The role of cardiolipin in mitophagy

Q Science (General);QH345 Biochemistry;QH426 Genetics

Galbraith, Laura Catherine Avril ; Gottlieb, Eyal

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: Mitophagy, Cardiolipin, Mitochondria, Barth's Syndrome, Microscopy, Tafazzin, oxidation, mitochondrial dynamics;   

Others  :  http://theses.gla.ac.uk/4913/1/2014GalbraithPhD.pdf

来源: University of Glasgow

【 摘 要 】

Mitophagy allows for the removal of damaged and dysfunctional mitochondria from the cell thereby attenuating any deleterious, potentially tumorigenic effects malfunctioning mitochondria may cause. Mitophagy is a specific from of macro-autophagy whereby mitochondria are selectively degraded. What controls this specificity is an area of active research. The translocation of various proteins such as PINK1 and PARKIN, to the mitochondria prior to mitophagy is thought to act as signals for recruitment of the autophagosome to the mitochondria. However what is the initiating signal for mitophagy that causes these proteins to act remains unclear. Damaged and dysfunctional mitochondria generate increased levels of reactive oxygen species and we hypothesized that these cause the oxidation of the mitochondrial membrane poly-unsaturated lipid, cardiolipin (CL), which acts as an indicator of mitochondrial health and as an initiating signal to the mitophagic machinery. Using human fibroblasts (derived from Barth’s syndrome patients) deficient in functional tafazzin (Taz), the enzyme responsible for CL maturation (poly-unsaturation), and control fibroblasts created by re-introducing a fully functional Taz gene into the parental Barth’s syndrome cells. The frequency at which mitophagy occurs in these deficient and revertant cell lines was analysed under different oxidative stress conditions, in conjunction with other factors known to affect the occurrence of mitophagy; such as mitochondrial morphology, dynamics, mass, membrane potential and function. We observed that not only were mitochondrial morphology, dynamics and function affected by the levels of polyunsaturated CL, but that indeed mitophagy is abrogated in cells lacking expression of functional TAZ and therefore lacking mature polyunsaturated CL. Further to this initial experiments have confirmed reduced levels of oxidized CL in the Barth’s syndrome cells, which combined with the evidence of reduced mitophagy suggests this could indeed be the initiating signal for mitophagy. Thus the data presented within this thesis provides evidence of the role of polyunsaturated CL, in mitophagy and suggests that through its oxidation it provides the initiating signal for mitophagy.