Abstract:Mitochondria, so much more than just being energy factories, also have the capacity to synthesize macromolecules including phospholipids, particularly cardiolipin (CL) and phosphatidylethanolamine (PE). Phospholipids are vital constituents of mitochondrial membranes, impacting the plethora of functions performed by this organelle. Hence, the orchestrated movement of phospholipids to and from the mitochondrion is essential for cellular integrity. In this review, we capture recent advances in the field of mitoch… Show more
“…Similar experiments in yeast also revealed a crucial role for PS import into mitochondria and membrane contact between the ER and mitochondria for optimal functioning of mitochondria [20,35,39]. These observations and many other experiments strongly support the hypothesis that contact sites between the ER/MAM and mitochondria are required for mediating PS import from the ER into mitochondria and for providing PE for the normal functioning of mitochondria [reviewed in [5,40]]. In addition, PS-derived PE is rapidly exported from mitochondria, perhaps via MAM, to other cellular organelles including the plasma membrane.…”
Section: Role Of Membrane Contacts In Lipid Metabolismsupporting
This article supplements a recent Perspective by Scorrano et al. in Nature Communications [10 [ (1)]:1287] in which the properties and functions of inter-organelle membrane contact sites were summarized. It is now clear that inter-organelle membrane contact sites are widespread in eukaryotic cells and that diverse pairs of organelles can be linked via unique protein tethers. An appropriate definition of what constitutes an inter-organelle membrane contact site was proposed in the Perspective. In addition, the various experimental approaches that are frequently used to study these organelle associations, as well as the advantages and disadvantages of each of these methods, were considered. The nature of the tethers that link the pairs of organelles at the contact sites was discussed in detail and some biological functions that have been ascribed to specific membrane contact sites were highlighted. Nevertheless, the functions of most types of organelle contact sites remain unclear. In the current article I have considered some of the points raised in the Perspective but have omitted detailed information on the roles of membrane contact sites in biological functions such as apoptosis, autophagy, calcium homeostasis and mitochondrial fusion. Instead, I have provided some background on the initial discovery of mitochondria-endoplasmic reticulum membrane contact sites, and have focussed on the known roles of membrane contact sites in inter-organelle lipid transport. In addition, potential roles for membrane contact sites in human diseases are briefly discussed.
“…Similar experiments in yeast also revealed a crucial role for PS import into mitochondria and membrane contact between the ER and mitochondria for optimal functioning of mitochondria [20,35,39]. These observations and many other experiments strongly support the hypothesis that contact sites between the ER/MAM and mitochondria are required for mediating PS import from the ER into mitochondria and for providing PE for the normal functioning of mitochondria [reviewed in [5,40]]. In addition, PS-derived PE is rapidly exported from mitochondria, perhaps via MAM, to other cellular organelles including the plasma membrane.…”
Section: Role Of Membrane Contacts In Lipid Metabolismsupporting
This article supplements a recent Perspective by Scorrano et al. in Nature Communications [10 [ (1)]:1287] in which the properties and functions of inter-organelle membrane contact sites were summarized. It is now clear that inter-organelle membrane contact sites are widespread in eukaryotic cells and that diverse pairs of organelles can be linked via unique protein tethers. An appropriate definition of what constitutes an inter-organelle membrane contact site was proposed in the Perspective. In addition, the various experimental approaches that are frequently used to study these organelle associations, as well as the advantages and disadvantages of each of these methods, were considered. The nature of the tethers that link the pairs of organelles at the contact sites was discussed in detail and some biological functions that have been ascribed to specific membrane contact sites were highlighted. Nevertheless, the functions of most types of organelle contact sites remain unclear. In the current article I have considered some of the points raised in the Perspective but have omitted detailed information on the roles of membrane contact sites in biological functions such as apoptosis, autophagy, calcium homeostasis and mitochondrial fusion. Instead, I have provided some background on the initial discovery of mitochondria-endoplasmic reticulum membrane contact sites, and have focussed on the known roles of membrane contact sites in inter-organelle lipid transport. In addition, potential roles for membrane contact sites in human diseases are briefly discussed.
