Molecular Hydrogen Enhances Proliferation of Cancer Cells That Exhibit Potent Mitochondrial Unfolded Protein Response

Abstract

Molecular hydrogen ameliorates pathological states in a variety of human diseases, animal models, and cell models, but the effects of hydrogen on cancer have been rarely reported. In addition, the molecular mechanisms underlying the effects of hydrogen remain mostly unelucidated. We found that hydrogen enhances proliferation of four out of seven human cancer cell lines (the responders). The proliferation-promoting effects were not correlated with basal levels of cellular reactive oxygen species. Expression profiling of the seven cells showed that the responders have higher gene expression of mitochondrial electron transport chain (ETC) molecules than the non-responders. In addition, the responders have higher mitochondrial mass, higher mitochondrial superoxide, higher mitochondrial membrane potential, and higher mitochondrial spare respiratory capacity than the non-responders. In the responders, hydrogen provoked mitochondrial unfolded protein response (mtUPR). Suppression of cell proliferation by rotenone, an inhibitor of mitochondrial ETC complex I, was rescued by hydrogen in the responders. Hydrogen triggers mtUPR and induces cell proliferation in cancer cells that have high basal and spare mitochondrial ETC activities.

Biological Effects of Hydrogen Water on Subjects with NAFLD: A Randomized, Placebo-Controlled Trial

“…This may also be true for the discrepant changes in inflammatory markers and heat shock proteins, which H 2 may increase or decrease depending on the time of testing [ 35 , 41 , 42 ]. It was recently shown that H 2 induces the mitochondrial unfolded protein response, which can subsequently improve mitochondrial function and cellular regeneration [ 43 ]. The mitochondria and other redox-active heme prosthetic groups may be important targets for molecular hydrogen [ 44 ].…”

Alpha Hope, via Molecular Hydrogen and Pyrroloquinoline Quinone, Dose-Dependently Increases Nrf2 and PGC-1α Levels in C2C12 Myoblasts

“…One of the main ways that H 2 exerts its antioxidant effect is, as mentioned previously, via the induction of the Nrf-2/keap1 pathway and the subsequent expression of various antioxidant enzymes including induction of heme-1 oxygenase [20]. Furthermore, in addition to its ability to increase PGC-1α levels and promote mitochondrial biogenesis, H 2 also induces the mitochondrial unfolded protein response (mtUPR) and alleviates mitochondrial stress induced by rotenone, an inhibitor of the mitochondrial electron transport chain complex I [51]. The induction of mtUPR leads to the rejuvenation of compromised mitochondria [52].…”

Mitochondria as a key target of molecular hydrogen

“…То же касается и активации Nrf2каскада -на первом этапе он активируется изза прооксидантного действия водорода (связанного с на рушением работы дыхательной цепи митохондрий), а далее экспрессия генов антиоксидантной системы защиты приводит, наоборот, к нейтрализации АФК и противовоспалительным эффектам. В пользу теории митохондриального гормезиса свидетельствует также то, что H 2 стимулировал пролиферацию раковых клеток за счет индукции митохондриального ответа на несвер нутые белки [32], который как раз и является типичным активатором митохондриального гормезиса [33,34]. Интересно отметить также, что при расщеплении гемов гемоксигеназой высвобождается также молекула монооксида углерода CO, которая сама является сиг нальной и известна как активатор Nrf2 и фактор, вызы вающий адаптацию к ишемии [39].…”