CytC1). In our model, TSGA10 optimizes electron transport to minimize reactive oxygen species (ROS) and heat production while enhancing Adenosine Triphosphate (ATP) synthesis. In cancer, TSGA10’s expression is context-dependent: Its downregulation in tumors like glioblastoma might disrupt mitochondrial coupling, promoting electron leakage, ROS accumulation, and genomic instability. This dysfunction would be predicted to contribute to a glycolytic shift, facilitating tumor survival under hypoxia. Conversely, TSGA10 overexpression in certain cancers suppresses HIF-1α, inhibiting glycolysis and metastasis. TSGA10 and HIF-1αengage in mutual counter-regulation—TSGA10 represses HIF-1αto sustain oxidative phosphorylation (OXPHOS), while HIF-1αsuppression of TSGA10 under hypoxia or thermal stress amplifies glycolytic dependency. This interplay is pivotal in tumors adapting to microenvironmental stressors, such as cold-induced mitochondrial uncoupling, which mimics brown adipose tissue thermogenesis to reduce ROS and sustain proliferation. Tissue-specific TSGA10 expression further modulates cancer susceptibility: high levels in the testes and brain may protect against thermal and oxidative damage, whereas low expression in the liver permits HIF-1α-driven metabolic plasticity. Altogether, our model suggests that TSGA10 plays a central role in mitochondrial fidelity. We suggest that its crosstalk with oncogenic pathways position it as a metabolic rheostat, whose dysregulation fosters tumorigenesis through ROS-mediated mutagenesis, metabolic reprogramming, and microenvironmental remodeling. Targeting the hypothesized TSGA10-mediated mitochondrial coupling may offer therapeutic potential to disrupt cancer’s adaptive energetics and restore metabolic homeostasis.
TSGA10是一种对线粒体偶联和代谢调控至关重要的多功能蛋白，在癌症进展和癌变过程中扮演着矛盾的角色。本文阐述TSGA10在肿瘤发生和温度调控中调节代谢的潜在机制。最初在精子发生过程中被发现的TSGA10可与线粒体复合体III相互作用：直接结合细胞色素c1（CytC1）。在我们的模型中，TSGA10通过优化电子传递以减少活性氧（ROS）和热量产生，同时增强三磷酸腺苷（ATP）合成。在癌症中，TSGA10的表达具有环境依赖性：其在胶质母细胞瘤等肿瘤中的下调可能破坏线粒体偶联，促进电子泄漏、ROS积累和基因组不稳定性。这种功能障碍预计会促进糖酵解转换，帮助肿瘤在缺氧条件下存活。相反，在某些癌症中TSGA10的过表达会抑制HIF-1α，从而抑制糖酵解和转移。TSGA10与HIF-1α形成相互拮抗调控关系——TSGA10通过抑制HIF-1α来维持氧化磷酸化（OXPHOS），而在缺氧或热应激条件下HIF-1α对TSGA10的抑制则会增强糖酵解依赖性。这种相互作用对于肿瘤适应微环境压力（如冷诱导的线粒体解偶联）至关重要，该过程模拟棕色脂肪组织产热以减少ROS并维持增殖。组织特异性TSGA10表达进一步调节癌症易感性：睾丸和大脑中的高水平表达可能提供对热和氧化损伤的保护，而肝脏中的低表达则允许HIF-1α驱动的代谢可塑性。总之，我们的模型表明TSGA10在线粒体保真性中发挥核心作用。我们认为其与致癌通路的交互作用使其成为代谢调节器，其失调通过ROS介导的突变发生、代谢重编程和微环境重塑促进肿瘤发生。靶向假设的TSGA10介导线粒体偶联机制，可能为破坏癌症适应性能量代谢和恢复代谢稳态提供治疗潜力。
TSGA10 as a Model of a Thermal Metabolic Regulator: Implications for Cancer Biology
肿瘤(癌症)患者之家