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

Abstract

This study examined the effects of molecular hydrogen on proliferation across seven human cancer cell lines. Four of the seven lines (designated responders) showed enhanced proliferation upon hydrogen exposure, an effect that was independent of baseline intracellular reactive oxygen species levels. Gene expression profiling revealed that responders had elevated transcription of mitochondrial electron transport chain (ETC) components compared with non-responders. Responders also displayed greater mitochondrial mass, higher mitochondrial superoxide levels, elevated membrane potential, and increased spare respiratory capacity. In these responder lines, hydrogen activated the mitochondrial unfolded protein response (mtUPR). Furthermore, hydrogen rescued proliferation suppressed by rotenone, a complex I inhibitor, specifically in responders. The findings indicate that hydrogen-induced mtUPR promotes cancer cell proliferation in cells characterized by high basal and spare mitochondrial ETC activity, highlighting a context-dependent, potentially adverse effect of hydrogen.

Mechanism

In cancer cells with elevated mitochondrial ETC activity, hydrogen triggers the mitochondrial unfolded protein response (mtUPR), sustaining mitochondrial function and thereby promoting cell proliferation, independent of cytosolic reactive oxygen species levels.