Radical-Driven Methane Formation in Humans Evidenced by Exogenous Isotope-Labeled DMSO and Methionine

Abstract

Methane (CH4), which is produced endogenously in animals and plants, was recently suggested to play a role in cellular physiology, potentially influencing the signaling pathways and regulatory mechanisms involved in nitrosative and oxidative stress responses. In addition, it was proposed that the supplementation of CH4 to organisms may be beneficial for the treatment of several diseases, including ischemia, reperfusion injury, and inflammation. However, it is still unclear whether and how CH4 is produced in mammalian cells without the help of microorganisms, and how CH4 might be involved in physiological processes in humans. In this study, we produced the first evidence of the principle that CH4 is formed non-microbially in the human body by applying isotopically labeled methylated sulfur compounds, such as dimethyl sulfoxide (DMSO) and methionine, as carbon precursors to confirm cellular CH4 formation. A volunteer applied isotopically labeled (2H and 13C) DMSO on the skin, orally, and to blood samples. The monitoring of stable isotope values of CH4 convincingly showed the conversion of the methyl groups, as isotopically labeled CH4 was formed during all experiments. Based on these results, we considered several hypotheses about endogenously formed CH4 in humans, including physiological aspects and stress responses involving reactive oxygen species (ROS). While further and broader validation studies are needed, the results may unambiguously serve as a proof of concept for the endogenous formation of CH4 in humans via a radical-driven process. Furthermore, these results might encourage follow-up studies to decipher the potential physiological role of CH4 and its bioactivity in humans in more detail. Of particular importance is the potential to monitor CH4 as an oxidative stress biomarker if the observed large variability of CH4 in breath air is an indicator of physiological stress responses and immune reactions. Finally, the potential role of DMSO as a radical scavenger to counteract oxidative stress caused by ROS might be considered in the health sciences. DMSO has already been investigated for many years, but its potential positive role in medical use remains highly uncertain.

Cellular ROS and Antioxidants: Physiological and Pathological Role

“…ROS serve essential roles in cell signaling processes; consequently, excessive neutralization of ROS by antioxidants can disrupt these signaling processes, affecting pathways mediated by intracellular messengers, such as NO, CO, H 2 S, and the recently described CH4. In this Special Issue, Keppler et al [57] showed the capability of eukaryotic cells to synthesize CH4 via a radical-driven process. In addition, Horváth et al [58] demonstrated that although CH4 is synthesized in a radical-dependent way, it protects mitochondrial function and maintains Ca 2+ homeostasis.…”

Fungal Methane Production Controlled by Oxygen Levels and Temperature

“…A significant portion of global CH4 emissions originates from biotic sources, exceeding contributions from abiotic sources like fossil fuel and biomass burning, as well as geogenic processes [2,3] Contrary to the earlier belief that biotic CH4 production occurs exclusively under anaerobic conditions by methanogenic archaea in environments such as wetlands, landfills and rice paddies, and in the digestion system of termites and ruminants, recent research has revealed that biotic CH4 can also be produced in the presence of oxygen (O2). The first evidence of CH4 formation by plants under aerobic conditions was presented by [4], and subsequent research expanded this finding to a range of eukaryotic CH4 and prokaryotic sources, including mosses and lichens [5], marine algae [6,7], terrestrial and marine cyanobacteria [8], plant cell cultures [9,10], non-methanogenic archaea [10], animals [11,12], human cell cultures and humans [10,[13][14][15][16], as well as fungi [10,17,18].…”

Fungal Methane Production Controlled by Oxygen Levels and Temperature

“…Contrary to the earlier assumption that biotic CH 4 production occurs exclusively under anaerobic conditions by methanogenic archaea in certain environments, such as wetlands, landfills, and rice paddies, and in the digestion system of termites and ruminants, recent research has revealed that biotic CH 4 can also be produced in the presence of oxygen (O 2 ). The first evidence of aerobic CH 4 formation by plants was presented by Keppler et al [4], and subsequent research expanded this finding to a range of eukaryotic CH 4 and prokaryotic sources, including mosses and lichens [5], marine algae [6,7], terrestrial and marine cyanobacteria [8], plant cell cultures [9,10], non-methanogenic archaea [10], animals [11,12], human cell cultures, and humans [10,[13][14][15][16], as well as fungi [10,17,18].…”