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Mitochondrion Nov 2021Mitochondria, the 'powerhouse' of eukaryotic cells, play a key role in cellular homeostasis. However, defective mitochondria increase mitochondrial ROS (mtROS)... (Review)
Review
Mitochondria, the 'powerhouse' of eukaryotic cells, play a key role in cellular homeostasis. However, defective mitochondria increase mitochondrial ROS (mtROS) production and cell-free mitochondrial DNA (mtDNA) release, leading to increased inflammation. Mitophagy is a vital pathway, which selectively removes defective mitochondria through the process of autophagy. Thus, an impairment in the mitophagy pathway might trigger the gradual accumulation of defective mitochondria. Accumulating evidence suggest that inflammation and mitochondrial dysfunction are linked to the pathogenesis of depression. In this article, we have reviewed the role of impaired mitophagy as a contributing factor in depression pathophysiology. Further, we have discussed the potential therapeutic interventions aimed at modulating mitophagy in depression.
Topics: Depression; Humans; Mitochondria; Mitophagy
PubMed: 34478906
DOI: 10.1016/j.mito.2021.08.016 -
Mitochondrion Sep 2020Mitochondria are eukaryotic organelles known best for their roles in energy production and metabolism. While often thought of as simply the 'powerhouse of the cell,'... (Review)
Review
Mitochondria are eukaryotic organelles known best for their roles in energy production and metabolism. While often thought of as simply the 'powerhouse of the cell,' these organelles participate in a variety of critical cellular processes including reactive oxygen species (ROS) production, regulation of programmed cell death, modulation of inter- and intracellular nutrient signaling pathways, and maintenance of cellular proteostasis. Disrupted mitochondrial function is a hallmark of eukaryotic aging, and mitochondrial dysfunction has been reported to play a role in many aging-related diseases. While mitochondria are major players in human diseases, significant questions remain regarding their precise mechanistic role. In this review, we detail mechanisms by which mitochondrial dysfunction participate in disease and aging based on findings from model organisms and human genetics studies.
Topics: Aging; Apoptosis; Energy Metabolism; Humans; Mitochondria; Oxidative Stress; Proteostasis; Reactive Oxygen Species
PubMed: 32738358
DOI: 10.1016/j.mito.2020.07.007 -
Metallomics : Integrated Biometal... Nov 2017All known eukaryotes require copper for their development and survival. The essentiality of copper reflects its widespread use as a co-factor in conserved enzymes that... (Review)
Review
All known eukaryotes require copper for their development and survival. The essentiality of copper reflects its widespread use as a co-factor in conserved enzymes that catalyze biochemical reactions critical to energy production, free radical detoxification, collagen deposition, neurotransmitter biosynthesis and iron homeostasis. However, the prioritized use of copper poses an organism with a considerable challenge because, in its unbound form, copper can potentiate free radical production and displace iron-sulphur clusters to disrupt protein function. Protective mechanisms therefore evolved to mitigate this challenge and tightly regulate the acquisition, trafficking and storage of copper such that the metal ion is rarely found in its free form in the cell. Findings by a number of groups over the last ten years emphasize that this regulatory framework forms the foundation of a system that is capable of monitoring copper status and reprioritizing copper usage at both the cellular and systemic levels of organization. While the identification of relevant molecular mechanisms and signaling pathways has proven to be difficult and remains a barrier to our full understanding of the regulation of copper homeostasis, mounting evidence points to the mitochondrion as a pivotal hub in this regard in both healthy and diseased states. Here, we review our current understanding of copper handling pathways contained within the organelle and consider plausible mechanisms that may serve to functionally couple their activity to that of other cellular copper handling machinery to maintain copper homeostasis.
