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The FEBS Journal Nov 2022To ensure correct function, mitochondria have developed several mechanisms of protein quality control (QC). Protein homeostasis highly relies on chaperones and proteases... (Review)
Review
To ensure correct function, mitochondria have developed several mechanisms of protein quality control (QC). Protein homeostasis highly relies on chaperones and proteases to maintain proper folding and remove damaged proteins that might otherwise form cell-toxic aggregates. Besides quality control, mitochondrial proteases modulate and regulate many essential functions, such as trafficking, processing and activation of mitochondrial proteins, mitochondrial dynamics, mitophagy and apoptosis. Therefore, the impaired function of mitochondrial proteases is associated with various pathological conditions, including cancer, metabolic syndromes and neurodegenerative disorders. This review recapitulates and discusses the emerging roles of two major proteases of the mitochondrial matrix, LON and ClpXP. Although commonly acknowledge for their protein quality control role, recent advances have uncovered several highly regulated processes controlled by the LON and ClpXP connected to mitochondrial gene expression and respiratory chain function maintenance. Furthermore, both proteases have been lately recognized as potent targets for anticancer therapies, and we summarize those findings.
Topics: Humans; Peptide Hydrolases; Mitochondria; Mitochondrial Proteins; Neoplasms; Molecular Chaperones; Endopeptidases
PubMed: 33971087
DOI: 10.1111/febs.15964 -
Cells Apr 2019Mitochondrion harbors its own DNA (mtDNA), which encodes many critical proteins for the assembly and activity of mitochondrial respiratory complexes. mtDNA is packed by... (Review)
Review
Mitochondrion harbors its own DNA (mtDNA), which encodes many critical proteins for the assembly and activity of mitochondrial respiratory complexes. mtDNA is packed by many proteins to form a nucleoid that uniformly distributes within the mitochondrial matrix, which is essential for mitochondrial functions. Defects or mutations of mtDNA result in a range of diseases. Damaged mtDNA could be eliminated by mitophagy, and all paternal mtDNA are degraded by endonuclease G or mitophagy during fertilization. In this review, we describe the role and mechanism of mtDNA distribution and elimination. In particular, we focus on the regulation of paternal mtDNA elimination in the process of fertilization.
Topics: DNA, Mitochondrial; Humans; Mitochondria; Mitophagy; Mutation
PubMed: 31027297
DOI: 10.3390/cells8040379 -
Cell Metabolism Feb 2023Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we...
Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration in vivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.
Topics: Osteogenesis; Mitochondria; Osteoblasts; Mitochondrial Dynamics; Cell Differentiation
PubMed: 36754021
DOI: 10.1016/j.cmet.2023.01.003 -
Biochimica Et Biophysica Acta.... Sep 2018Mitochondrial oxidative phosphorylation is incompletely coupled, since protons translocated to the intermembrane space by specific respiratory complexes of the electron... (Review)
Review
Mitochondrial oxidative phosphorylation is incompletely coupled, since protons translocated to the intermembrane space by specific respiratory complexes of the electron transport chain can return to the mitochondrial matrix independently of the ATP synthase -a process known as proton leak- generating heat instead of ATP. Proton leak across the inner mitochondrial membrane increases the respiration rate and decreases the electrochemical proton gradient (Δp), and is an important mechanism for energy dissipation that accounts for up to 25% of the basal metabolic rate. It is well established that mitochondrial superoxide production is steeply dependent on Δp in isolated mitochondria and, correspondingly, mitochondrial uncoupling has been identified as a cytoprotective strategy under conditions of oxidative stress, including diabetes, drug-resistance in tumor cells, ischemia-reperfusion (IR) injury or aging. Mitochondrial uncoupling proteins (UCPs) are able to lower the efficiency of oxidative phosphorylation and are involved in the control of mitochondrial reactive oxygen species (ROS) production. There is strong evidence that UCP2 and UCP3, the UCP1 homologues expressed in the heart, protect against mitochondrial oxidative damage by reducing the production of ROS. This review first analyzes the relationship between mitochondrial proton leak and ROS generation, and then focuses on the cardioprotective role of chemical uncoupling and uncoupling mediated by UCPs. This includes their protective effects against cardiac IR, a condition known to increase ROS production, and their roles in modulating cardiovascular risk factors such as obesity, diabetes and atherosclerosis.
