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![(A) Traditional 2D scheme of mitochondrial cristae (modified from Reference [41]) and (B) actual 3D topology of cristae within a segment of mitochondrial network tubule (OMM, green) with all possible localizations of mitochondrial phospholipase. The FIB/SEM (focused ion beam/scanning electron microscopy) 3D image of the mitochondrial tubule segment of the mitochondrial network in HepG-2 cells was acquired as described in Reference [42]. The 3D image shows cristae, including the intracristal space as rendered by yellow surface lamellae, representing intracristal membranes (an invaginated IMM portion) together with coated proteins of ATP-synthase and respiratory chain supercomplexes. Red lines illustrate the probable location of the membrane (IMM, not in scale), red ellipses depict the crista outlets, in reality, surrounded by MICOS-SAM joined supercomplexes (cf. Panel A), which are indicated only by thin blue lines. Note that intracristal or intermembrane space location for iPLA2γ is hypothetical. The latter location must exist if iPLA2γ participates in remodeling of cardiolipin acyl chains (see Section 5).](publication/351143902/figure/fig1/AS:1023047305818113@1620924893397/A-Traditional-2D-scheme-of-mitochondrial-cristae-modified-from-Reference-41-and-B.png)
(A) Traditional 2D scheme of mitochondrial cristae (modified from Reference [41]) and (B) actual 3D topology of cristae within a segment of mitochondrial network tubule (OMM, green) with all possible localizations of mitochondrial phospholipase. The FIB/SEM (focused ion beam/scanning electron microscopy) 3D image of the mitochondrial tubule segment of the mitochondrial network in HepG-2 cells was acquired as described in Reference [42]. The 3D image shows cristae, including the intracristal space as rendered by yellow surface lamellae, representing intracristal membranes (an invaginated IMM portion) together with coated proteins of ATP-synthase and respiratory chain supercomplexes. Red lines illustrate the probable location of the membrane (IMM, not in scale), red ellipses depict the crista outlets, in reality, surrounded by MICOS-SAM joined supercomplexes (cf. Panel A), which are indicated only by thin blue lines. Note that intracristal or intermembrane space location for iPLA2γ is hypothetical. The latter location must exist if iPLA2γ participates in remodeling of cardiolipin acyl chains (see Section 5).
Source publication
Patatin-like phospholipase domain-containing protein PNPLA8, also termed Ca2+-independent phospholipase A2γ (iPLA2γ), is addressed to the mitochondrial matrix (or peroxisomes), where it may manifest its unique activity to cleave phospholipid side-chains from both sn-1 and sn-2 positions, consequently releasing either saturated or unsaturated fatty...
Contexts in source publication
Context 1
... isoforms containing the N-terminal mitochondrial localization sequence are imported into the mitochondrial matrix, where the addressing sequence is cleaved off. Therefore, instantly after the import, iPLA2γ may affect the IMM inner lipid leaflet (Figure 2). It is not known whether other types of protein import mechanism allow locations of iPLA2γ in the intracristal space or the outer intermembrane space, i.e., in the layer between OMM and inner-boundary membrane (IBM; the part of IMM comprising the cylindrical portion parallel to the cylindrical OMM of mitochondrial network tubules) (Figure 2). ...
Context 2
... instantly after the import, iPLA2γ may affect the IMM inner lipid leaflet (Figure 2). It is not known whether other types of protein import mechanism allow locations of iPLA2γ in the intracristal space or the outer intermembrane space, i.e., in the layer between OMM and inner-boundary membrane (IBM; the part of IMM comprising the cylindrical portion parallel to the cylindrical OMM of mitochondrial network tubules) (Figure 2). The iPLA2γ mRNA was found in multiple human parenchymal tissues, including skeletal muscle, heart, placenta, brain, liver, and pancreas [37]; and in lymphocytes [38]. ...
Context 3
... Complex I [112], Complex IV [113], and ANT [114] require contacts with cardiolipin for their proper function, as well as the membrane F O moiety of the ATP-synthase [115]. The crista outlets are surrounded by crista junctions where OMM and IMM mutually interact (Figure 2). These contacts are ensured by protein complexes termed MICOS join with the SAM complexes of OMM [116,117], as well as by the specific structure of cardiolipin. ...
