{Reference Type}: Journal Article
{Title}: Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
{Author}: Mao C;Lei G;Horbath A;Wang M;Lu Z;Yan Y;Liu X;Kondiparthi L;Chen X;Cheng J;Li Q;Xu Z;Zhuang L;Fang B;Marszalek JR;Poyurovsky MV;Olszewski K;Gan B;
{Journal}: Mol Cell
{Volume}: 84
{Issue}: 10
{Year}: 2024 May 16
{Factor}: 19.328
{DOI}: 10.1016/j.molcel.2024.04.009
{Abstract}: The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.