Topics: Animals; Cardiovascular Diseases; Humans; Membrane Potential, Mitochondrial; Mitochondria; Reactive Oxygen Species; Uncoupling Agents
PubMed: 29859845
DOI: 10.1016/j.bbabio.2018.05.019 -
Journal of Biochemistry Mar 2022In addition to the cytoplasmic translation system, eukaryotic cells house additional protein synthesis machinery in mitochondria. The importance of this in organello... (Review)
Review
In addition to the cytoplasmic translation system, eukaryotic cells house additional protein synthesis machinery in mitochondria. The importance of this in organello translation is exemplified by clinical pathologies associated with mutations in mitochondrial translation factors. Although a detailed understanding of mitochondrial translation has long been awaited, quantitative, comprehensive and spatiotemporal measurements have posed analytic challenges. The recent development of novel approaches for studying mitochondrial protein synthesis has overcome these issues and expands our understanding of the unique translation system. Here, we review the current technologies for the investigation of mitochondrial translation and the insights provided by their application.
Topics: Mitochondria; Mitochondrial Proteins; Mitochondrial Ribosomes; Protein Biosynthesis
PubMed: 35080613
DOI: 10.1093/jb/mvac005 -
The Journal of Physiology Feb 2021Mitochondrial structures were probably observed microscopically in the 1840s, but the idea of oxidative phosphorylation (OXPHOS) within mitochondria did not appear until... (Review)
Review
Mitochondrial structures were probably observed microscopically in the 1840s, but the idea of oxidative phosphorylation (OXPHOS) within mitochondria did not appear until the 1930s. The foundation for research into energetics arose from Meyerhof's experiments on oxidation of lactate in isolated muscles recovering from electrical contractions in an O atmosphere. Today, we know that mitochondria are actually reticula and that the energy released from electron pairs being passed along the electron transport chain from NADH to O generates a membrane potential and pH gradient of protons that can enter the molecular machine of ATP synthase to resynthesize ATP. Lactate stands at the crossroads of glycolytic and oxidative energy metabolism. Based on reported research and our own modelling in silico, we contend that lactate is not directly oxidized in the mitochondrial matrix. Instead, the interim glycolytic products (pyruvate and NADH) are held in cytosolic equilibrium with the products of the lactate dehydrogenase (LDH) reaction and the intermediates of the malate-aspartate and glycerol 3-phosphate shuttles. This equilibrium supplies the glycolytic products to the mitochondrial matrix for OXPHOS. LDH in the mitochondrial matrix is not compatible with the cytoplasmic/matrix redox gradient; its presence would drain matrix reducing power and substantially dissipate the proton motive force. OXPHOS requires O as the final electron acceptor, but O supply is sufficient in most situations, including exercise and often acute illness. Recent studies suggest that atmospheric normoxia may constitute a cellular hyperoxia in mitochondrial disease. As research proceeds appropriate oxygenation levels should be carefully considered.
Topics: Energy Metabolism; Glycolysis; Mitochondria; NAD; Oxidation-Reduction; Oxidative Phosphorylation
PubMed: 32358865
DOI: 10.1113/JP278930 -
Trends in Biochemical Sciences Mar 2020Members of the mitochondrial carrier family (SLC25) provide the transport steps for amino acids, carboxylic acids, fatty acids, cofactors, inorganic ions, and... (Review)
Review
Members of the mitochondrial carrier family (SLC25) provide the transport steps for amino acids, carboxylic acids, fatty acids, cofactors, inorganic ions, and nucleotides across the mitochondrial inner membrane and are crucial for many cellular processes. Here, we use new insights into the transport mechanism of the mitochondrial ADP/ATP carrier to examine the structure and function of other mitochondrial carriers. They all have a single substrate-binding site and two gates, which are present on either side of the membrane and involve salt-bridge networks. Transport is likely to occur by a common mechanism, in which the coordinated movement of six structural elements leads to the alternating opening and closing of the matrix or cytoplasmic side of the carriers.
Topics: Animals; Biological Transport; Cytoplasm; Humans; Mitochondria; Mitochondrial ADP, ATP Translocases
PubMed: 31787485
DOI: 10.1016/j.tibs.2019.11.001 -
Mitochondrion May 2021Mitochondrial RNA degradation plays an important role in maintenance of the mitochondria genetic integrity. Mitochondrial localization of p53 was observed in...
