Cardiolipin and Its Different Properties in Mitophagy and Apoptosis

Abstract

SummaryCardiolipin (CL) is a unique dimeric phospholipid that exists almost exclusively in the inner mitochondrial membrane (IMM) in eukaryotic cells. Two chiral carbons and four fatty acyl chains in CL result in a flexible body allowing interactions with respiratory chain complexes and mitochondrial substrate carriers. Due to its high content of unsaturated fatty acids, CL is particularly prone to reactive oxygen species (ROS)-induced oxidative attacks. Under mild mitochondrial damage, CL is redistributed to the outer mitochondrial membrane (OMM) and serves as a recognition signal for dysfunctional mitochondria, which are rapidly sequestered by autophagosomes. However, peroxidation of CL is far greater in response to severe stress than under normal or mild-damage conditions. The accumulation of oxidized CL on the OMM results in recruitment of Bax and formation of the mitochondrial permeability transition pore (MPTP), which releases Cytochrome c (Cyt c) from mitochondria. Over the past decade, the significance of CL in the function of mitochondrial bioenergy has been explored. Moreover, approaches to analyzing CL have become more effective and accurate. In this review, we discuss the unique structural features of CL as well as the current understanding of CL-based molecular mechanisms of mitophagy and apoptosis. Keywords apoptosis, cardiolipin, mitophagy, oxidation, translocation 302Li et al. such as phosphatidylethanolamine (PE) and phosphatidylserine (PS)?The dimeric structure and polyunsaturated fatty acyl chains of CL may be responsible for its ability to switch between lamellar and negative curvature profiles. The biosynthesis of CL is a little more complex than that of PE and PS and involves two pathways: de novo synthesis and remodeling steps (Hatch 1998;Schlame et al. 2000) (Fig. 1). The de novo reactions originate from phosphatidic acid (PA). First, PA is transformed into cytidine diphosphate-diacylglycerol (CDP-DAG) in the presence of CDP-DAG synthase (Houtkooper and Vaz 2008). Then, CDP-DAG is converted to phosphatidylglycerol phosphate (PGP) by displacement of the cytidine monophosphate (CMP) moiety by sn-glycerol-3-phosphate through the activity of the PGP synthase. This is followed by a dephosphorylation reaction to produce PG (Chang et al. 1998;Stanacev et al. 1967). Finally, the combination of PG and CDP-DAG yields CL through the activity of cardiolipin synthase (CLS) (Chicco and Sparagna 2007;Lu et al. 2006). On the other hand, PE and PS possess relatively simple structures composed of a glycerol with two fatty acyl chains. Two chiral carbons on the two side glycerols of CL allow the four acyl chains to combine in different spatial locations. These distinct spatial structures may have important roles in the fluidity of cristae as well as in the fixation of proteins in mitochondrial membranes.CLS has no preference for certain acyl chains, indicating that post-synthetic remodeling is essential to produce specific polyunsaturated fatty acyl chains in CL. Remodeling is a cycle of deacylation and rea...

Mitochondrial biogenesis and clearance: a balancing act

“…The nucleoside diphosphate kinase‐D (NDPK‐D) and the mitochondrial creatine kinase (MtCK) are IMS proteins that mediate CL transfer from the IMM to the IMS‐facing side of the OMM. Subsequently, the phospholipid scramblase 3 (PLS3) facilitates transmigration of CL to the cytoplasm‐facing side of the OMM, where it functions as an ‘eat‐me’ signal . In addition to CL, ceramide is a sphingolipid that can also interact with LC3‐II.…”

NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

“…36 All these findings add to an emerging paradigm, namely that the myriad of different cellular lipid species, and in particular CL, have not just a supportive structural role, but are very actively involved in regulatory and signaling functions. 19,[37][38][39][40][41] …”

Cardiolipin Interactions with Proteins

“…In addition to its structural role for the proteins of the electron transport chain, it also plays roles in different stages of apoptosis (5), adenylate translocase ion transport (6), and translocation by NDPK-D (7). Lately, extramitochondrial functions of CL in regulating the process of mitophagy (8)(9)(10)(11) and orchestrating the NLRP3 inflammasome and maturation of IL-1b (12,13) have been documented. Not surprisingly, CL has been implicated in a number of different diseases, such as Barth syndrome, diabetes, heart disease, radiation damage, Parkinson's disease, and others.…”