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Cell Reports May 2022Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide...
Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.
Topics: Acetyl Coenzyme A; Apoptosis; Fatty Acids; Humans; Membrane Lipids; Mitochondrial Membranes; Oxidation-Reduction; Phospholipids; Triple Negative Breast Neoplasms
PubMed: 35649368
DOI: 10.1016/j.celrep.2022.110870 -
Cell Reports Dec 2023Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A....
Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A. Either APOL1 C-terminal truncation (APOL1Δ) or APOL3 deletion (APOL3-KO [knockout]) reduces PI4KB activity and triggers actomyosin reorganization. We report that APOL3, but not APOL1, controls PI4KB activity through interaction with PI4KB and neuronal calcium sensor-1 or calneuron-1. Both APOLs are present in Golgi-derived autophagy-related protein 9A vesicles, which are involved in PI4KB trafficking. Like APOL3-KO, APOL1Δ induces PI4KB dissociation from APOL3, linked to reduction of mitophagy flux and production of mitochondrial reactive oxygen species. APOL1 and APOL3, respectively, can interact with the mitophagy receptor prohibitin-2 and the mitophagosome membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). While APOL1 conditions PI4KB and APOL3 involvement in mitochondrion fission and mitophagy, APOL3-VAMP8 interaction promotes fusion between mitophagosomal and endolysosomal membranes. We propose that APOL3 controls mitochondrial membrane dynamics through interactions with the fission factor PI4KB and the fusion factor VAMP8.
Topics: Apolipoprotein L1; Mitochondrial Membranes; Golgi Apparatus; Mitochondria; 1-Phosphatidylinositol 4-Kinase; Apolipoproteins; Mitochondrial Dynamics
PubMed: 38041817
DOI: 10.1016/j.celrep.2023.113528 -
International Journal of Biological... Apr 2023Mitochondria are centers of energy metabolism. The mitochondrial network is shaped by mitochondrial dynamics, including the processes of mitochondrial fission and fusion... (Review)
Review
Mitochondria are centers of energy metabolism. The mitochondrial network is shaped by mitochondrial dynamics, including the processes of mitochondrial fission and fusion and cristae remodeling. The cristae folded by the inner mitochondrial membrane are sites of the mitochondrial oxidative phosphorylation (OXPHOS) system. However, the factors and their coordinated interplay in cristae remodeling and linked human diseases have not been fully demonstrated. In this review, we focus on key regulators of cristae structure, including the mitochondrial contact site and cristae organizing system, optic atrophy-1, mitochondrial calcium uniporter, and ATP synthase, which function in the dynamic remodeling of cristae. We summarized their contribution to sustaining functional cristae structure and abnormal cristae morphology, including a decreased number of cristae, enlarged cristae junctions, and cristae as concentric ring structures. These abnormalities directly impact cellular respiration and are caused by dysfunction or deletion of these regulators in diseases such as Parkinson's disease, Leigh syndrome, and dominant optic atrophy. Identifying the important regulators of cristae morphology and understanding their role in sustaining mitochondrial morphology could be applied to explore the pathologies of diseases and to develop relevant therapeutic tools.
Topics: Humans; Mitochondrial Membranes; Mitochondria; Oxidative Phosphorylation; Energy Metabolism; Mitochondrial Proteins
PubMed: 36812974
DOI: 10.1016/j.ijbiomac.2023.123755 -
Biomolecules Aug 2023Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can... (Review)
Review
Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can cause the dysfunction of these organelles. In this scenario, mitochondrial dynamics proteins and the phospholipid composition of the mitochondrial membrane are key for fine-tuning the modulation of mitochondrial architecture. In addition, several factors including post-translational modifications such as the phosphorylation, acetylation, SUMOylation, and o-GlcNAcylation of mitochondrial dynamics proteins contribute to shaping the plasticity of this architecture. In this regard, several studies have evidenced that, upon metabolic stress, mitochondrial dynamics proteins are post-translationally modified, leading to the alteration of mitochondrial architecture. Interestingly, several proteins that sustain the mitochondrial lipid composition also modulate mitochondrial morphology and organelle communication. In this context, pharmacological studies have revealed that the modulation of mitochondrial shape and function emerges as a potential therapeutic strategy for metabolic diseases. Here, we review the factors that modulate mitochondrial architecture.
