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Essays in Biochemistry Oct 2016Mitochondria are essential constituents of a eukaryotic cell by supplying ATP and contributing to many mayor metabolic processes. As endosymbiotic organelles, they... (Review)
Review
Mitochondria are essential constituents of a eukaryotic cell by supplying ATP and contributing to many mayor metabolic processes. As endosymbiotic organelles, they represent a cellular subcompartment exhibiting many autonomous functions, most importantly containing a complete endogenous machinery responsible for protein expression, folding and degradation. This article summarizes the biochemical processes and the enzymatic components that are responsible for maintaining mitochondrial protein homoeostasis. As mitochondria lack a large part of the required genetic information, most proteins are synthesized in the cytosol and imported into the organelle. After reaching their destination, polypeptides must fold and assemble into active proteins. Under pathological conditions, mitochondrial proteins become misfolded or damaged and need to be repaired with the help of molecular chaperones or eventually removed by specific proteases. Failure of these protein quality control mechanisms results in loss of mitochondrial function and structural integrity. Recently, novel mechanisms have been identified that support mitochondrial quality on the organellar level. A mitochondrial unfolded protein response allows the adaptation of chaperone and protease activities. Terminally damaged mitochondria may be removed by a variation of autophagy, termed mitophagy. An understanding of the role of protein quality control in mitochondria is highly relevant for many human pathologies, in particular neurodegenerative diseases.
Topics: Animals; Humans; Mitochondria; Mitochondrial Proteins; Protein Aggregates; Protein Biosynthesis; Protein Folding; Proteolysis
PubMed: 27744337
DOI: 10.1042/EBC20160009 -
Apoptosis : An International Journal on... Dec 2016Mitochondria are the cell's power plant that must be in a proper functional state in order to produce the energy necessary for basic cellular functions, such as... (Review)
Review
Mitochondria are the cell's power plant that must be in a proper functional state in order to produce the energy necessary for basic cellular functions, such as proliferation. Mitochondria are 'dynamic' in that they are constantly undergoing fission and fusion to remain in a functional state throughout the cell cycle, as well as during other vital processes such as energy supply, cellular respiration and programmed cell death. The mitochondrial fission/fusion machinery is involved in generating young mitochondria, while eliminating old, damaged and non-repairable ones. As a result, the organelles change in shape, size and number throughout the cell cycle. Such precise and accurate balance is maintained by the cytoskeletal transporting system via microtubules, which deliver the mitochondrion from one location to another. During the gap phases G and G, mitochondria form an interconnected network, whereas in mitosis and S-phase fragmentation of the mitochondrial network will take place. However, such balance is lost during neoplastic transformation and autoimmune disorders. Several proteins, such as Drp1, Fis1, Kif-family proteins, Opa1, Bax and mitofusins change in activity and might link the mitochondrial fission/fusion events with processes such as alteration of mitochondrial membrane potential, apoptosis, necrosis, cell cycle arrest, and malignant growth. All this indicates how vital proper functioning of mitochondria is in maintaining cell integrity and preventing carcinogenesis.
Topics: Animals; Apoptosis; Cell Cycle; Humans; Mitochondria; Mitochondrial Dynamics
PubMed: 27658785
DOI: 10.1007/s10495-016-1295-5 -
International Journal of Molecular... Sep 2021In spite of the continuous improvement in our knowledge of the nature of cancer, the causes of its formation and the development of new treatment methods, our knowledge... (Review)
Review
In spite of the continuous improvement in our knowledge of the nature of cancer, the causes of its formation and the development of new treatment methods, our knowledge is still incomplete. A key issue is the difference in metabolism between normal and cancer cells. The features that distinguish cancer cells from normal cells are the increased proliferation and abnormal differentiation and maturation of these cells, which are due to regulatory changes in the emerging tumour. Normal cells use oxidative phosphorylation (OXPHOS) in the mitochondrion as a major source of energy during division. During OXPHOS, there are 36 ATP molecules produced from one molecule of glucose, in contrast to glycolysis which provides an ATP supply of only two molecules. Although aerobic glucose metabolism is more efficient, metabolism based on intensive glycolysis provides intermediate metabolites necessary for the synthesis of nucleic acids, proteins and lipids, which are in constant high demand due to the intense cell division in cancer. This is the main reason why the cancer cell does not "give up" on glycolysis despite the high demand for energy in the form of ATP. One of the evolving trends in the development of anti-cancer therapies is to exploit differences in the metabolism of normal cells and cancer cells. Currently constructed therapies, based on cell metabolism, focus on the attempt to reprogram the metabolic pathways of the cell in such a manner that it becomes possible to stop unrestrained proliferation.