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Citations
... Based on results obtained by mass spectrometry and molecular dynamic (MD) simulations, we previously suggested that the formation of RA-PE adducts reshapes PE, thereby changing the intrinsic curvature of this lipid [41]. Another contribution to the transformation of the lipid shape during oxidative stress in mitochondria comes from the amplified action of membrane-bound phospholipase A2 (mPLA2) [42,43], which converts membrane lipids to lysolipids (C 0 > 0) and free fatty acids (FAs). The released FAs represent the raw material for the production of more RAs, which then target the headgroup of the PE and form more RA-PE adducts. ...
... Next, we measured the impact of inverted conical lipid 1-hydroxy-2-oleoyl-sn-glycero-3-phosphocholine (OPC; C 0,OPC > 0) on the elasticity of PE-containing membranes. The presence of OPC mimics the accumulation of lysolipids in the IMM due to increased phospholipase activity in response to oxidative stress [42,43]. Therefore, we measured the changes in the σ and k of DOPC membranes (C 0,DOPC ≈ 0) induced by the addition of DOPE alone or simultaneously with OPC in the molar ratios indicated in the figure descriptions ( Figure 3 and Supplementary Figure S1C,D). ...
Oxidative stress and ROS are important players in the pathogenesis of numerous diseases. In addition to directly altering proteins, ROS also affects lipids with negative intrinsic curvature such as phosphatidylethanolamine (PE), producing PE adducts and lysolipids. The formation of PE adducts potentiates the protonophoric activity of mitochondrial uncoupling proteins, but the molecular mechanism remains unclear. Here, we linked the ROS-mediated change in lipid shape to the mechanical properties of the membrane and the function of uncoupling protein 1 (UCP1) and adenine nucleotide translocase 1 (ANT1). We show that the increase in the protonophoric activity of both proteins occurs due to the decrease in bending modulus in lipid bilayers in the presence of lysophosphatidylcholines (OPC and MPC) and PE adducts. Moreover, MD simulations showed that modified PEs and lysolipids change the lateral pressure profile of the membrane in the same direction and by the similar amplitude, indicating that modified PEs act as lipids with positive intrinsic curvature. Both results indicate that oxidative stress decreases stored curvature elastic stress (SCES) in the lipid bilayer membrane. We demonstrated that UCP1 and ANT1 sense SCES and proposed a novel regulatory mechanism for the function of these proteins. The new findings should draw the attention of the scientific community to this important and unexplored area of redox biochemistry.
... Structural Characteristics PNPLA8 is a close homolog of PNPLA9/iPLA 2 β and has a similar active center but less homology at the N-terminus [93]. PNPLA9/iPLA 2 β has four possible translation initiation sites, giving rise to proteins of 88, 77, 74, and 63 kDa. ...
Phospholipase A1 (PLA1) is an enzyme that cleaves an ester bond at the sn-1 position of glycerophospholipids, producing a free fatty acid and a lysophospholipid. PLA1 activities have been detected both extracellularly and intracellularly, which are well conserved in higher eukaryotes, including fish and mammals. All extracellular PLA1s belong to the lipase family. In addition to PLA1 activity, most mammalian extracellular PLA1s exhibit lipase activity to hydrolyze triacylglycerol, cleaving the fatty acid and contributing to its absorption into the intestinal tract and tissues. Some extracellular PLA1s exhibit PLA1 activities specific to phosphatidic acid (PA) or phosphatidylserine (PS) and serve to produce lysophospholipid mediators such as lysophosphatidic acid (LPA) and lysophosphatidylserine (LysoPS). A high level of PLA1 activity has been detected in the cytosol fractions, where PA-PLA1/DDHD1/iPLA1 was responsible for the activity. Many homologs of PA-PLA1 and PLA2 have been shown to exhibit PLA1 activity. Although much has been learned about the pathophysiological roles of PLA1 molecules through studies of knockout mice and human genetic diseases, many questions regarding their biochemical properties, including their genuine in vivo substrate, remain elusive.