Topics: Mitochondria; Mitochondrial Membranes; Acetylation; Mitochondrial Dynamics; Mitochondrial Proteins
PubMed: 37627290
DOI: 10.3390/biom13081225 -
Biochimica Et Biophysica Acta. Proteins... Feb 2021OMA1 is a mitochondrial protease. Among its substrates are DELE1, a signaling peptide, which can elicit the integrated stress response, as well as the membrane-shaping... (Review)
Review
OMA1 is a mitochondrial protease. Among its substrates are DELE1, a signaling peptide, which can elicit the integrated stress response, as well as the membrane-shaping dynamin-related GTPase OPA1, which can drive mitochondrial outer membrane permeabilization. OMA1 is dormant under physiological conditions but rapidly activated upon mitochondrial stress, such as loss of membrane potential or excessive reactive oxygen species. Accordingly, OMA1 was found to be activated in a number of disease conditions, including cancer and neurodegeneration. OMA1 has a predicted transmembrane domain and is believed to be tethered to the mitochondrial inner membrane. Yet, its structure has not been resolved and its context-dependent regulation remains obscure. Here, I review the literature with focus on OMA1's biochemistry. I provide a good homology model of OMA1's active site with a root-mean-square deviation of 0.9 Å and a DALI Z-score of 19.8. And I build a case for OMA1 actually being an integral membrane protease based on OMA1's role in the generation of small signaling peptides, its functional overlap with PARL, and OMA1's homology with ZMPSTE24. The refined understanding of this important enzyme can help with the design of tool compounds and development of chemical probes in the future.
Topics: Apoptosis; Humans; Membrane Proteins; Metalloendopeptidases; Mitochondria; Mitochondrial Membranes; Peptide Hydrolases; Signal Transduction; Structural Homology, Protein
PubMed: 33130089
DOI: 10.1016/j.bbapap.2020.140558 -
Mitochondrion Nov 2023Allotopic expression is the functional transfer of an organellar gene to the nucleus, followed by synthesis of the gene product in the cytosol and import into the... (Review)
Review
Allotopic expression is the functional transfer of an organellar gene to the nucleus, followed by synthesis of the gene product in the cytosol and import into the appropriate organellar sub compartment. Here, we focus on mitochondrial genes encoding OXPHOS subunits that were naturally transferred to the nucleus, and critically review experimental evidence that claim their allotopic expression. We emphasize aspects that may have been overlooked before, i.e., when modifying a mitochondrial gene for allotopic expression━besides adapting the codon usage and including sequences encoding mitochondrial targeting signals━three additional constraints should be considered: (i) the average apparent free energy of membrane insertion (μΔG) of the transmembrane stretches (TMS) in proteins earmarked for the inner mitochondrial membrane, (ii) the final, functional topology attained by each membrane-bound OXPHOS subunit; and (iii) the defined mechanism by which the protein translocator TIM23 sorts cytosol-synthesized precursors. The mechanistic constraints imposed by TIM23 dictate the operation of two pathways through which alpha-helices in TMS are sorted, that eventually determine the final topology of membrane proteins. We used the biological hydrophobicity scale to assign an average apparent free energy of membrane insertion (μΔG) and a "traffic light" color code to all TMS of OXPHOS membrane proteins, thereby predicting which are more likely to be internalized into mitochondria if allotopically produced. We propose that the design of proteins for allotopic expression must make allowance for μΔG maximization of highly hydrophobic TMS in polypeptides whose corresponding genes have not been transferred to the nucleus in some organisms.
Topics: Mitochondria; Mitochondrial Membranes; Membrane Proteins; Genes, Mitochondrial; Protein Transport; Saccharomyces cerevisiae Proteins
PubMed: 37739243
DOI: 10.1016/j.mito.2023.09.004 -
Biochemical Society Transactions Apr 2021Mitochondria are double-membrane bound organelles that not only provide energy for intracellular metabolism, but also play a key role in the regulation of cell death.... (Review)
Review
Mitochondria are double-membrane bound organelles that not only provide energy for intracellular metabolism, but also play a key role in the regulation of cell death. Mitochondrial outer membrane permeabilization (MOMP), allowing the release of intermembrane space proteins like cytochrome c, is considered a point of no return in apoptosis. MOMP is controlled by the proteins of the B-cell lymphoma 2 (BCL-2) family, including pro-and anti-apoptotic members, whose balance determines the decision between cell death and survival. Other factors such as membrane lipid environment, membrane dynamics, and inter-organelle communications are also known to influence this process. MOMP and apoptosis have been acknowledged as immunologically silent. Remarkably, a growing body of evidence indicates that MOMP can engage in various pro-inflammatory signaling functions. In this mini-review, we discuss about our current knowledge on the mechanisms of mitochondrial apoptosis, as well as the involvement of mitochondria in other kinds of programmed cell death pathways.