Topics: Adenosine Triphosphate; Animals; Glucose; Glycolysis; Humans; Mitochondria; Neoplasms; Oxidative Phosphorylation
PubMed: 34502416
DOI: 10.3390/ijms22179507 -
Adipocyte Dec 2019Individual cell types vary enormously in the amount of different organelles they contain. One such organelle is the mitochondrion. Understanding how mitochondrial levels... (Review)
Review
Individual cell types vary enormously in the amount of different organelles they contain. One such organelle is the mitochondrion. Understanding how mitochondrial levels are controlled is essential since so many disease states seem to involve mitochondrial function. The beige adipocyte is an inducible form of adipocyte that emerges in response to cold exposure and some other external stimuli. To perform its thermogenic function, its level of mitochondria increases dramatically. If the stimuli are removed the mitochondrial levels return to base line. Following the withdrawal of external stimuli, beige adipocytes directly acquire a white fat-like phenotype through mitophagy-mediated mitochondrial degradation. The beige cell is therefore a dynamic model for studying the mechanism of mitochondrial biogenesis and degradation.
Topics: Adipocytes; Adipocytes, Beige; Adipose Tissue, Beige; Adipose Tissue, White; Animals; Humans; Mitochondria; Mitophagy; Organelle Biogenesis; Phenotype; Signal Transduction; Thermogenesis; Uncoupling Protein 1
PubMed: 30686106
DOI: 10.1080/21623945.2019.1574194 -
Molecular Medicine Reports May 2019Leucine zipper/EF‑hand‑containing transmembrane protein 1 (LETM1) has been identified as the gene responsible for Wolf‑Hirschhorn syndrome (WHS), which is... (Review)
Review
Leucine zipper/EF‑hand‑containing transmembrane protein 1 (LETM1) has been identified as the gene responsible for Wolf‑Hirschhorn syndrome (WHS), which is characterized by intellectual disability, epilepsy, growth delay and craniofacial dysgenesis. LETM1 is a mitochondrial inner membrane protein that encodes a homolog of the yeast protein Mdm38, which is involved in mitochondrial morphology. In the present review, the importance of LETM1 in WHS and its role within the mitochondrion was explored. LETM1 governs the mitochondrion ion channel and is involved in mitochondrial respiration. Recent studies have reported that LETM1 acts as a mitochondrial Ca2+/H+ antiporter. LETM1 has also been identified as a K+/H+ exchanger, and serves a role in Mg2+ homeostasis. The function of LETM1 in mitochondria regulation is regulated by its binding partners, carboxyl‑terminal modulator protein and mitochondrial ribosomal protein L36. Therefore, we describe the remarkable role of LETM1 in mitochondrial network physiology and its function in mitochondrion‑mediated cell death. In the context of these findings, we suggest that the participation of LETM1 in tumorigenesis through the alteration of cancer metabolism should be investigated. This review provides a comprehensive description of LETM1 function, which is required for mitochondrial homeostasis and cellular viability.
Topics: Animals; Calcium-Binding Proteins; Cell Survival; Cell Transformation, Neoplastic; Energy Metabolism; Homeostasis; Humans; Membrane Proteins; Mitochondria; Structure-Activity Relationship
PubMed: 30896806
DOI: 10.3892/mmr.2019.10041 -
Oxidative Medicine and Cellular... 2016Reactive oxygen species (ROS) play a crucial role in the inflammatory response and cytokine outbreak, such as during virus infections, diabetes, cancer, cardiovascular... (Review)
Review
Reactive oxygen species (ROS) play a crucial role in the inflammatory response and cytokine outbreak, such as during virus infections, diabetes, cancer, cardiovascular diseases, and neurodegenerative diseases. Therefore, antioxidant is an important medicine to ROS-related diseases. For example, ascorbic acid (vitamin C, VC) was suggested as the candidate antioxidant to treat multiple diseases. However, long-term use of high-dose VC causes many side effects. In this review, we compare and analyze all kinds of mitochondrion-permeable antioxidants, including edaravone, idebenone, α-Lipoic acid, carotenoids, vitamin E, and coenzyme Q10, and mitochondria-targeted antioxidants MitoQ and SkQ and propose astaxanthin (a special carotenoid) to be the best antioxidant for ROS-burst-mediated acute diseases, like avian influenza infection and ischemia-reperfusion. Nevertheless, astaxanthins are so unstable that most of them are inactivated after oral administration. Therefore, astaxanthin injection is suggested hypothetically. The drawbacks of the antioxidants are also reviewed, which limit the use of antioxidants as coadjuvants in the treatment of ROS-associated disorders.
