Cardiolipin regulates mitophagy through the protein kinase C pathway

Zheni Shen, Yiran Li, Alexander N. Gasparski, Hagai Abeliovich, Miriam L. Greenberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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 genes ATG8, ATG18, and ATG32 synthetically interact with CL synthase mutant crd1Δ. 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 genes SHO1, SSK1, STE50, and HOG1 exacerbated crd1Δ 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 in crd1Δ cells, and up-regulation of the PKC pathway by expression of the PKC1R398P gene, which encodes constitutively activated Pkc1p, rescued crd1Δ 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.

Original languageAmerican English
Pages (from-to)2916-2923
Number of pages8
JournalJournal of Biological Chemistry
Volume292
Issue number7
DOIs
StatePublished - 17 Feb 2017

Bibliographical note

Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

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