La mitofagia es un proceso autofágico por el cual las células eliminan las mitocondrias dañadas transfiriéndolas a los lisosomas para su degradación. La translocación del lípido cardiolipina a la membrana mitocondrial externa sirve como señal para la mitofagia. En este estudio se ha identificado a la proteína LC3A como un nuevo miembro de la subfamilia LC3 implicado en mitofagia, y se han detectado en dicha proteína residuos importantes para el reconocimiento de la cardiolipina.
Resumen
Externalization of the phospholipid cardiolipin (CL) to the outer mitochondrial membrane has been proposed to act as a mitophagy trigger. CL would act as a signal for binding the LC3 macroautophagy/autophagy proteins. As yet, the behavior of the LC3-subfamily members has not been directly compared in a detailed way. In the present contribution, an analysis of LC3A, LC3B and LC3C interaction with CL-containing model membranes, and of their ability to translocate to mitochondria, is described. Binding of LC3A to CL was stronger than that of LC3B; both proteins showed a similar ability to colocalize with mitochondria upon induction of CL externalization in SH-SY5Y cells. Besides, the double silencing of LC3A and LC3B proteins was seen to decrease CCCP-induced mitophagy. Residues 14 and 18 located in the N-terminal region of LC3A were shown to be important for its recognition of damaged mitochondria during rotenone- or CCCP-induced mitophagy. Moreover, the in vitro results suggested a possible role of LC3A, but not of LC3B, in oxidized-CL recognition as a counterweight to excessive apoptosis activation. In the case of LC3C, even if this protein showed a stronger CL binding than LC3B or LC3A, the interaction was less specific, and colocalization of LC3C with mitochondria was not rotenone dependent. These results suggest that, at variance with LC3A, LC3C does not participate in cargo recognition during CL-mediated-mitophagy. The data support the notion that the various LC3-subfamily members might play different roles during autophagy initiation, identifying LC3A as a novel stakeholder in CL-mediated mitophagy.
agosto 2022
Referencia del artículo
Marina N. Iriondo*, Asier Etxaniz*, Yaiza R. Varela, Uxue Ballesteros, Javier H. Hervás, L. Ruth Montes, Félix M. Goñi & Alicia Alonso (2022): LC3 subfamily in cardiolipin-mediated mitophagy: a comparison of the LC3A, LC3B and LC3C homologs, Autophagy
Sobre el grupo investigador
Nuestro grupo estudia las interacciones lípido-proteína que tienen lugar en las primeras etapas de la autofagia, en particular durante la formación y expansión del autofagosoma y durante la selección de la carga. Reconstituimos estos fenómenos en sistemas funcionales mínimos, y utilizando proteínas autofágicas recombinantes, lo que nos permite comprender en detalle el mecanismo a nivel molecular.