... This induces FA-mediated H + transport, leading to a mild dissipation of the mitochondrial protonmotive force (also termed mild mitochondrial uncoupling) [37][38][39][40][41][42][43][44]. This leads to the attenuation of mitochondrial superoxide formation ( [34][35][36], reviewed in [45,46]). Therefore, iPLA 2 γ is a crucial component of a feedback regulation, where partial ROS increase is subsequently eliminated by mitochondrial uncoupling due to activation of the iPLA 2 γ-UCP(ANT) antioxidant synergy [45,46]. ...
... This leads to the attenuation of mitochondrial superoxide formation ( [34][35][36], reviewed in [45,46]). Therefore, iPLA 2 γ is a crucial component of a feedback regulation, where partial ROS increase is subsequently eliminated by mitochondrial uncoupling due to activation of the iPLA 2 γ-UCP(ANT) antioxidant synergy [45,46]. ...
... These results are consistent with the ability of iPLA 2 γ to be reversibly inhibited by thiol reducing compounds, either directly or indirectly. They support the hypothesis of redox activation of iPLA 2 γ by oxidative posttranslational modification of accessible protein thiols [46]. ...
Mitochondrial Ca2+-independent phospholipase A2γ (iPLA2γ/PNPLA8) was previously shown to be directly activated by H2O2 and release free fatty acids (FAs) for FA-dependent H+ transport mediated by the adenine nucleotide translocase (ANT) or uncoupling protein 2 (UCP2). The resulting mild mitochondrial uncoupling and consequent partial attenuation of mitochondrial superoxide production lead to an antioxidant effect. However, the antioxidant role of iPLA2γ in the brain is not completely understood. Here, using wild-type and iPLA2γ-KO mice, we demonstrate the ability of tert-butylhydroperoxide (TBHP) to activate iPLA2γ in isolated brain mitochondria, with consequent liberation of FAs and lysophospholipids. The liberated FA caused an increase in respiratory rate, which was fully inhibited by carboxyatractyloside (CATR), a specific inhibitor of ANT. Employing detailed lipidomic analysis, we also demonstrate a typical cleavage pattern for TBHP-activated iPLA2γ, reflecting cleavage of glycerophospholipids from both sn-1 and sn-2 positions releasing saturated FAs, monoenoic FAs, and predominant polyunsaturated FAs. The acute antioxidant role of iPLA2γ-released FAs is supported by monitoring both intramitochondrial superoxide and extramitochondrial H2O2 release. We also show that iPLA2γ-KO mice were more sensitive to stimulation by pro-inflammatory lipopolysaccharide, as reflected by the concomitant increase in protein carbonyls in the brain and pro-inflammatory IL-6 release in the serum. These data support the antioxidant and anti-inflammatory role of iPLA2γ in vivo. Our data also reveal a substantial decrease of several high molecular weight cardiolipin (CL) species and accumulation of low molecular weight CL species in brain mitochondria of iPLA2γ-KO mice. Collectively, our results support a key role of iPLA2γ in the remodeling of lower molecular weight immature cardiolipins with predominantly saturated acyl chains to high molecular weight mature cardiolipins with highly unsaturated PUFA acyl chains, typical for the brain.
... The transcriptional regulation of mitochondrial redox equilibria is described by Scholtes and Giguère, presenting estrogen-related receptors as targetable redox sensors [5]. Jabůrek et al. [6] describe examples of both intramitochondrial redox signaling, as well as protein synergy leading to an antioxidant action. The former targets the H 2 O 2 -activated phospholipase iPLA2γ, relaying intramitochondrial redox signaling to free fatty acids as second messengers and simultaneously as cycling substrates of adenine nucleotide translocase and certain uncoupling protein isoforms. ...
Mitochondria undoubtedly represent a metabolic hub, but also act as a redox hub, controlling cell fate and emanating superoxide/H2O2, which in a regulated form and timing provide redox signaling [...]
... Genetic deletion of iPLA2γ also shows decrease in cardiolipin (CL), the specific phospholipid in mitochondrial membrane. There is further evidence for iPLA2γ to target oxidized CL [68,69]. Some of these activities may be due to the putative serine residues in this molecule, rendering it susceptible to phosphorylation by protein kinases including protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) [70,71]. ...
