Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells

By C. Chu, Jing Ji, R. Dagda, Jianfei Jiang, Y. Tyurina, A. Kapralov, V. Tyurin, N. Yanamala, I. Shrivastava, D. Mohammadyani and 16 more. Nature Cell Biology, 2013

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Recognition of injured mitochondria for degradation by macroautophagy is essential for cellular health, but the mechanisms remain poorly understood. Cardiolipin is an inner mitochondrial membrane phospholipid. We found that rotenone, staurosporine, 6-hydroxydopamine and other pro-mitophagy stimuli caused externalization of cardiolipin to the mitochondrial surface in primary cortical neurons and SH-SY5Y cells. RNAi knockdown of cardiolipin synthase or of phospholipid scramblase-3, which transports cardiolipin to the outer mitochondrial membrane, decreased the delivery of mitochondria to autophagosomes. Furthermore, we found that the autophagy protein microtubule-associated-protein-1 light chain 3 (LC3), which mediates both autophagosome formation and cargo recognition, contains cardiolipin-binding sites important for the engulfment of mitochondria by the autophagic system. Mutation of LC3 residues predicted as cardiolipin-interaction sites by computational modelling inhibited its participation in mitophagy. These data indicate that redistribution of cardiolipin serves as an ‘eat-me’ signal for the elimination of damaged mitochondria from neuronal cells.

Subfields: Biochemistry, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/474fd5f088808d116ec4c78d027a064c8813bb6f

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Citations in the corpus

Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “cardiolipin and ceramide) (Chu et al., 2013) contribute to mitophagy under different mitochondrial stresses (e.”
Mitochondrial dynamics and mitochondrial quality control (2014, background): “Interestingly, cardiolipin regulates both apoptosis and mitophagy depending on its peroxidation status.”
Metabolic control of cell death (2014, background): “CL has been shown to constitute a signal for the autophagic removal of permeabilized mitochondria (127), hence playing amajor role in themaintenance of intracellular homeostasis.”
Molecular definitions of autophagy and related processes (2017, positive): “Cardiolipin, a mitochondrial lipid, has also been proposed to directly interact with LC3 upon mitochondrial damage caused by a variety of stimuli (Chu et al , 2013; Kagan et al , 2016).”
To be or not to be? How selective autophagy and cell death govern cell fate. (2014, neutral): “Damaged mitochondria expose cardiolipin, which is normally present predominantly on the inner mitochondrial membrane, on the outer membrane (Chu et al., 2013).”
Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation (2023, background): “Additionally, FUNDC1 is a mitochondrial outer membrane protein, which can induce Parkin-independent mitophagy in mammalian cells under hypoxia by interacting with LC3 [42].”
The mitophagy pathway and its implications in human diseases (2023, background): “155 Interestingly, compared to CCCP-treated HeLa cells, damaged primary neurons had a higher fold in externalized mitochondrial CL. 153 This observation is consistent with the ﬁ nding that translocation of Parkin in response to CCCP treatment is diminished or delayed in primary neurons, suggesting…”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, positive): “for externalized cardiolipin can also be considered a good marker for damaged mitochondria and early mitophagy.(145) Colocaliza-”
Mitochondria ROS and mitophagy in acute kidney injury (2022, background): “Furthermore, these ROS oxidize ergosterol to ergosterol peroxide in the OMM [36], which acts as a signal to recruit VCP (valosin containing protein) associated mitochondrial stress responsive 1, a component of a mitochondrial surveillance system [37], to damaged mitochondria for the subsequent signa”