-
Seminars in Cell & Developmental Biology Feb 2020Mitochondria are the key energy-producing organelles and cellular source of reactive species. They are responsible for managing cell life and death by a balanced... (Review)
Review
Mitochondria are the key energy-producing organelles and cellular source of reactive species. They are responsible for managing cell life and death by a balanced homeostasis passing through a network of structures, regulated principally via fission and fusion. Herein we discuss about the most advanced findings considering mitochondria as dynamic biophysical systems playing compelling roles in the regulation of energy metabolism in both physiologic and pathologic processes controlling cell death and survival. Precisely, we focus on the mitochondrial commitment to the onset, maintenance and counteraction of apoptosis, autophagy and senescence in the bioenergetic reprogramming of cancer cells. In this context, looking for a pharmacological manipulation of cell death processes as a successful route for future targeted therapies, there is major biotechnological challenge in underlining the location, function and molecular mechanism of mitochondrial proteins. Based on the critical role of mitochondrial functions for cellular health, a better knowledge of the main molecular players in mitochondria disfunction could be decisive for the therapeutical control of degenerative diseases, including cancer.
Topics: Animals; Apoptosis; Autophagy; Cellular Senescence; Humans; Mitochondria
PubMed: 31154010
DOI: 10.1016/j.semcdb.2019.05.022 -
Mitochondrion Sep 2021There is growing scientific interest to develop scalable biological measures that capture mitochondrial (dys)function. Mitochondria have their own genome, the... (Review)
Review
There is growing scientific interest to develop scalable biological measures that capture mitochondrial (dys)function. Mitochondria have their own genome, the mitochondrial DNA (mtDNA). It has been proposed that the number of mtDNA copies per cell (mtDNA copy number; mtDNAcn) reflects mitochondrial health. The common availability of stored DNA material or existing DNA sequencing data, especially from blood and other easy-to-collect samples, has made its quantification a popular approach in clinical and epidemiological studies. However, the interpretation of mtDNAcn is not univocal, and either a reduction or elevation in mtDNAcn can indicate dysfunction. The major determinants of blood-derived mtDNAcn are the heterogeneous cell type composition of leukocytes and platelet abundance, which can change with time of day, aging, and with disease. Hematopoiesis is a likely driver of blood mtDNAcn. Here we discuss the rationale and available methods to quantify mtDNAcn, the influence of blood cell type variations, and consider important gaps in knowledge that need to be resolved to maximize the scientific value around the investigation of blood mtDNAcn.
Topics: DNA Copy Number Variations; DNA, Mitochondrial; Humans; Mitochondria
PubMed: 34157430
DOI: 10.1016/j.mito.2021.06.010 -
Molecular Cell Mar 2023Mitochondria have emerged as signaling organelles with roles beyond their well-established function in generating ATP and metabolites for macromolecule synthesis....
Mitochondria have emerged as signaling organelles with roles beyond their well-established function in generating ATP and metabolites for macromolecule synthesis. Healthy mitochondria integrate various physiologic inputs and communicate signals that control cell function or fate as well as adaptation to stress. Dysregulation of these mitochondrial signaling networks are linked to pathology. Here we outline a few modes of signaling between the mitochondrion and the cytoplasm. To view this SnapShot, open or download the PDF.
Topics: Mitochondria; Signal Transduction; Cytoplasm; Organelles; Acclimatization
PubMed: 36931250
DOI: 10.1016/j.molcel.2023.01.008 -
Biomolecules Dec 2021Hyperbaric oxygen treatment (HBOT)-the administration of 100% oxygen at atmospheric pressure (ATA) greater than 1 ATA-increases the proportion of dissolved oxygen in the... (Review)
Review
Hyperbaric oxygen treatment (HBOT)-the administration of 100% oxygen at atmospheric pressure (ATA) greater than 1 ATA-increases the proportion of dissolved oxygen in the blood five- to twenty-fold. This increase in accessible oxygen places the mitochondrion-the organelle that consumes most of the oxygen that we breathe-at the epicenter of HBOT's effects. As the mitochondrion is also a major site for the production of reactive oxygen species (ROS), it is possible that HBOT will increase also oxidative stress. Depending on the conditions of the HBO treatment (duration, pressure, umber of treatments), short-term treatments have been shown to have deleterious effects on both mitochondrial activity and production of ROS. Long-term treatment, on the other hand, improves mitochondrial activity and leads to a decrease in ROS levels, partially due to the effects of HBOT, which increases antioxidant defense mechanisms. Many diseases and conditions are characterized by mitochondrial dysfunction and imbalance between ROS and antioxidant scavengers, suggesting potential therapeutic intervention for HBOT. In the present review, we will present current views on the effects of HBOT on mitochondrial function and oxidative stress, the interplay between them and the implications for several diseases.
