Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7

Abstract

Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.

Lethal COVID-19 Associates With RAAS-Induced Inflammation For Multiple Organ Damage Including Mediastinal Lymph Nodes

“…EFI2AK4/GCN2 or EFI2AK1/HRI , which sense mitochondrial dysfunction, were upregulated in the human tissues ( Fig S9B) . PGC-1α , which regulates mitochondrial biogenesis and quality control 88 , and GPX4 , AIFM2 , PARL , and STARD7 , which detoxify lipid-peroxidation and inhibit ferroptosis 89,90 , were strongly downregulated in the human heart and kidney. Their downregulation would elevate mROS and the innate immune response in these tissues ( Fig.…”

Ferroptosis: Potential opportunities for natural products in cancer therapy

“…CoQ is a key antioxidant that protects cells from lipid peroxidation and ferroptosis, and is reduced to ubiquinol (CoQH 2 ) by FSP1 to exert its effect (Bersuker et al, 2019). Recent findings have confirmed that the StAR-related lipid transfer domain containing 7 (STARD7) is cleaved into two parts by presenilin-associated rhomboid-like (PARL) when entering the mitochondria (Deshwal et al, 2023). One part remained in the mitochondria to maintain the essential functions of this organelle, whereas the other part reduced the sensitivity of cancer cells to ferroptosis by transferring CoQ from the mitochondria to the cell membrane.…”

Exogenous and Endogenous Dual-Activated Nanoladder for Precise Imaging of Mitochondrial Ferroptosis-Related Inhibition miRNA with Tumor Cell Specificity

“…3 Therefore, highly sensitive and precise imaging of specific mitochondrial miRNA in tumor cells that can inhibit ferroptosis could afford patent therapeutic opportunities for cancer treatment as well as innovative pathways for the development of anticancer drugs. 4 As a classical signal amplification strategy, hybrid chain reaction (HCR) has been widely used for highly sensitive miRNA analysis in living cells with various degrees of success. 5−8 Compared with the common enzyme-mediated isothermal amplification technique rolling ring amplification (RCA), which will affect the sensing performance and limit its wide biological application because the involvement of enzymes will cause the risk of inactivation in the complex cellular environment, HCR is a more ideal signal amplification method.…”

“…Ferroptosis, as a new type of programmed cell death with significant clinical potentials, has attracted extensive attention in cancer treatment. , However, emerging evidence implicated that ferroptosis can be inhibited by specific mitochondrial miRNA in tumor cells, leading to the poor cancer treatment . Therefore, highly sensitive and precise imaging of specific mitochondrial miRNA in tumor cells that can inhibit ferroptosis could afford patent therapeutic opportunities for cancer treatment as well as innovative pathways for the development of anticancer drugs . As a classical signal amplification strategy, hybrid chain reaction (HCR) has been widely used for highly sensitive miRNA analysis in living cells with various degrees of success. − Compared with the common enzyme-mediated isothermal amplification technique rolling ring amplification (RCA), which will affect the sensing performance and limit its wide biological application because the involvement of enzymes will cause the risk of inactivation in the complex cellular environment, HCR is a more ideal signal amplification method. , Despite progress made, an inevitable limitation is that traditional HCR can not be precisely controlled at the desired location and time because of the “always-active” state and the passive triggering patterns with initiator sequences .…”