Yulia Y. Tyurina, Ph.D.; Valerian E. Kagan, PhD, DSc
University of Pittsburgh
NIEHS Grants R01ES020693, R21ES021068
NIEHS-supported researchers have provided evidence that the externalization of the mitochondrial phospholipid cardiolipin signals for the elimination of damaged mitochondria in neuronal cells. Dysfunctioning mitochondria generate reactive oxygen species and release mediators that kill cells, so recognizing and breaking down unhealthy mitochondria by autophagy is essential for cellular health.
Cardiolipin is found in the inner membrane of healthy mitochondria and is not present in any other organelle. Using primary cortical neurons and neuroblastoma cells, the researchers found that the insecticide rotenone; substances that destroy dopaminergic and noradrenergic neurons (staurosporine and 6-hydroxydopamine); and other pro-mitophagy stimuli caused cardiolipin to move from the inner mitochondrial membrane to the mitochondrial surface. If they inhibited cardiolipin synthase or a protein that transports cardiolipin to the outer mitochondrial membrane, delivery of mitochondria to autophagosomes decreased.
The researchers also found that the autophagy protein microtubule-associated-protein-1 light chain 3 (LC3) contains cardiolipin-binding sites important for the engulfment of mitochondria. LC3 mediates both autophagosome formation and cargo recognition.
The findings from this study point to a mechanism by which externalized cardiolipin in injured mitochondria interacts with LC3, mediating targeted autophagy of mitochondria in primary neurons and transformed neuronal cells.
Citation: Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, Tyurin VA, Yanamala N, Shrivastava IH, Mohammadyani D, Qiang Wang KZ, Zhu J, Klein-Seetharaman J, Balasubramanian K, Amoscato AA, Borisenko G, Huang Z, Gusdon AM, Cheikhi A, Steer EK, Wang R, Baty C, Watkins S, Bahar I, Bayır H, Kagan VE. 2013. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol (10):1197-1205.