Topics: Humans; Hyperbaric Oxygenation; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Time Factors
PubMed: 34944468
DOI: 10.3390/biom11121827 -
Journal of Enzyme Inhibition and... Dec 2021COVID-19, a pandemic disease caused by a viral infection, is associated with a high mortality rate. Most of the signs and symptoms, e.g. cytokine storm, electrolytes... (Review)
Review
COVID-19, a pandemic disease caused by a viral infection, is associated with a high mortality rate. Most of the signs and symptoms, e.g. cytokine storm, electrolytes imbalances, thromboembolism, etc., are related to mitochondrial dysfunction. Therefore, targeting mitochondrion will represent a more rational treatment of COVID-19. The current work outlines how COVID-19's signs and symptoms are related to the mitochondrion. Proper understanding of the underlying causes might enhance the opportunity to treat COVID-19.
Topics: Antiviral Agents; COVID-19; Humans; Mitochondria; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34107824
DOI: 10.1080/14756366.2021.1937144 -
Mitochondrion Mar 2020This paper is written for non-specialists in mitochondrial biology to provide access to an important area of science that has broad implications for all people. The cell... (Review)
Review
This paper is written for non-specialists in mitochondrial biology to provide access to an important area of science that has broad implications for all people. The cell danger response (CDR) is a universal response to environmental threat or injury. Once triggered, healing cannot be completed until the choreographed stages of the CDR are returned to an updated state of readiness. Although the CDR is a cellular response, it has the power to change human thought and behavior, child development, physical fitness and resilience, fertility, and the susceptibility of entire populations to disease. Mitochondria regulate the CDR by monitoring and responding to the physical, chemical, and microbial conditions within and around the cell. In this way, mitochondria connect cellular health to environmental health. Over 7,000 chemicals are now made or imported to the US for industrial, agricultural, and personal care use in amounts ranging from 25,000 to over 1 million pounds each year, and plastic waste now exceeds 83 billion pounds/year. This chemical load creates a rising tide of manmade pollutants in the oceans, air, water, and food chain. Fewer than 5% of these chemicals have been tested for developmental toxicity. In the 1980s, 5-10% of children lived with a chronic illness. As of 2018, 40% of children, 50% of teens, 60% of adults under age 65, and 90% of adults over 65 live with a chronic illness. Several studies now report the presence of dozens to hundreds of manmade chemicals and pollutants in placenta, umbilical cord blood, and newborn blood spots. New methods in metabolomics and exposomics allow scientists to measure thousands of chemicals in blood, air, water, soil, and the food chain. Systematic measurements of environmental chemicals can now be correlated with annual and regional patterns of childhood illness. These data can be used to prepare a prioritized list of molecules for congressional action, ranked according to their impact on human health.
Topics: Cell Biology; Chronic Disease; Environmental Exposure; Environmental Health; Environmental Pollutants; Humans; Metabolomics; Mitochondria
PubMed: 31877376
DOI: 10.1016/j.mito.2019.12.005 -
MBio Aug 2021Apicomplexan parasites, such as Toxoplasma gondii and Plasmodium falciparum, are the cause of many important human and animal diseases. While T. gondii tachyzoites... (Review)
Review
Apicomplexan parasites, such as Toxoplasma gondii and Plasmodium falciparum, are the cause of many important human and animal diseases. While T. gondii tachyzoites replicate through endodyogeny, during which two daughter cells are formed within the parental cell, P. falciparum replicates through schizogony, where up to 32 parasites are formed in a single infected red blood cell and even thousands of daughter cells during mosquito- or liver-stage development. These processes require a tightly orchestrated division and distribution over the daughter parasites of one-per-cell organelles such as the mitochondrion and apicoplast. Although proper organelle segregation is highly essential, the molecular mechanism and the key proteins involved remain largely unknown. In this review, we describe organelle dynamics during cell division in T. gondii and P. falciparum, summarize the current understanding of the molecular mechanisms underlying organelle fission in these parasites, and introduce candidate fission proteins.