Phospholipids are major components in the lipid bilayer of cell membranes. These molecules are comprised of two acyl or alkyl groups and different phospho-base groups linked to the glycerol backbone. Over the years, substantial interest has focused on metabolism of phospholipids by phospholipases and the role of their metabolic products in mediating cell functions. The high levels of polyunsaturated fatty acids (PUFA) in the central nervous system (CNS) have led to studies centered on phospholipases A2 (PLA2s), enzymes responsible for cleaving the acyl groups at the sn-2 position of the phospholipids and resulting in production of PUFA and lysophospholipids. Among the many subtypes of PLA2s, studies have centered on three major types of PLA2s, namely, the calcium-dependent cytosolic cPLA2, the calcium-independent iPLA2 and the secretory sPLA2. These PLA2s are different in their molecular structures, cellular localization and, thus, production of lipid mediators with diverse functions. In the past, studies on specific role of PLA2 on cells in the CNS are limited, partly because of the complex cellular make-up of the nervous tissue. However, understanding of the molecular actions of these PLA2s have improved with recent advances in techniques for separation and isolation of specific cell types in the brain tissue as well as development of sensitive molecular tools for analyses of proteins and lipids. A major goal here is to summarize recent studies on the characteristics and dynamic roles of the three major types of PLA2s and their oxidative products towards brain health and neurological disorders.
... Group IV possesses Ca 2+ -based as well as arachidonyl particular PLA2 that are located in the cytoplasm. Principally, they might influence the outer PL leaflet of OMM (Fig1)[reviewed in [23] . Group VI has Palatin -like PL Domain -Containing Proteins (PNPLAs) [15], that are Ca 2+ -independent iPLA possessing lipase (GXGXXG) as well as nucleotide binding (GXGXXG) consensus sequences. ...
... Since the PLA2iPLA2γ is a main modulator liberating oxidized aliphatic chains(i.e. hydroperoxy FAs) from cardiolipin [44] , in addition to part played by ANT is in oleate hydroperoxide -stimulated uncoupling [67] , Juzarek et al. [23] , posited that redox-sensitive iPLA2sin combination with ANT might further possess anti-oxidant working that gets stimulated by mitochondrial lipids peroxidation(fig3 as well as 4). ...
... Furthermore, the escalated generation of mitochondrial oxidants runs adjacent to switch in a Cysteine thiol redox status along with results in sulfenylation of UCP1 Cys 253 [115] . Since these observations, a recent posit was made by Jaburek et al. [23] that the escalated amounts of oxidants result in activation of redox sensitive mitochondrial phospholipase iPLA2γ,that further yields budding fatty acids for the UCP1-modulated uncoupling, hence verifying heat generation [112] . However, the particular part of FA's along with lysophospholipids secondary to enzymatic action of the mitochondrial phospholipase iPLA2γ in BAT mitochondria are still to be unraveled. ...
Palatin-like PhosphoLipaseA2Domain-Containing Protein-8(PNPLA8)alias Ca 2+ independent phospholipase A2γ(iPLA2γ)is the one that is restricted to the mitochondrial matrix or peroxisomes where it might demonstrate its individual action of cleaving of the phospholipid side chain from sn1 awa sn2 position, leading to liberation of either saturated FAs or poly unsaturated FAs(PUFA)that include oxidized fatty acids. Furthermore iPLA2γ gets directly activated by H2O2 as well as thus get stimulated by redox signaling or oxidative stress. This redox stimulation allows the anti oxidant synergism with the mitochondrial uncoupling protein(UCPs)or other SLC25 mitochondrial family agents acting as carriers by the FA-modulated protonophoretic action also termed mild uncoupling which results in reduction of mitochondrial superoxide generation. This mode permits for the sustenance of the steady state redox status of the cell. Other than its anti oxidant part here the association of iPLA2γ to lipid peroxidation is reviewed here as iPLA2γ gets alternatively stimulated by cardiolipin hydroperoxides in addition to supposedly by structural changes of the lipid bilayer secondary to lipid peroxidation. Rest of iPLA2γ part are mitochondrial (or peroxisomal) membranes besides the production of particular lipid second messengers. Hence like at the time of FAs β oxidationin case of pancreatic β cells, H2O2 stimulated iPLA2γ provides the G-protein coupled receptor (GPR40)metabotropic receptor for multiplication of FA-stimulated insulin liberation. Moreover the cytoshielding part of iPLA2γ in the heart as well as brain,along with role in brown adipose tissue (BAT) metabolism is further detailed. The major work in this field has been by the groups of Jezek P from Chez and Gross RW, Mancuso DJ gourps. Thus this knowledge gives further insight in unraveling the alterations in lipid metabolism in diseases like obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepapititis (NASH), where ectopic fat deposition and accumulation is behind the pathophysiology of these diseases, besides understanding the severity of generation of APS Syndrome resulting in life threatening conditions.
