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Mitochondrion Jan 2020Mitochondrial function relies on the activity of oxidative phosphorylation to synthesise ATP and generate an electrochemical gradient across the inner mitochondrial... (Review)
Review
Mitochondrial function relies on the activity of oxidative phosphorylation to synthesise ATP and generate an electrochemical gradient across the inner mitochondrial membrane. These coupled processes are mediated by five multi-subunit complexes that reside in this inner membrane. These complexes are the product of both nuclear and mitochondrial gene products. Defects in the function or assembly of these complexes can lead to mitochondrial diseases due to deficits in energy production and mitochondrial functions. Appropriate biogenesis and function are mediated by a complex number of assembly factors that promote maturation of specific complex subunits to form the active oxidative phosphorylation complex. The understanding of the biogenesis of each complex has been informed by studies in both simple eukaryotes such as Saccharomyces cerevisiae and human patients with mitochondrial diseases. These studies reveal each complex assembles through a pathway using specific subunits and assembly factors to form kinetically distinct but related assembly modules. The current understanding of these complexes has embraced the revolutions in genomics and proteomics to further our knowledge on the impact of mitochondrial biology in genetics, medicine, and evolution.
Topics: Animals; Electron Transport Chain Complex Proteins; Electron Transport Complex IV; Gene Expression Regulation, Enzymologic; Mammals; Mitochondria; Yeasts
PubMed: 31669617
DOI: 10.1016/j.mito.2019.10.008 -
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 -
Mitochondrion Mar 2020Autophagy is a ubiquitous homeostatic mechanism for the degradation or turnover of cellular components. Degradation of mitochondria via autophagy (mitophagy) is involved... (Review)
Review
Autophagy is a ubiquitous homeostatic mechanism for the degradation or turnover of cellular components. Degradation of mitochondria via autophagy (mitophagy) is involved in a number of physiological processes including cellular homeostasis, differentiation and aging. Upon stress or injury, mitophagy prevents the accumulation of damaged mitochondria and the increased steady state levels of reactive oxygen species leading to oxidative stress and cell death. A number of human diseases, particularly neurodegenerative disorders, have been linked to the dysregulation of mitophagy. In this mini-review, we aimed to review the molecular mechanisms involved in the regulation of mitophagy and their relationship with redox signaling and oxidative stress.
Topics: Aging; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Dynamics; Mitophagy; Neurodegenerative Diseases; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species
PubMed: 31972372
DOI: 10.1016/j.mito.2020.01.002 -
Cell Calcium Dec 2021
Topics: Mitochondria
PubMed: 34784537
DOI: 10.1016/j.ceca.2021.102498 -
Experimental & Molecular Medicine Dec 2023Mitochondria participate in a wide range of cellular processes. One essential function of mitochondria is to be a platform for antiviral signaling proteins during the... (Review)
Review
Mitochondria participate in a wide range of cellular processes. One essential function of mitochondria is to be a platform for antiviral signaling proteins during the innate immune response to viral infection. Recently, studies have revealed that mitochondrion-derived DNAs and RNAs are recognized as non-self molecules and act as immunogenic ligands. More importantly, the cytosolic release of these mitochondrial nucleic acids (mt-NAs) is closely associated with the pathogenesis of human diseases accompanying aberrant immune activation. The release of mitochondrial DNAs (mtDNAs) via BAX/BAK activation and/or VDAC1 oligomerization activates the innate immune response and inflammasome assembly. In addition, mitochondrial double-stranded RNAs (mt-dsRNAs) are sensed by pattern recognition receptors in the cytosol to induce type I interferon expression and initiate apoptotic programs. Notably, these cytosolic mt-NAs also mediate adipocyte differentiation and contribute to mitogenesis and mitochondrial thermogenesis. In this review, we summarize recent studies of innate immune signaling pathways regulated by mt-NAs, human diseases associated with mt-NAs, and the emerging physiological roles of mt-NAs.
Topics: Humans; Nucleic Acids; Immunity, Innate; Signal Transduction; Receptors, Pattern Recognition; Mitochondria
PubMed: 38036728
DOI: 10.1038/s12276-023-01121-x -
Journal of Molecular Medicine (Berlin,... Dec 2023The unfolded protein response (UPR) is a cellular stress response mechanism induced by the accumulation of unfolded or misfolded proteins. Within the endoplasmic... (Review)
Review
The unfolded protein response (UPR) is a cellular stress response mechanism induced by the accumulation of unfolded or misfolded proteins. Within the endoplasmic reticulum and mitochondria, a dynamic balance exists between protein folding mechanisms and unfolded protein levels under normal conditions. Disruption of this balance or an accumulation of unfolded proteins in these organelles can result in stress responses and UPR. The UPR restores organelle homeostasis and promotes cell survival by increasing the expression of chaperone proteins, regulating protein quality control systems, and enhancing the protein degradation pathway. However, prolonged or abnormal UPR can also have negative effects, including cell death. Therefore, many diseases, especially neurodegenerative diseases, are associated with UPR dysfunction. Neurodegenerative diseases are characterized by misfolded proteins accumulating and aggregating, and neuronal cells are particularly sensitive to misfolded proteins and are prone to degeneration. Many studies have shown that the UPR plays an important role in the pathogenesis of neurodegenerative diseases. Here, we will discuss the possible contributions of the endoplasmic reticulum unfolded protein response (UPR) and the mitochondrial unfolded protein response (UPR) in the development of several neurodegenerative diseases.
