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Iron overload inhibits late stage autophagic flux leading to insulin resistance
Author(s) -
Jahng James Won Suk,
Alsaadi Reham Musaibeh,
Palanivel Rengasamy,
Song Erfei,
Hipolito Victoria Emily Barbosa,
Sung Hye Kyoung,
Botelho Roberto Jorge,
Russell Ryan Charles,
Sweeney Gary
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201947911
Subject(s) - autophagy , insulin resistance , flux (metallurgy) , microbiology and biotechnology , mitochondrion , biology , insulin , chemistry , endocrinology , genetics , apoptosis , organic chemistry
Iron overload, a common clinical occurrence, is implicated in the metabolic syndrome although the contributing pathophysiological mechanisms are not fully defined. We show that prolonged iron overload results in an autophagy defect associated with accumulation of dysfunctional autolysosomes and loss of free lysosomes in skeletal muscle. These autophagy defects contribute to impaired insulin‐stimulated glucose uptake and insulin signaling. Mechanistically, we show that iron overload leads to a decrease in Akt‐mediated repression of tuberous sclerosis complex ( TSC 2) and Rheb‐mediated mTORC 1 activation on autolysosomes, thereby inhibiting autophagic‐lysosome regeneration. Constitutive activation of mTORC 1 or iron withdrawal replenishes lysosomal pools via increased mTORC 1‐ UVRAG signaling, which restores insulin sensitivity. Induction of iron overload via intravenous iron‐dextran delivery in mice also results in insulin resistance accompanied by abnormal autophagosome accumulation, lysosomal loss, and decreased mTORC 1‐ UVRAG signaling in muscle. Collectively, our results show that chronic iron overload leads to a profound autophagy defect through mTORC 1‐ UVRAG inhibition and provides new mechanistic insight into metabolic syndrome‐associated insulin resistance.