... We found that insulin secretion stimulated by branchedchain ketoacids (BCKAs) (194) and partly by fatty acids (FAs) (98,103) essentially relies on mitochondrial retrograde redox signaling. Due to the relatively low content of cytosolic glutathione (17,(135)(136)(137)270), the redox milieu of pancreatic b-cells promotes the signal spreading from mitochondria up to the targets within the plasma membrane, which can further switch-on Ca V opening and action potential firing, followed by IGV exocytosis. ...
... Elevated ATP from OXPHOS fortified by FA b-oxidation and elevated cytosolic H 2 O 2 due to the increased H 2 O 2 -release from the matrix close the K ATP channel (possibly also TRPM2), as they do upon GSIS. Overactivation of GPR40: pathways (A, B) are also interconnected because of the intramitochondrial redox signaling [elevated matrix superoxide/H 2 O 2 due to FA b-oxidation (Fig. 11) directly activates mitochondrial phospholipase iPLA2c/PNPLA8 (98,103,105)]. The phospholipase iPLA2c cleaves both saturated and unsaturated FAs from the phospholipids of mitochondrial membranes. ...
... Redox-sensitive mitochondrial phospholipase iPLA2c amplifies FASIS. Notably, the first FASIS phase (the second FASIS phase only moderately) was highly amplified by the action of mitochondrial phospholipase iPLA2c (Ca 2+independent phospholipase A2 isoform c [PNPLA8]), providing the cleaved mitochondrial FAs to GPR40 in insulinoma INS-1E cells (98,103) and in mouse islets (Holendová et al., unpublished data). The iPLA2c is directly activated by H 2 O 2 , and it is also activated by the intramitochondrial redox signaling resulting from FA b-oxidation (103). ...
Significance:
Mitochondria determine glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells by elevating ATP synthesis. As the metabolic and redox hub, mitochondria provide numerous links to the plasma membrane channels, insulin granule vesicles (IGVs), cell redox, NADH, NADPH, and Ca2+-homeostasis, all affecting insulin secretion. Recent Advances: Mitochondrial redox signaling was implicated in several modes of insulin secretion (branched-chain ketoacid-, fatty acid-stimulated). Mitochondrial Ca2+-influx was found to enhance GSIS, reflecting cytosolic Ca2+-oscillations induced by action potential spikes (intermittent opening of voltage-dependent Ca2+ and K+ channels) or the superimposed Ca2+-release from the endoplasmic reticulum (ER). The ATPase inhibitory factor IF1 was reported to tune the glucose-sensitivity range for GSIS. Mitochondrial protein kinase-A was implicated in preventing the IF1-mediated inhibition of the ATP-synthase.
Critical issues:
It is unknown how the redox signal spreads up to the plasma membrane and what its targets are, what the differences in metabolic, redox, NADH/NADPH, and Ca2+-signaling and homeostasis are between the 1st and 2nd GSIS phase; and whether mitochondria can replace ER in the amplification of IGV exocytosis.
Future directions:
Metabolomics studies performed to distinguish between the mitochondrial matrix and cytosolic metabolites will elucidate further details. Identifying the targets of cell signaling into mitochondria and of mitochondrial retrograde metabolic and redox signals to the cell will uncover further molecular mechanisms for insulin secretion stimulated by glucose, branched-chain keto acids, and fatty acids, and the amplification of secretion by GLP-1 and metabotropic receptors. They will identify the distinction between the hub β-cells and their followers in intact/diabetic states.
