Cited by 1,083Autophagy in Disease and TherapyMitochondrial Function and PathologyParkinson's Disease Mechanisms and Treatments

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

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Chu, Charleen T., Ji, Jing, Dagda, Ruben K., Jiang, Jian Fei, Tyurina, Yulia Y., Kapralov, Alexandr A., Tyurin, Vladimir A., Yanamala, Naveena +18 more·2013·Nature Cell Biology

Abstract

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.

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  • Changes in LC3-II amounts are tissue- and cell context-dependent.

    “changes in LC3-II amounts are tissue- and cell context-dependent.”

    From Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). (2016) · cites this paper as [145]

    The Results section on cargo recognition reports no significant effect of cardiolipin synthase knockdown on the LC3-II shift in primary neurons. The Discussion suggests that cell types may differ in their thresholds for engaging mitophagy pathways, but does not address whether changes in LC3-II amounts depend on tissue or cell context. Searches for LC3-II and cell-type differences found no comparison that establishes the claim; page numbers were unavailable in our copy. (LLM, conf=0.72)

    Experimental — accuracy not yet measured
  • In the absence of lysosomal protease inhibitors, starvation results in a modest increase (HEK 293 cells) or even a decrease (HeLa cells) in LC3-II, and inhibitors reveal this decrease is due to lysosome-dependent degradation.

    “In the absence of lysosomal protease inhibitors, starvation results in a modest increase (HEK 293 cells) or even a decrease (HeLa cells) in the amount of LC3-II. The use of inhibitors reveals that this apparent decrease is due to lysosome-dependent degradation.”

    From Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). (2016) · cites this paper as [145]

    The Results section on rotenone-induced autophagy reports lysosomal delivery of mitochondrial cargo and reversal of mitochondrial protein loss by bafilomycin, but not starvation-induced LC3-II changes. Searches for HEK 293, starvation, LC3-II, and lysosomal protease inhibitors found no passage comparing HEK 293 and HeLa cells or explaining an LC3-II decrease under starvation. (LLM, conf=0.76)

    Experimental — accuracy not yet measured
  • Cardiolipin, normally segregated to the inner mitochondrial membrane and essential to mitochondrial architecture and function, when herniated outside a damaged mitochondrial membrane, stimulates mitophagy, a process that eliminates dysfunctional mitochondria and promotes the formation of new mitochondria.

    “Cardiolipin — a phospholipid that is normally segregated to the inner mitochondrial membrane and is essential to the maintenance of mitochondrial architecture and function — when herniated outside a damaged mitochondrial membrane, stimulates mitophagy, a process that eliminates dysfunctional mitochondria and promotes the formation of new mitochondria (79).”

    From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [79]

  • Translocation of cardiolipin from the inner to outer mitochondrial membrane is another event that can trigger mitophagy.

    “It should also be mentioned that the translocation of cardiolipin from the inner to outer mitochondrial membrane is another event that can trigger mitophagy [144].”

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Authors
Chu, C. T., Ji, J., Dagda, R. K., Jiang, J. F., Tyurina, Y. Y., Kapralov, A. A., Tyurin, V. A., Yanamala, N., Shrivastava, I. H., Mohammadyani, D., Qiang Wang, K. Z., Zhu, J., Klein-Seetharaman, J., Balasubramanian, K., Amoscato, A. A., Borisenko, G., Huang, Z., Gusdon, A. M., Cheikhi, A., Steer, E. K., Wang, R., Baty, C., Watkins, S., Bahar, I., Bayır, H., & Kagan, V. E.
Affiliations
University of Pittsburgh (US)
Corresponding author
  • Chu, Charleen T.
  • Tyurina, Yulia Y.
  • Bayır, Hülya
  • Kagan, Valerian E.
Venue
Nature Cell Biology
Published
2013-09-15
Volume
15
Issue
10
Pages
1197-1205
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
OpenAlex
W2135592618
Cited by
1,083
References
66
Citations by year
2026: 75 · 2025: 96 · 2024: 102 · 2023: 87 · 2022: 83 · 2021: 105 · 2020: 104 · 2019: 82 · 2018: 73 · 2017: 85 · 2016: 60 · 2015: 65 · 2014: 59 · 2013: 6
FWCI
46.15
Type
journal article
Language
en
Open access
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Public Health Service (U19AIO68021)
  • National Institute on Aging (AG026389, F32AG030821, R01AG026389)
  • National Heart, Lung, and Blood Institute (HL-70755, R01HL070755, R01HL094488)
  • National Institute of General Medical Sciences (P20GM103554, P41GM103712)
  • National Institute of Allergy and Infectious Diseases (U19AI068021)
  • National Institute of Neurological Disorders and Stroke (NS065789, NS076511, R01NS061817, R01NS065789, NS061817, R56NS065789, R37NS061817, R01NS076511)
  • National Institute of Environmental Health Sciences (R21ES021068, ES 020693, R01ES020693)
  • National Institute for Occupational Safety and Health (R01 OH008282, OH008282)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD057587)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
cardiolipin, mitophagy, mitochondrial outer membrane, LC3, cardiolipin synthase, autophagy, neurons, mitochondrial damage, autophagosome formation, rotenone, staurosporine, 6-hydroxydopamine
MeSH terms
Amino Acid Sequence, Animals, Autophagy, Biological Transport, Cardiolipins, Cells, Cultured, HeLa Cells, Humans, Mitochondria, Models, Molecular, Molecular Sequence Data, Neurons, Rotenone, Uncoupling Agents, Signal Transduction, Oxidopamine, Rats, Sprague-Dawley, Protein Structure, Tertiary, Cell Line, Tumor, Mitochondrial Membranes, Rats, Gene Knockdown Techniques, Mitophagy

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