Topics: Acute Disease; Administration, Oral; Animals; Antioxidants; Humans; Mitochondria; Reactive Oxygen Species; Respiratory Burst
PubMed: 26649144
DOI: 10.1155/2016/6859523 -
Physiologia Plantarum Jul 2016In this overview of recent trends in plant mitochondrial research, four questions are considered: (1) How large is the mitochondrial proteome? It appears to be in excess... (Review)
Review
In this overview of recent trends in plant mitochondrial research, four questions are considered: (1) How large is the mitochondrial proteome? It appears to be in excess of 1500 proteins in a tissue at any given time. It is proposed that the fusion-fission frequently observed for plant mitochondria provides a vital mixing function ensuring that all low-abundance proteins are present in each mitochondrion at least some of the time. (2) What is the significance of posttranslational modifications (PTM) of proteins? As a result of PTM, many proteins are present in a very large number of slightly different forms. The most well-studied PTMs, such as protein phosphorylation, acetylation and reversible cysteine oxidation, are known to regulate mitochondrial function. Recent studies have provided examples of the importance of this regulation, but it remains a research area with a massive growth potential. (3) What is the role(s) of pentatricopeptide repeat (PPR) proteins in plant mitochondria? There is general agreement that PPR proteins are involved in RNA metabolism such as RNA editing. Recent comprehensive proteomic studies raise the question of how many of the potential 250-300 mitochondrial PPR proteins encoded in the nuclear DNA are required to be present for a mitochondrion to be able to grow and divide. (4) What is the mechanism(s) of retrograde signal transduction from the mitochondria to the nucleus? The nature of the signal transduction molecule is still unknown, but calcium ions, hydrogen peroxide and/or oxidized peptides are potential candidates. Recent results place a receptor for the activation of a group of nuclear genes on the endoplasmic reticulum, possibly close to ER-mitochondrial contact points.
Topics: Mitochondria; Mitochondrial Proteins; Plant Proteins; Plants; Protein Processing, Post-Translational; Proteome; Proteomics; Signal Transduction
PubMed: 27094909
DOI: 10.1111/ppl.12456 -
Mitochondrion Jul 2018Mitophagy is a selective form of autophagy in which damaged or dysfunctional mitochondria are specifically targeted by autophagosomes for lysosomal degradation. Studies... (Review)
Review
Mitophagy is a selective form of autophagy in which damaged or dysfunctional mitochondria are specifically targeted by autophagosomes for lysosomal degradation. Studies have demonstrated that loss of autophagy/mitophagy can lead to a build-up of cytosolic reactive oxygen species and mitochondrial DNA, which can, in turn, activate immune signalling pathways that ultimately lead to the releases of inflammatory cytokines, including IL-1α, IL-1β, IL-18, type I IFN and macrophage migration inhibitory factor (MIF). Moreover, release of these cytokines can subsequently promote the release of others, including IL-23 and IL-17. Thus, as well as being essential for normal cell homeostasis and mitochondrial health, mitophagy may represent an important regulatory mechanism controlling inflammatory responses in immune cells. This review discusses our current understanding of the mechanisms through which mitophagy regulates inflammatory cytokine release.
Topics: Animals; Autophagy; Cytokines; Humans; Inflammasomes; Inflammation Mediators; Metabolic Diseases; Mitochondria
PubMed: 29107116
DOI: 10.1016/j.mito.2017.10.009 -
Mitochondrion Jan 2020The mitochondrion is "jack of many trades and master of one". Despite being a master in energy generation, it plays a significant role in other cellular processes,... (Review)
Review
The mitochondrion is "jack of many trades and master of one". Despite being a master in energy generation, it plays a significant role in other cellular processes, including calcium homeostasis, cell death, and iron metabolism. Since mitochondria employ the majority of cellular iron, it plays a central role in the iron homeostasis. Iron could be a major regulator of mitochondrial dynamics as the excess of iron leads to oxidative stress, which causes a disturbance in mitochondrial dynamics. Remarkably, abnormal iron accumulation has been observed in the brain regions of the neurodegenerative disorders patients. These neurodegenerative disorders are also often associated with the abnormal mitochondrial dynamics. Here in this article, we will mainly discuss the studies focused on unravelling the role of iron in mitochondrial dynamics.
Topics: Animals; Biological Transport; Gene Expression Regulation; Homeostasis; Iron; Mitochondria
PubMed: 31669623
DOI: 10.1016/j.mito.2019.09.007 -
Mitochondrion Sep 2017Many reports have illustrated a tight connection between vision and mitochondrial function. Not only are most mitochondrial diseases associated with some form of vision... (Review)
Review
Many reports have illustrated a tight connection between vision and mitochondrial function. Not only are most mitochondrial diseases associated with some form of vision impairment, many ophthalmological disorders such as glaucoma, age-related macular degeneration and diabetic retinopathy also show signs of mitochondrial dysfunction. Despite a vast amount of evidence, vision loss is still only treated symptomatically, which is only partially a consequence of resistance to acknowledge that mitochondria could be the common denominator and hence a promising therapeutic target. More importantly, clinical support of this concept is only emerging. Moreover, only a few drug candidates and treatment strategies are in development or approved that selectively aim to restore mitochondrial function. This review rationalizes the currently developed therapeutic approaches that target mitochondrial function by discussing their proposed mode(s) of action and provides an overview on their development status with regards to optic neuropathies.
Topics: Humans; Mitochondria; Neuroprotective Agents; Optic Nerve Diseases
PubMed: 27476756
DOI: 10.1016/j.mito.2016.07.013