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

Abstract

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.

Keywords: Complex III (CytC1); HIF-1α; TSGA10; Warburg effect; carcinogenesis; mitochondrial coupling.

Figure 1

RNA expression level of TSGA10 in different human tissues (courtesy of the open-source The Human Atlas Protein [26]). Colors indicate tissue types, with male reproductive being light blue and neuronal being yellow.

Figure 2

TSGA10 protein association with mitochondria in NIH3T3 cells. This schematic outlines the experimental workflow to demonstrate TSGA10’s association with mitochondria, where TSGA10 interacts with CytC1. The process includes a yeast two-hybrid (Y2H) assay; TSGA10 is used as the bait protein to screen a testis cDNA library, leading to the identification of CytC1 as an interacting partner. Then, the interaction is validated in mammalian cells through co-immunoprecipitation (CO-IP) followed by Western blot (WB); CytC1 antibody is used for immunoprecipitation, and the presence of TSGA10 in the complex is confirmed using TSGA10 and GFP antibodies during WB. Finally, a immunofluorescence (IF) colocalization study isperformed to visualize the subcellular localization of TSGA10 and CytC1 in mitochondria. Together, these experiments confirm the physical interaction and mitochondrial co-localization of TSGA10 and CytC1.

Figure 3

Proposed role of TSGA10 interaction with cytochrome c1 in mitochondria. The left panel illustrates the electron transport chain (ETC) in the mitochondrial inner membrane, where Complexes I–IV facilitate electron transfer and proton pumping to generate ATP through oxidative phosphorylation.

Figure 4

TSGA10-mediated regulation of mitochondrial coupling and metabolic balance in hypoxia and normoxia. The left panel represents the hypoxic state, where TSGA10 downregulation and increased HIF-1$\alpha$ activity are observed, promoting glycolysis and heat production while increasing ROS generation. This results in mitochondrial uncoupling, reducing ATP synthesis through OXPHOS. The right panel illustrates the normoxic condition, where TSGA10 enhances mitochondrial coupling, supporting efficient ATP production via OXPHOS while minimizing ROS accumulation and HIF-1$\alpha$ activity. The balance between mitochondrial coupling (normoxia) and uncoupling (hypoxia) is depicted as a metabolic scale, highlighting the role of TSGA10 in regulating cellular energy homeostasis.

Figure 5

TSGA10’s interaction with CytC1 and its downstream consequences: On the left (blue), TSGA10 binds to CytC1 in Complex III of the mitochondrial electron transport chain, enhancing electron transfer and promoting OXPHOS. This leads to improved mitochondrial coupling, increased ATP production (↑), and reduced reactive oxygen species (ROS) levels (↓), as indicated by green checkmarks. On the right (red), loss of TSGA10 disrupts mitochondrial coupling (×), decreases ATP output (↓), and increases ROS production (↑), which triggers HIF-1$\alpha$ stabilization, DNA damage, and oncogenic signaling due to mitochondrial dysfunction and metabolic reprogramming. TSGA10.