bims-noxint 2019-04-14 papers

Issue of 2019–04–14
two papers selected by
Laia Caja Puigsubira, Uppsala University

Redox Biol. 2019 Apr 03. pii: S2213-2317(19)30177-6. [Epub ahead of print]24 101188

Adaptations to high-intensity interval training in skeletal muscle require NADPH oxidase 2.

Carlos Henríquez-Olguín, Leila Baghersad Renani, Lyne Arab-Ceschia, Steffen H Raun, Aakash Bhatia, Zhencheng Li, Jonas R Knudsen, Rikard Holmdahl, Thomas E Jensen.

OBJECTIVE: Reactive oxygen species (ROS) have been proposed as signaling molecules mediating exercise training adaptation, but the ROS source has remained unclear. This study aimed to investigate if increased NADPH oxidase (NOX)2-dependent activity during exercise is required for long-term high-intensity interval training (HIIT) in skeletal muscle using a mouse model lacking functional NOX2 complex due to absent p47phox (Ncf1) subunit expression (ncf1* mutation).
METHODS: HIIT was investigated after an acute bout of exercise and after a chronic intervention (3x/week for 6 weeks) in wild-type (WT) vs. NOX2 activity-deficient (ncf1*) mice. NOX2 activation during HIIT was measured using an electroporated genetically-encoded biosensor. Immunoblotting and single-fiber microscopy was performed to measure classical exercise-training responsive endpoints in skeletal muscle.
RESULTS: A single bout of HIIT increased NOX2 activity measured as p47-roGFP oxidation immediately after exercise but not 1 h or 4 h after exercise. After a 6-week HIIT regimen, improvements in maximal running capacity and some muscle training-markers responded less to HIIT in the ncf1* mice compared to WT, including superoxide dismutase 2, catalase, hexokinase II, pyruvate dehydrogenase and protein markers of mitochondrial oxidative phosphorylation complexes. Strikingly, HIIT-training increased mitochondrial network area and decreased fragmentation in WT mice only.
CONCLUSION: This study suggests that HIIT exercise increases NOX2 activity in skeletal muscle and shows that NOX2 activity is required for specific skeletal muscle adaptations to HIIT relating to antioxidant defense, glucose metabolism, and mitochondria.

Keywords: Exercise; High-intensity interval training; Reactive oxygen species; Redox

DOI: https://doi.org/10.1016/j.redox.2019.101188

J Biol Chem. 2019 Apr 08. pii: jbc.RA118.005953. [Epub ahead of print]

H2O2 induces nuclear transport of the receptor tyrosine kinase c-MET in breast cancer cells via a membrane-bounded retrograde trafficking mechanism.

Mei-Kuang Chen, Yi Du, Linlin Sun, Jennifer L Hsu, Yu-Han Wang, Yuan Gao, Jiaxing Huang, Mien-Chie Hung.

Reactive oxygen species (ROS) are cellular byproducts produced from metabolism and also anticancer agents, such as ionizing irradiation and chemotherapy drugs. The ROS hydrogen peroxide (H2O2) has high rates of production in cancer cells due to their rapid proliferation. ROS oxidize DNA, protein, and lipids, causing oxidative stress in cancer cells and making them vulnerable to other stresses. Therefore, cancer cell survival relies on maintaining ROS-induced stress at tolerable levels. Hepatocyte growth factor receptor (HGFR or c-MET) is a receptor tyrosine kinase overexpressed in malignant cancer types, including breast cancer. Full-length c-MET triggers a signal transduction cascade from the plasma membrane that, through downstream signaling proteins, up-regulates cell proliferation and migration. Recently, c-MET was shown to interact and phosphorylate poly(ADP-ribose) polymerase 1 (PARP1) in the nucleus and to induce PARP inhibitor resistance. However, it remains unclear how c-MET moves from the cell membrane to the nucleus. Here, we demonstrate that H2O2 induces retrograde transport of membrane-associated full-length c-MET into the nucleus of human MCF10A and MCF12A or primary breast cancer cells. We further show that knocking down either coatomer protein complex subunit gamma 1 (COPG1) or Sec61 translocon beta subunit (SEC61β) attenuates the accumulation of full-length nuclear c-MET. However, a c-MET kinase inhibitor did not block nuclear c-MET transport. Moreover, nuclear c-MET interacted with Ku proteins in breast cancer cells, suggesting a role of full-length nuclear c-MET in ROS-induced DNA damage repair. We conclude that a membrane-bound retrograde vesicle transport mechanism facilitates membrane-to-nucleus transport of c-MET in breast cancer cells.

Keywords: breast cancer; c-MET; hepatocyte growth factor receptor (HGFR); hydrogen peroxide; nuclear transport; nucleus; reactive oxygen species (ROS); receptor tyrosine kinase; vesicle trafficking

DOI: https://doi.org/10.1074/jbc.RA118.005953