Mitochondria are dynamic cellular organelles with complex roles in metabolism and signalling. Primary mitochondrial disorders are a group of approximately 400 monogenic disorders arising from pathogenic genetic variants impacting mitochondrial structure, ultrastructure and/or function. Amongst these disorders, defects of complex lipid biosynthesis, especially of the unique mitochondrial membrane lipid cardiolipin, and membrane biology are an emerging group characterised by clinical heterogeneity, but with recurrent features including cardiomyopathy, encephalopathy, neurodegeneration, neuropathy and 3‐methylglutaconic aciduria. This review discusses lipid synthesis in the mitochondrial membrane, the mitochondrial contact site and cristae organising system (MICOS), mitochondrial dynamics and trafficking, and the disorders associated with defects of each of these processes. We highlight overlapping functions of proteins involved in lipid biosynthesis and protein import into the mitochondria, pointing to an overarching coordination and synchronisation of mitochondrial functions. This review also focuses on membrane interactions between mitochondria and other organelles, namely the endoplasmic reticulum, peroxisomes, lysosomes and lipid droplets. We signpost disorders of these membrane interactions that may explain the observation of secondary mitochondrial dysfunction in heterogeneous pathological processes. Disruption of these organellar interactions ultimately impairs cellular homeostasis and organismal health, highlighting the central role of mitochondria in human health and disease.
Aims
Metabolic reprogramming in cancer cells has been linked to mitochondrial dysfunction. The mitochondrial 2‐oxoglutarate/malate carrier (OGC) has been suggested as a potential target for preventing cancer progression. Although OGC is involved in the malate/aspartate shuttle, its exact role in cancer metabolism remains unclear. We aimed to investigate whether OGC may contribute to the alteration of mitochondrial inner membrane potential by transporting protons.
Methods
The expression of OGC in mouse tissues and cancer cells was investigated by PCR and Western blot analysis. The proton transport function of recombinant murine OGC was evaluated by measuring the membrane conductance ( G m ) of planar lipid bilayers. OGC‐mediated substrate transport was measured in proteoliposomes using ¹⁴ C‐malate.
Results
OGC increases proton G m only in the presence of natural (long‐chain fatty acids, FA) or chemical (2,4‐dinitrophenol) protonophores. The increase in OGC activity directly correlates with the increase in the number of unsaturated bonds of the FA. OGC substrates and inhibitors compete with FA for the same protein binding site. Arginine 90 was identified as a critical amino acid for the binding of FA, ATP, 2‐oxoglutarate, and malate, which is a first step towards understanding the OGC‐mediated proton transport mechanism.
Conclusion
OGC extends the family of mitochondrial transporters with dual function: (i) metabolite transport and (ii) proton transport facilitated in the presence of protonophores. Elucidating the contribution of OGC to uncoupling may be essential for the design of targeted drugs for the treatment of cancer and other metabolic diseases.
BACKGROUND
Patatin like phospholipase domain containing 8 (PNPLA8) has been shown to play a significant role in various cancer entities. Previous studies have focused on its roles as an antioxidant and in lipid peroxidation. However, the role of PNPLA8 in colorectal cancer (CRC) progression is unclear.
AIM
To explore the prognostic effects of PNPLA8 expression in CRC.
METHODS
A retrospective cohort containing 751 consecutive CRC patients was enrolled. PNPLA8 expression in tumor samples was evaluated by immunohistochemistry staining and semi-quantitated with immunoreactive scores. CRC patients were divided into high and low PNPLA8 expression groups based on the cut-off values, which were calculated by X-tile software. The prognostic value of PNPLA8 was identified using univariate and multivariate Cox regression analysis. The overall survival (OS) rates of CRC patients in the study cohort were compared with Kaplan-Meier analysis and Log-rank test.
RESULTS
PNPLA8 expression was significantly associated with distant metastases in our cohort (P = 0.048). CRC patients with high PNPLA8 expression indicated poor OS (median OS = 35.3, P = 0.005). CRC patients with a higher PNPLA8 expression at either stage I and II or stage III and IV had statistically significant shorter OS. For patients with left-sided colon and rectal cancer, the survival curves of two PNPLA8-expression groups showed statistically significant differences. Multivariate analysis also confirmed that high PNPLA8 expression was an independent prognostic factor for overall survival (hazard ratio HR = 1.328, 95%CI: 1.016-1.734, P = 0.038).
CONCLUSION
PNPLA8 is a novel independent prognostic factor for CRC. These findings suggest that PNPLA8 is a potential target in clinical CRC management.