Topics: Animals; Biological Transport; Cation Transport Proteins; Copper; Copper Transporter 1; Glutathione; Homeostasis; Humans; Mitochondria; Models, Biological
PubMed: 28952650
DOI: 10.1039/c7mt00221a -
Molecular Therapy : the Journal of the... Jul 2017Polyethylenimine (PEI) is a gold standard polycationic transfectant. However, the highly efficient transfecting activity of PEI and many of its derivatives is... (Review)
Review
Polyethylenimine (PEI) is a gold standard polycationic transfectant. However, the highly efficient transfecting activity of PEI and many of its derivatives is accompanied by serious cytotoxic complications and safety concerns at innate immune levels, which impedes the development of therapeutic polycationic nucleic acid carriers in general and their clinical applications. In recent years, the dilemma between transfection efficacy and adverse PEI activities has been addressed from in-depth investigations of cellular processes during transfection and elucidation of molecular mechanisms of PEI-mediated toxicity and translation of these integrated events to chemical engineering of novel PEI derivatives with an improved benefit-to-risk ratio. This review addresses these perspectives and discusses molecular events pertaining to dynamic and multifaceted PEI-mediated cytotoxicity, including membrane destabilization, mitochondrial dysfunction, and perturbations of glycolytic flux and redox homeostasis as well as chemical strategies for the generation of better tolerated polycations. We further examine the effect of PEI and its derivatives on complement activation and interaction with Toll-like receptors. These perspectives are intended to lay the foundation for an improved understanding of interlinked mechanisms controlling transfection and toxicity and their translation for improved engineering of polycation-based transfectants.
Topics: Animals; Cell Membrane; Complement Activation; Complement System Proteins; Gene Expression Regulation; Gene Transfer Techniques; Genetic Therapy; Glycolysis; Humans; Mitochondria; Oxidation-Reduction; Polyethyleneimine; Toll-Like Receptors
PubMed: 28274797
DOI: 10.1016/j.ymthe.2017.01.024 -
Endocrinology Aug 2022Immune cells infiltrate adipose tissue as a function of age, sex, and diet, leading to a variety of regulatory processes linked to metabolic disease and dysfunction....
Immune cells infiltrate adipose tissue as a function of age, sex, and diet, leading to a variety of regulatory processes linked to metabolic disease and dysfunction. Cytokines and chemokines produced by resident macrophages, B cells, T cells and eosinophils play major role(s) in fat cell mitochondrial functions modulating pyruvate oxidation, electron transport and oxidative stress, branched chain amino acid metabolism, fatty acid oxidation, and apoptosis. Indeed, cytokine-dependent downregulation of numerous genes affecting mitochondrial metabolism is strongly linked to the development of the metabolic syndrome, whereas the potentiation of mitochondrial metabolism represents a counterregulatory process improving metabolic outcomes. In contrast, inflammatory cytokines activate mitochondrially linked cell death pathways such as apoptosis, pyroptosis, necroptosis, and ferroptosis. As such, the adipocyte mitochondrion represents a major intersection point for immunometabolic regulation of central metabolism.
Topics: Adipocytes; Adipose Tissue; Cytokines; Mitochondria; Oxidative Stress
PubMed: 35752995
DOI: 10.1210/endocr/bqac094 -
Microbiology and Molecular Biology... Sep 2017How mitochondria came to reside within the cytosol of their host has been debated for 50 years. Though current data indicate that the last eukaryote common ancestor... (Review)
Review
How mitochondria came to reside within the cytosol of their host has been debated for 50 years. Though current data indicate that the last eukaryote common ancestor possessed mitochondria and was a complex cell, whether mitochondria or complexity came first in eukaryotic evolution is still discussed. In autogenous models (complexity first), the origin of phagocytosis poses the limiting step at eukaryote origin, with mitochondria coming late as an undigested growth substrate. In symbiosis-based models (mitochondria first), the host was an archaeon, and the origin of mitochondria was the limiting step at eukaryote origin, with mitochondria providing bacterial genes, ATP synthesis on internalized bioenergetic membranes, and mitochondrion-derived vesicles as the seed of the eukaryote endomembrane system. Metagenomic studies are uncovering new host-related archaeal lineages that are reported as complex or phagocytosing, although images of such cells are lacking. Here we review the physiology and components of phagocytosis in eukaryotes, critically inspecting the concept of a phagotrophic host. From ATP supply and demand, a mitochondrion-lacking phagotrophic archaeal fermenter would have to ingest about 34 times its body weight in prokaryotic prey to obtain enough ATP to support one cell division. It would lack chemiosmotic ATP synthesis at the plasma membrane, because phagocytosis and chemiosmosis in the same membrane are incompatible. It would have lived from amino acid fermentations, because prokaryotes are mainly protein. Its ATP yield would have been impaired relative to typical archaeal amino acid fermentations, which involve chemiosmosis. In contrast, phagocytosis would have had great physiological benefit for a mitochondrion-bearing cell.
