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SUMMARY Mitochondria undergo fission and fusion to maintain homeostasis, and tumors exhibit the dysregulation of mitochondrial dynamics. We recently demonstrated that ectopic HRas G12V promotes mitochondrial fragmentation and tumor growth through Erk phosphorylation of the mitochondrial fission GTPase Dynamin-related protein 1 (Drp1). However, the role of Drp1 in the setting of endogenous oncogenic KRas remains unknown. Here, we show that Drp1 is required for KRas-driven anchorage-independent growth in fibroblasts and patient-derived pancreatic cancer cell lines, and it promotes glycolytic flux, in part through the regulation of hexokinase 2 (HK2). Furthermore, Drp1 deletion imparts a significant survival advantage in a model of KRas-driven pancreatic cancer, and tumors exhibit a strong selective pressure against complete Drp1 deletion. Rare tumors that arise in the absence of Drp1 have restored glycolysis but exhibit defective mitochondrial metabolism. This work demonstrates that Drp1 plays dual roles in KRas-driven tumor growth: supporting both glycolysis and mitochondrial function through independent mechanisms.

The restoration of the ancient Silk Road intends to reconnect China with Africa, the Middle East, and Europe through a railway network, airports, roads, seaports, and an optical fiber system. The Belt and Road Initiative (BRI) has three components. One Belt, One Road (OBOR) is based upon two parts of the BRI; the maritime Silk Road and the Silk Road economic belt. OBOR is based upon six economic corridors. The China-Pakistan Economic Corridor (CPEC) is the smartest corridor under OBOR, which passes only through Pakistan, and after completion, will provide a safe and cheap route for China to import oil and energy. CPEC is a multidimensional project under which much infrastructure development initiative has been started to improve the infrastructure and economic development of Pakistan. Infrastructure development is an essential requirement in economic growth, one which further leads to industrialization and is helpful in economic development. The present study was conducted in Pakistan and explored how infrastructure development under the CPEC is useful for the sustainable development of Pakistan, as well as which kind of infrastructure development projects have been included in the CPEC to improve the socio-economic paradigm of Pakistan. A sample of 500 respondents was selected through a multistage sampling technique from the two-node cities. A questionnaire survey was used to collect primary data. The results of the study show that the CPEC is a catalyst for Pakistan to improve its socio-economic conditions and to achieve sustainable development. The participants of the survey agreed that CPEC will improve the socio-economic paradigm of Pakistan and will be helpful in the achievement of sustainable development goals.

Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1(-/-)) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1(-/-) mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1(-/-) mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1(-/-) mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1(-/-) mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1(-/-) mice and between male Tbc1d1(-/-) mice in different studies due to variations in body composition and nutrient handling.