TSGA10 as a Model of a Thermal Metabolic Regulator: Implications for Cancer Biology.

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-1α engage in mutual counter-regulation-TSGA10 represses HIF-1α to sustain oxidative phosphorylation (OXPHOS), while HIF-1α suppression 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.