Topics: Adenosine Triphosphate; Archaea; Biological Evolution; Endocytosis; Energy Metabolism; Eukaryotic Cells; Metagenomics; Mitochondria; Phagocytosis; Phylogeny; Prokaryotic Cells; Symbiosis
PubMed: 28615286
DOI: 10.1128/MMBR.00008-17 -
International Journal of Molecular... Aug 2020Mitochondrial stress is considered as a factor that reprograms the mitochondrial biogenesis and metabolism. As known, SUMOylation occurs through a series of... (Review)
Review
Mitochondrial stress is considered as a factor that reprograms the mitochondrial biogenesis and metabolism. As known, SUMOylation occurs through a series of stress-induced biochemical reactions. During the process of SUMOylation, the small ubiquitin-like modifier (SUMO) and its specific proteases (SENPs) are key signal molecules. Furthermore, they are considered as novel mitochondrial stress sensors that respond to the signals produced by various stresses. The responses are critical for mitochondrial homeostasis. The scope of this review is to provide an overview of the function of SUMOylation in the mitochondrial stress response, to delineate a SUMOylation-involved signal network diagram, and to highlight a number of key questions that remain answered.
Topics: Animals; Caloric Restriction; Humans; Mitochondria; Organelle Biogenesis; Stress, Physiological; Sumoylation; Unfolded Protein Response
PubMed: 32781782
DOI: 10.3390/ijms21165657 -
Cell Reports Dec 2022Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA)...
Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA) numbers and leads to aging-related phenotypes. Here we show that the bZIP (basic leucine zipper) protein ATFS-1, a mediator of the mitochondrial unfolded protein response (UPR), is required to promote growth and establish a functional germline after prolonged starvation. We find that recovery of mtDNA copy numbers and development after starvation requires mitochondrion-localized ATFS-1 but not its nuclear transcription activity. We also find that the insulin-like receptor DAF-2 functions upstream of ATFS-1 to modulate mtDNA content. We show that reducing DAF-2 activity represses ATFS-1 nuclear function while causing an increase in mtDNA content, partly mediated by mitochondrion-localized ATFS-1. Our data indicate the importance of the UPR in recovering mitochondrial mass and suggest that atfs-1-dependent mtDNA replication precedes mitochondrial network expansion after starvation.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Genome, Mitochondrial; DNA, Mitochondrial; Mitochondria; Unfolded Protein Response
PubMed: 36577367
DOI: 10.1016/j.celrep.2022.111875 -
Molecular Biology and Evolution Aug 2015Eukaryotes were born of a chimeric union between two prokaryotes--the progenitors of the mitochondrial and nuclear genomes. Early in eukaryote evolution, most... (Review)
Review
Eukaryotes were born of a chimeric union between two prokaryotes--the progenitors of the mitochondrial and nuclear genomes. Early in eukaryote evolution, most mitochondrial genes were lost or transferred to the nucleus, but a core set of genes that code exclusively for products associated with the electron transport system remained in the mitochondrion. The products of these mitochondrial genes work in intimate association with the products of nuclear genes to enable oxidative phosphorylation and core energy production. The need for coadaptation, the challenge of cotransmission, and the possibility of genomic conflict between mitochondrial and nuclear genes have profound consequences for the ecology and evolution of eukaryotic life. An emerging interdisciplinary field that I call "mitonuclear ecology" is reassessing core concepts in evolutionary ecology including sexual reproduction, two sexes, sexual selection, adaptation, and speciation in light of the interactions of mitochondrial and nuclear genomes.
Topics: Animals; Cell Nucleus; Evolution, Molecular; Genes, Mitochondrial; Genome, Mitochondrial; Humans; Mitochondria
PubMed: 25931514
DOI: 10.1093/molbev/msv104 -
Mitochondrion Mar 2020
Topics: Energy Metabolism; Homeostasis; Humans; Mitochondria; Mitochondrial Diseases
PubMed: 31917323
DOI: 10.1016/j.mito.2019.12.007