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 genes ,, and synthetically interact with CL synthase mutantΔ. 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 ,, , and exacerbated Δ 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 inΔ cells, and up-regulation of the PKC pathway by expression of the gene, which encodes constitutively activated Pkc1p, rescuedΔ 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.

Enhancing Mitochondrial Health to Treat Hypertension

“…Preservation of the integrity of the inner mitochondrial membrane is also important to sustain mitophagy. We have previously shown in swine renovascular hypertension that restoration of myocardial cardiolipin improved mitophagy [27], in agreement with the previous observation of decreased mitophagy in cardiolipin-deficient cells [56]. Therefore, pharmacological agents that target mitochondrial homeostasis might offer the prospect of decreasing hypertension related end-organ damage.…”

PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection

“…It is noteworthy that the PKC family functions many signal transduction downstream, and PKCα is the predominant conventional PKC isoform expressed in mouse, rat and human heart . Furthermore, several studies have also demonstrated that mitophagy is associated with the PKC pathway . Altogether, this inspired us to explore the physical relevance between PKCα and ULK1 in PEDF‐treated OGD cardiomyocytes.…”

“…14 Furthermore, several studies have also demonstrated that mitophagy is associated with the PKC pathway. 15,16 Altogether, this inspired us to explore the physical relevance between PKCα and ULK1 in PEDF-treated OGD cardiomyocytes.…”

Operation of mitochondrial machinery in viral infection-induced immune responses

“…In addition, different with the general concept that ROS is required for the inflammasome activators to induce inflammasome signaling, Lyer et al found that the oxazolidinone antibiotic linezolid, a NLRP3 agonist, activates the NLRP3 inflammasome independently of ROS, whereas mitochondrial cardiolipin is required for NLRP3 inflammasome activation [66]. Under cardiolipin deficiency, mitophagy is defective likely due to the impairment of MAPK signaling and the reduced activation of the protein kinase C pathway [67].…”