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The Endoplasmic Reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation stimulate mitochondrial bioenergetics and formation of respiratory supercomplexes (SCs) through the eukaryotic translation initiation factor 2-alpha kinase 3 (PERK). Genetic ablation or pharmacological inhibition of PERK suppresses nutrient and ER stress mediated increases in SC levels and reduces oxidative phosphorylation-dependent ATP production. Conversely, PERK activation augmented respiratory SCs. PERK-eIF2α-ATF4 axis increases the SC assembly factor 1 (SCAF1 or COX7A2L) promoting SCs and enhanced mitochondrial respiration. Remarkably, PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. These studies have identified an energetic communication between the ER and mitochondria with implications in cell survival and diseases associated with mitochondrial failures.

Phosphoenolpyruvate carboxykinase (PEPCK) is well known for its role in gluconeogenesis. However, PEPCK is also a key regulator of TCA cycle flux. The TCA cycle integrates glucose, amino acid and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. We show here an unexpected role for PEPCK in promoting cancer cell proliferation in vitro and in vivo by increasing glucose and glutamine utilization toward anabolic metabolism. Unexpectedly, PEPCK also increased the synthesis of ribose from non-carbohydrate sources, such as glutamine, a phenomenon not previously described. Finally, we show that the effects of PEPCK on glucose metabolism and cell proliferation are in part mediated via activation of mTORC1. Taken together, these data demonstrate a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation.