Bladder cancer (BC) is a common cancer but diagnostic modalities, such as cystoscopy and urinary cytology, have limitations. Here, high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOFMS) was used to profile urine metabolites of 138 patients with BC and 121 control subjects (69 healthy people and 52 patients with hematuria due to non-malignant disease). Multivariate statistical analysis revealed that the cancer group could be clearly distinguished from the control groups on the basis of their metabolomic profiles, even when the hematuric control group was included. Patients with muscle-invasive BC could also be distinguished from patients with non-muscle-invasive BC on the basis of their metabolomic profiles. Successive analyses identified 12 differential metabolites that contributed to the distinction between the BC and control groups, and many of them turned out to be involved in glycolysis and betaoxidation. The association of these metabolites with cancer was corroborated by microarray results showing that carnitine transferase and pyruvate dehydrogenase complex expressions are significantly altered in cancer groups. In terms of clinical applicability, the differentiation model diagnosed BC with a sensitivity and specificity of 91.3% and 92.5%, respectively, and comparable results were obtained by receiver operating characteristic analysis (AUC = 0.937). Multivariate regression also suggested that the metabolic profile correlates with cancer-specific survival time. The excellent performance and simplicity of this metabolomics-based approach suggests that it has the potential to augment or even replace the current modalities for BC diagnosis.

The glycerol 3-phosphate shuttle (GPS) is composed of two different enzymes: cytosolic NAD⁺-linked glycerol 3-phosphate dehydrogenase 1 (GPD1) and mitochondrial FAD-linked glycerol 3-phosphate dehydrogenase 2 (GPD2). These two enzymes work together to act as an NADH shuttle for mitochondrial bioenergetics and function as an important bridge between glucose and lipid metabolism. Since these genes were discovered in the 1960s, their abnormal expression has been described in various metabolic diseases and tumors. Nevertheless, it took a long time until scientists could investigate the causal relationship of these enzymes in those pathophysiological conditions. To date, numerous studies have explored the involvement and mechanisms of GPD1 and GPD2 in cancer and other diseases, encompassing reports of controversial and non-conventional mechanisms. In this review, we summarize and update current knowledge regarding the functions and effects of GPS to provide an overview of how the enzymes influence disease conditions. The potential and challenges of developing therapeutic strategies targeting these enzymes are also discussed.

Although colorectal cancer (CRC) is considered one of the most preventable cancers, no non-invasive, accurate diagnostic tool to screen CRC exists. We explored the potential of urine nuclear magnetic resonance (NMR) metabolomics as a diagnostic tool for early detection of CRC, focusing on advanced adenoma and stage 0 CRC. Urine metabolomics profiles from patients with colorectal neoplasia (CRN; 36 advanced adenomas and 56 CRCs at various stages, n = 92) and healthy controls (normal, n = 156) were analyzed by NMR spectroscopy. Healthy and CRN groups were statistically discriminated using orthogonal projections to latent structure discriminant analysis (OPLS-DA). The class prediction model was validated by three-fold cross-validation. The advanced adenoma and stage 0 CRC were grouped together as pre-invasive CRN. The OPLS-DA score plot showed statistically significant discrimination between pre-invasive CRN as well as advanced CRC and healthy controls with a Q2 value of 0.746. In the prediction validation study, the sensitivity and specificity for diagnosing pre-invasive CRN were 96.2% and 95%, respectively. The grades predicted by the OPLS-DA model showed that the areas under the curve were 0.823 for taurine, 0.783 for alanine, and 0.842 for 3-aminoisobutyrate. In multiple receiver operating characteristics curve analyses, taurine, alanine, and 3-aminoisobutyrate were good discriminators for CRC patients. NMR-based urine metabolomics profiles significantly and accurately discriminate patients with pre-invasive CRN as well as advanced CRC from healthy individuals. Urine-NMR metabolomics has potential as a screening tool for accurate diagnosis of pre-invasive CRN.

Cell growth and survival depend on a delicate balance between energy production and synthesis of metabolites. Here, we provide evidence that an alternative mitochondrial complex II (CII) assembly, designated as CII_low, serves as a checkpoint for metabolite biosynthesis under bioenergetic stress, with cells suppressing their energy utilization by modulating DNA synthesis and cell cycle progression. Depletion of CII_low leads to an imbalance in energy utilization and metabolite synthesis, as evidenced by recovery of the de novo pyrimidine pathway and unlocking cell cycle arrest from the S-phase. In vitro experiments are further corroborated by analysis of paraganglioma tissues from patients with sporadic, SDHA and SDHB mutations. These findings suggest that CII_low is a core complex inside mitochondria that provides homeostatic control of cellular metabolism depending on the availability of energy.