“…In mammalian cells, de novo synthesis of CL (Figure 3) begins at the matrix leaflet of the IMM with phosphatidic acid (PA) [6]. PA is synthesized via several distinct enzymes that reside in the ER or on the OMM [125] and possibly in the IMM by acylglycerol kinase [126]. PA made in or transported to the OMM from the ER is moved across the IMS by the heterodimeric complex TP53-regulated inhibitor of apoptosis 1-protein of relevant evolutionary and lymphoid interest domain (TRIAP1-PRELID1) [27], before combining with cytidine triphosphate (CTP), in a reaction catalyzed by TAM41 translocator assembly and maintenance homologue (TAMM41), to generate cytidine diphosphate-diacylglycerol (CDP-DAG reacylated by tafazzin (TAZ) and, through a series of deacylation/reacylation reactions, the characteristic four acyl chains of mature CL are formed [6].…”
Over the past decade, it has become clear that lipid homeostasis is central to cellular metabolism. Lipids are particularly abundant in the central nervous system (CNS) where they modulate membrane fluidity, electric signal transduction, and synaptic stabilization. Abnormal lipid profiles reported in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), are further support for the importance of lipid metablism in the nervous system. Cardiolipin (CL), a mitochondria-exclusive phospholipid, has recently emerged as a focus of neurodegenerative disease research. Aberrant CL content, structure, and localization are linked to impaired neurogenesis and neuronal dysfunction, contributing to aging and the pathogenesis of several neurodegenerative diseases, such as AD and PD. Furthermore, the highly tissue-specific acyl chain composition of CL confers it significant potential as a biomarker to diagnose and monitor the progression in several neurological diseases. CL also represents a potential target for pharmacological strategies aimed at treating neurodegeneration. Given the equipoise that currently exists between CL metabolism, mitochondrial function, and neurological disease, we review the role of CL in nervous system physiology and monogenic and neurodegenerative disease pathophysiology, in addition to its potential application as a biomarker and pharmacological target.
Lipids and the Central Nervous SystemThe central nervous system (CNS) is rich in lipids, which account for approximately 50% of the total brain dry weight [1]. They are primarily localized to biological membranes, where they sustain CNS architecture and function. Sphingolipids, glycerophospholipids, and cholesterol are the predominant species and participate in a broad range of physiological functions, including cellular signaling (e.g., myelination to enable neuronal communication and nerve conduction, and lipid raft formation), energy balance, blood-brain barrier formation, and inflammatory responses [2]. It is therefore unsurprising that dysregulation of the CNS lipidome is associated with a broad spectrum of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) [2].Neuronal cellular functions have an extremely high metabolic rate, with the brain consuming up to 20% of the total body energy [2]. To fulfil this extensive energy requirement, neurons rely on glucose metabolism and mitochondrial oxidative phosphorylation (OXPHOS). Indeed, mitochondria function as sophisticated energy sensors that rapidly modulate their morphology and activity according to cellular energy demands. In addition to energy metabolism, mitochondria also participate in numerous biochemical and signaling pathways that are crucial for brain homeostasis, including cell death signaling, generation of free radical species, and lipid synthesis [3]. As a consequence of their bacterial ancestry, mitochondria have distinctive features that include multiple copies of a circular geno...
“…6 , B and C ). These results indicate that LRP1 deficiency alters mitochondrial morphology and activities independent of cristae structure, but is a result of changes in phospholipid composition, particularly the lower phosphatidylethanolamine and cardiolipin contents in the mitochondrial membrane ( 26 , 27 , 28 , 29 ). Figure 5 Hepatic LRP1 deficiency reduces anionic phospholipid content in the mitochondria.…”
The LDL receptor-related protein 1 (LRP1) is a multifunctional transmembrane protein with endocytosis and signal transduction functions. Previous studies have shown that hepatic LRP1 deficiency exacerbates diet-induced steatohepatitis and insulin resistance
via
mechanisms related to increased lysosome and mitochondria permeability and dysfunction. The current study examined the impact of LRP1 deficiency on mitochondrial function in the liver. Hepatocytes isolated from liver-specific LRP1 knockout (
hLrp1
−/−
) mice showed reduced oxygen consumption compared with control mouse hepatocytes. The mitochondria in
hLrp1
−/−
mouse livers have an abnormal morphology and their membranes contain significantly less anionic phospholipids, including lower levels of phosphatidylethanolamine and cardiolipin that increase mitochondrial fission and impair fusion. Additional studies showed that LRP1 complexes with phosphatidylinositol 4-phosphate 5-kinase like protein-1 (PIP5KL1) and phosphatidylinositol 4-phosphate 5-kinase-1β (PIP5K1β). The absence of LRP1 reduces the levels of both PIP5KL1 and PIP5K1β in the plasma membrane and also lowers phosphatidylinositol(4,5) bisphosphate (PI(4,5)P
2
) levels in hepatocytes. These data indicate that LRP1 recruits PIP5KL1 and PIP5K1β to the plasma membrane for PI(4,5)P
2
biosynthesis. The lack of LRP1 reduces lipid kinase expression, leading to lower PI(4,5)P
2
levels, thereby decreasing the availability of this lipid metabolite in the cardiolipin biosynthesis pathway to cause cardiolipin reduction and the impairment in mitochondria homeostasis. Taken together, the current study identifies another signaling mechanism by which LRP1 regulates cell functions: binding and recruitment of PIP5KL1 and PIP5K1β to the membrane for PI(4,5)P
2
synthesis. In addition, it highlights the importance of this mechanism for maintaining the integrity and functions of intracellular organelles.
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