title: Cardiolipin Regulates Mitophagy through the Protein Kinase C Pathway.
abstract: Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, is important for cardiovascular health, and perturbation of CL metabolism is implicated in cardiovascular disease. Although the role of CL in mitochondrial function, biogenesis, and genome stability has been studied, recent findings indicate that it is essential for functions apart from mitochondrial bioenergetics. In this study, we report that mitophagy is perturbed in CL-deficient yeast cells. Mutants of autophagy/mitophagy genesATG8,ATG18, andATG32synthetically interact with CL synthase mutantcrd1Δ. CL-deficient cells exhibited decreased GFP-tagged mitochondrial proteins inside the vacuole and decreased free GFP, consistent with decreased mitophagy. Both PKC and high osmolarity glycerol (HOG) MAPK pathways were shown previously to be required for mitophagy. Activation of both MAPKs was defective in CL-deficient cells. Deletion of HOG pathway genesSHO1,SSK1,STE50, andHOG1exacerbatedcrd1Δ growth. 1 m sorbitol and 0.2 m NaCl, which induce the HOG pathway, rescued growth of the mutant. Activation of the MAPK Slt2p was defective incrd1Δ cells, and up-regulation of the PKC pathway by expression of thePKC1R398Pgene, which encodes constitutively activated Pkc1p, rescuedcrd1Δ growth and mitophagy defects. These findings indicate that loss of CL impairs MAPK pathway activation, and decreased activation of the PKC pathway leads to defective mitophagy.
authors.affiliation: From the Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202 and.
authors.forename: Zheni
authors.initials: Z
authors.lastname: Shen
authors.affiliation: From the Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202 and.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202 and.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Gasparski
authors.affiliation: the Institute of Biochemistry, Food Science and Nutrition, Hebrew University of Jerusalem, 76100 Rehovot, Israel.
authors.forename: Hagai
authors.initials: H
authors.lastname: Abeliovich
authors.affiliation: From the Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202 and mgreenberg@wayne.edu.
authors.forename: Miriam L
authors.initials: ML
authors.lastname: Greenberg
mesh_terms: D002308:Cardiolipins / Q000502:physiology*; D063306:Mitophagy / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002308:Cardiolipins; D011493:Protein Kinase C
keywords: cardiolipin; mitochondria; mitogen-activated protein kinase (MAPK); mitophagy; protein kinase C (PKC)