||Obesity, type 2 diabetes and cancer are serious threats to human health and are increasing at an alarming rate. Dysregulation of energy homeostasis, both at the whole body and cellular level, has been implicated in the pathogenesis of those disorders. Cellular energy homeostasis is a delicate balance between ATP production and consumption. ATP production, mainly from oxidative phosphorylation in mitochondria, is responsive to nutrient availability and cellular energy demand. Therefore, nutrient sensing is critical to maintain cellular energy homeostasis. There are two wellcharacterized nutrient sensing kinases, AMPK and mTOR. We studied another nutrientresponsive kinase named PASK. Using PASKA mice, the role of PASK in cellular energy homeostasis was revealed. PASK deletion caused nearly complete protection from the deleterious effects of a high-fat diet, including obesity, insulin resistance and hepatic steatosis. This protection is likely due to the increased metabolic rate of PASKA mice, which can be recapitulated in cultured cells upon PASK knockdown. Therefore, we conclude that PASK acts as a cell-autonomous metabolic sensor to maintain cellular energy homeostasis. In addition to PASK, we studied a previously uncharacterized but highly conserved mitochondrial protein that we later named Sdh5. Using yeast as primary model system, we showed that Sdh5 is necessary and probably sufficient for insertion of the requisite FAD cofactor into the catalytic subunit of the succinate dehydrogenase (SDH) complex. SDH deficiency has been associated with several types of cancer, predominantly paraganglioma (PGL). Indeed, three out of four familial PGL genes have been mapped to SDH subunits. We discovered a point mutation in the human SDH5 gene that perfectly cosegregates with disease in a Dutch PGL2 lineage. This mutation completely abolishes hSDH5 function and, as expected, PGL2 tumors exhibit a loss of FAD insertion in succinate dehydrogenase. Our studies of PASK and SDH5 not only contribute significant conceptual advances in cellular nutrient sensing and mitochondrial metabolism, but also provides new screening biomarkers and therapeutic targets for diagnosing and treating the metabolic syndrome and cancer.