Mitochondrial RNA degradation plays an important role in maintenance of the mitochondria genetic integrity. Mitochondrial localization of p53 was observed in non-stressed and stressed cells. p53, as an RNA-binding protein, exerts 3'→5' exoribonuclease activity. The data suggest that in non-stressed cells, mitochondrial matrix-localized p53, with exoribonuclease activity, may play a housekeeping positive role. p53, through restriction the formation of new RNA/DNA hybrid and processing R-loop, might serve as mitochondrial R-loop suppressor. Conversely, stress-induced matrix-p53 decreases the amount of mitochondrial single-stranded RNA transcripts (including polyA- and non-polyA RNAs), thereby leading to the decline in the amount of mitochondria-encoded oxidative phosphorylation components.
Topics: Humans; Mitochondria; RNA Stability; RNA, Mitochondrial; Tumor Suppressor Protein p53
PubMed: 33775872
DOI: 10.1016/j.mito.2021.03.007 -
Free Radical Biology & Medicine Aug 2000Mitochondria have been described as "the powerhouses of the cell" because they link the energy-releasing activities of electron transport and proton pumping with the... (Review)
Review
Mitochondria have been described as "the powerhouses of the cell" because they link the energy-releasing activities of electron transport and proton pumping with the energy conserving process of oxidative phosphorylation, to harness the value of foods in the form of ATP. Such energetic processes are not without dangers, however, and the electron transport chain has proved to be somewhat "leaky." Such side reactions of the mitochondrial electron transport chain with molecular oxygen directly generate the superoxide anion radical (O2*-), which dismutates to form hydrogen peroxide (H2O2), which can further react to form the hydroxyl radical (HO*). In addition to these toxic electron transport chain reactions of the inner mitochondrial membrane, the mitochondrial outer membrane enzyme monoamine oxidase catalyzes the oxidative deamination of biogenic amines and is a quantitatively large source of H2O2 that contributes to an increase in the steady state concentrations of reactive species within both the mitochondrial matrix and cytosol. In this article we review the mitochondrial rates of production and steady state levels of these reactive oxygen species. Reactive oxygen species generated by mitochondria, or from other sites within or outside the cell, cause damage to mitochondrial components and initiate degradative processes. Such toxic reactions contribute significantly to the aging process and form the central dogma of "The Free Radical Theory of Aging." In this article we review current understandings of mitochondrial DNA, RNA, and protein modifications by oxidative stress and the enzymatic removal of oxidatively damaged products by nucleases and proteases. The possible contributions of mitochondrial oxidative polynucleotide and protein turnover to apoptosis and aging are explored.
Topics: Animals; Apoptosis; Cellular Senescence; DNA Damage; Electron Transport; Free Radicals; Glutathione; Hydrogen Peroxide; Mitochondria; Oxidants; Oxidative Stress; Reactive Oxygen Species
PubMed: 11035250
DOI: 10.1016/s0891-5849(00)00317-8 -
Molecular Cell Aug 2022Protein import into mitochondria is a highly regulated process, yet how cells clear mitochondria undergoing dysfunctional protein import remains poorly characterized....
Protein import into mitochondria is a highly regulated process, yet how cells clear mitochondria undergoing dysfunctional protein import remains poorly characterized. Here we showed that mitochondrial protein import stress (MPIS) triggers localized LC3 lipidation. This arm of the mitophagy pathway occurs through the Nod-like receptor (NLR) protein NLRX1 while, surprisingly, without the engagement of the canonical mitophagy protein PINK1. Mitochondrial depolarization, which itself induces MPIS, also required NLRX1 for LC3 lipidation. While normally targeted to the mitochondrial matrix, cytosol-retained NLRX1 recruited RRBP1, a ribosome-binding transmembrane protein of the endoplasmic reticulum, which relocated to the mitochondrial vicinity during MPIS, and the NLRX1/RRBP1 complex in turn controlled the recruitment and lipidation of LC3. Furthermore, NLRX1 controlled skeletal muscle mitophagy in vivo and regulated endurance capacity during exercise. Thus, localization and lipidation of LC3 at the site of mitophagosome formation is a regulated step of mitophagy controlled by NLRX1/RRBP1 in response to MPIS.
Topics: Endoplasmic Reticulum; Mitochondria; Mitochondrial Proteins; Mitophagy; Protein Transport
PubMed: 35752171
DOI: 10.1016/j.molcel.2022.06.004