Origin of breath isoprene in humans is revealed via multi-omic investigations

Abstract

Isoprene is amongst the most abundant volatile metabolites produced by plants and animals. Human exhaled isoprene is related to various pathophysiology but the origin was yet uncertain. Among 2000 individuals screened within consecutive mass-spectrometric studies, five healthy adults without breath isoprene were identified. Whole exome sequencing in these individuals revealed a shared homozygous (< 1% prevalent) IDI2 stop-gain mutation preventing conversion of isopentenyl diphosphate to dimethylallyl diphosphate (DMAPP) in cholesterol metabolism. Targeted sequencing depicted that the IDI2 variant is heterozygous in isoprene deficient blood-relatives and absent in unrelated isoprene normal adults. Wildtype IDI1 and cholesterol metabolism related serological parameters were normal in everyone. IDI2 determines isoprene production as DMAPP is the only source of isoprene and unlike plants, humans lack isoprene synthase and its homologue. Human IDI2 is only expressed in skeletal-myocyte peroxisomes and instant spikes in isoprene exhalation during muscle activity confirm the origin from muscular lipolytic cholesterol metabolism. Well-defined endogenous origin translated isoprene as a clinically interpretable breath biomarker.