Topics: Animals; Apoptosis; Cell Death; Ferroptosis; Humans; Mitochondria; Mitochondrial Membranes; Models, Biological; Pyroptosis; Signal Transduction
PubMed: 33704419
DOI: 10.1042/BST20200522 -
Journal of Inherited Metabolic Disease Jan 2022Energy-demanding organs like the heart are strongly dependent on oxidative phosphorylation in mitochondria. Oxidative phosphorylation is governed by the respiratory... (Review)
Review
Energy-demanding organs like the heart are strongly dependent on oxidative phosphorylation in mitochondria. Oxidative phosphorylation is governed by the respiratory chain located in the inner mitochondrial membrane. The inner mitochondrial membrane is the only cellular membrane with significant amounts of the phospholipid cardiolipin, and cardiolipin was found to directly interact with a number of essential protein complexes, including respiratory chain complexes I to V. An inherited defect in the biogenesis of cardiolipin causes Barth syndrome, which is associated with cardiomyopathy, skeletal myopathy, neutropenia and growth retardation. Energy conversion is dependent on reducing equivalents, which are replenished by oxidative metabolism in the Krebs cycle. Cardiolipin deficiency in Barth syndrome also affects Krebs cycle activity, metabolite transport and mitochondrial morphology. During excitation-contraction coupling, calcium (Ca ) released from the sarcoplasmic reticulum drives sarcomeric contraction. At the same time, Ca influx into mitochondria drives the activation of Krebs cycle dehydrogenases and the regeneration of reducing equivalents. Reducing equivalents are essential not only for energy conversion, but also for maintaining a redox buffer, which is required to detoxify reactive oxygen species (ROS). Defects in CL may also affect Ca uptake into mitochondria and thereby hamper energy supply and demand matching, but also detoxification of ROS. Here, we review the impact of cardiolipin deficiency on mitochondrial function in Barth syndrome and discuss potential therapeutic strategies.
Topics: Animals; Barth Syndrome; Calcium; Cardiolipins; Cardiomyopathies; Disease Models, Animal; Humans; Mitochondria; Mitochondrial Membranes; Oxidation-Reduction; Reactive Oxygen Species
PubMed: 34423473
DOI: 10.1002/jimd.12427 -
Biomolecules Jul 2020Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize... (Review)
Review
Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors utilize a specialized translocation pathway dedicated to the biogenesis of carriers and related proteins, the carrier translocase of the inner membrane (TIM22) pathway. After recognition and import through the mitochondrial outer membrane via the translocase of the outer membrane (TOM) complex, carrier precursors are ushered through the intermembrane space by hexameric TIM chaperones and ultimately integrated into the inner membrane by the TIM22 carrier translocase. Recent advances have shed light on the mechanisms of TOM translocase and TIM chaperone function, uncovered an unexpected versatility of the machineries, and revealed novel components and functional crosstalk of the human TIM22 translocase.
Topics: Biological Transport; Carrier Proteins; Humans; Membrane Transport Proteins; Mitochondria; Mitochondrial Membranes; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Signal Transduction
PubMed: 32645990
DOI: 10.3390/biom10071008 -
Current Opinion in Cell Biology Aug 2023Phosphatidylserine (PS) is a negatively charged glycerophospholipid found mainly in the plasma membrane (PM) and in the late secretory/endocytic compartments, where it... (Review)
Review
Phosphatidylserine (PS) is a negatively charged glycerophospholipid found mainly in the plasma membrane (PM) and in the late secretory/endocytic compartments, where it regulates cellular activity and can mediate apoptosis. Export of PS from the endoplasmic reticulum, its site of synthesis, to other compartments, and its transbilayer asymmetry must therefore be precisely regulated. We review recent findings on nonvesicular transport of PS by lipid transfer proteins (LTPs) at membrane contact sites, on PS flip-flop between membrane leaflets by flippases and scramblases, and on PS nanoclustering at the PM. We also discuss emerging data on cooperation between scramblases and LTPs, how perturbation of PS distribution can lead to disease, and the specific role of PS in viral infection.
Topics: Phosphatidylserines; Cell Membrane; Biological Transport; Endoplasmic Reticulum; Mitochondrial Membranes
PubMed: 37413778
DOI: 10.1016/j.ceb.2023.102192