Topics: Humans; Neurodegenerative Diseases; Endoplasmic Reticulum Stress; Unfolded Protein Response; Endoplasmic Reticulum; Mitochondria
PubMed: 37817014
DOI: 10.1007/s00109-023-02382-9 -
Mitochondrion Jul 2022O-GlcNAcylation, a ubiquitous post-translational modification, rapidly modulates protein activity through the reversible addition and removal of O-GlcNAc groups from... (Review)
Review
O-GlcNAcylation, a ubiquitous post-translational modification, rapidly modulates protein activity through the reversible addition and removal of O-GlcNAc groups from serine or threonine residues in target proteins, and is involved in multiple metabolic pathways. With the discovery of enzymes and substrates for O-GlcNAc cycling in mitochondria, mitochondrial O-GlcNAc modification and its regulatory role in mitochondrial function deserve extensive attention. Adaptive regulation of the O-GlcNAc cycling in response to energy perturbations is demonstrated to be important in maintaining mitochondrial homeostasis. Dysregulation of O-GlcNAcylation in mitochondria has been associated with various mitochondrial dysfunctions, such as abnormal mitochondrial dynamics, reduced mitochondrial biosynthesis, disruption of the electron transport chain, oxidative stress and the calcium paradox, as well as activation of mitochondrial apoptosis pathways. Here, we outline the current understanding of O-GlcNAc modification in mitochondria and the key discovery of O-GlcNAcylation in regulating mitochondrial network homeostasis. This review will provide insights into targeting mitochondrial O-GlcNAcylation, as well as the mechanisms linking mitochondrial dysfunction and disease.
Topics: Acetylglucosamine; Calcium; Homeostasis; Mitochondria; Protein Processing, Post-Translational
PubMed: 35513218
DOI: 10.1016/j.mito.2022.04.007 -
Mitochondrion Jul 2023Pulmonary fibrosis (PF) is a serious lung disease characterized by diffuse alveolitis and disruption of alveolar structure, with a poor prognosis and unclear... (Review)
Review
Pulmonary fibrosis (PF) is a serious lung disease characterized by diffuse alveolitis and disruption of alveolar structure, with a poor prognosis and unclear etiopathogenesis. While ageing, oxidative stress, metabolic disorders, and mitochondrial dysfunction have been proposed as potential contributors to the development of PF, effective treatments for this condition remain elusive. However, Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), a peptide encoded by the mitochondrial genome, has shown promising effects on glucose and lipid metabolism, cellular and mitochondrial homeostasis, as well as the reduction of systemic inflammatory responses, and is being investigated as a potential exercise mimetic. Additionally, dynamic expression changes of MOTS-c have been closely linked to ageing and ageing-related diseases, indicating its potential as an exercise mimetic. Therefore, the review aims to comprehensively analyze the available literature on the potential role of MOTS-c in improving PF development and to identify specific therapeutic targets for future treatment strategies.
Topics: Humans; Mitochondria; Peptides; Aging; Transcription Factors; Fibrosis; Mitochondrial Proteins
PubMed: 37307934
DOI: 10.1016/j.mito.2023.06.002 -
Mitochondrion Sep 2020
Topics: Animals; Biological Transport; Energy Metabolism; Humans; Mitochondria; Plants
PubMed: 32569844
DOI: 10.1016/j.mito.2020.06.009 -
Mitochondrion Jul 2021Mitochondria are dynamic organelles, which serve various purposes, including but not limited to the production of ATP and various metabolites, buffering ions, acting as... (Review)
Review
Mitochondria are dynamic organelles, which serve various purposes, including but not limited to the production of ATP and various metabolites, buffering ions, acting as a signaling hub, etc. In recent years, mitochondria are being seen as the central regulators of cellular growth, development, and death. Since neurons are highly specialized cells with a heavy metabolic demand, it is not surprising that neurons are one of the most mitochondria-rich cells in an animal. At synapses, mitochondrial function and dynamics is tightly regulated by synaptic calcium. Calcium influx during synaptic activity causes increased mitochondrial calcium influx leading to an increased ATP production as well as buffering of synaptic calcium. While increased ATP production is required during synaptic transmission, calcium buffering by mitochondria is crucial to prevent faulty neurotransmission and excitotoxicity. Interestingly, mitochondrial calcium also regulates the mobility of mitochondria within synapses causing mitochondria to halt at the synapse during synaptic transmission. In this review, we summarize the various roles of mitochondrial calcium at the synapse.
Topics: Animals; Calcium; Humans; Mitochondria; Mitochondrial Dynamics; Synapses; Synaptic Transmission
PubMed: 33895346
DOI: 10.1016/j.mito.2021.04.006