Premium
Evolutionary and functional analyses demonstrate conserved ferroptosis protection by Arabidopsis GPXs in mammalian cells
Author(s) -
Song Wangyang,
Xin Shan,
He Meng,
Pfeiffer Susanne,
Cao Aiping,
Li Hongbin,
Schick Joel A.,
Jin Xiang
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000856r
Subject(s) - gpx4 , arabidopsis , biology , functional divergence , lipid peroxidation , gene , genetics , oxidative stress , selenocysteine , biochemistry , cysteine , gene family , genome , glutathione peroxidase , enzyme , mutant , catalase
Abstract Species have evolved unique mechanisms to combat the effects of oxidative stress inside cells. A particularly devastating consequence of an unhindered oxidation of membrane lipids in the presence of iron results in cell death, known as ferroptosis. Hallmarks of ferroptosis, including peroxidation of polyunsaturated fatty acids, are conserved among animals and plants, however, early divergence of an ancestral mammalian GPX4 (mGPX4) has complicated our understanding of mechanistic similarities between species. To this end, we performed a comprehensive phylogenetic analysis and identified that orthologous Arabidopsis GPXs (AtGPXs) are more highly related to mGPX4 than mGPX4 is to other mammalian GPXs. This high degree of conservation suggested that experimental substitution may be possible. We, therefore, ectopically expressed AtGPX1‐8 in ferroptosis‐sensitive mouse fibroblasts. This substitution experiment revealed highest protection against ferroptosis induction by AtGPX5, as well as moderate protection by AtGPX2, −7, and −8. Further analysis of these cells revealed substantial abatement of lipid peroxidation in response to pharmacological challenge. The results suggest that the presence of ancestral GPX4 resulted in later functional divergence and specialization of GPXs in plants. The results also challenge a strict requirement for selenocysteine activity and suggest thioredoxin as a potent parallel antioxidant system in both plants and mammals.