Topics: Animals; Apicoplasts; Erythrocytes; Humans; Mitochondria; Parasites; Plasmodium falciparum; Protozoan Proteins; Toxoplasma
PubMed: 34425697
DOI: 10.1128/mBio.01409-21 -
Nature Reviews. Rheumatology Nov 2022The mitochondrion is an intracellular organelle thought to originate from endosymbiosis between an ancestral eukaryotic cell and an α-proteobacterium. Mitochondria are... (Review)
Review
The mitochondrion is an intracellular organelle thought to originate from endosymbiosis between an ancestral eukaryotic cell and an α-proteobacterium. Mitochondria are the powerhouses of the cell, and can control several important processes within the cell, such as cell death. Conversely, dysregulation of mitochondria possibly contributes to the pathophysiology of several autoimmune diseases. Defects in mitochondria can be caused by mutations in the mitochondrial genome or by chronic exposure to pro-inflammatory cytokines, including type I interferons. Following the release of intact mitochondria or mitochondrial components into the cytosol or the extracellular space, the bacteria-like molecular motifs of mitochondria can elicit pro-inflammatory responses by the innate immune system. Moreover, antibodies can target mitochondria in autoimmune diseases, suggesting an interplay between the adaptive immune system and mitochondria. In this Review, we discuss the roles of mitochondria in rheumatic diseases such as systemic lupus erythematosus, antiphospholipid syndrome and rheumatoid arthritis. An understanding of the different contributions of mitochondria to distinct rheumatic diseases or manifestations could permit the development of novel therapeutic strategies and the use of mitochondria-derived biomarkers to inform pathogenesis.
Topics: Humans; Rheumatic Diseases; Autoimmune Diseases; Mitochondria; Lupus Erythematosus, Systemic; Biomarkers; Cytokines; Interferon Type I
PubMed: 36175664
DOI: 10.1038/s41584-022-00834-z -
Metal Ions in Life Sciences Mar 2020Iron-sulfur clusters are ubiquitous protein cofactors composed of iron and inorganic sulfur. These cofactors are among the most ancient ones and may have contributed to...
Iron-sulfur clusters are ubiquitous protein cofactors composed of iron and inorganic sulfur. These cofactors are among the most ancient ones and may have contributed to the birth of life on Earth. Therefore, they are found even today in many enzymes central to metabolic processes like nitrogen fixation, respiration, and DNA processing and repair. Due to the toxicity associated with iron and sulfur ions, living organisms evolved dedicated machineries to synthetize and then transfer iron-sulfur clusters into client proteins. The iron-sulfur cluster (ISC) machinery is responsible for iron-sulfur cluster biogenesis in prokaryotes and in the mitochondrion of eukaryotes; the sulfur mobilization (SUF) machinery is present in prokaryotes and in the chloroplasts of plants; finally, the cytosolic iron-sulfur assembly (CIA) machinery is only present in the cytoplasm of eukaryotes. Genome analysis allowed the prediction of the proteins containing iron-sulfur clusters across a broad variety of living organisms, establishing links between the size and composition of iron-sulfur proteomes and the types of organisms that encode them. For example, the iron-sulfur proteomes of aerobes are generally smaller than those of anaerobes with similar genome size; furthermore, aerobes are enriched in [2Fe-2S] proteins compared to anaerobes, which predominantly use [4Fe-4S] proteins. This relates to the lower bioavailability of iron and the higher lability of [4Fe-4S] clusters within aerobic environments. Analogous considerations apply to humans, where the occurrence and functions of iron-sulfur proteins depend on the cellular compartment where they are localized. For example, an emerging primary role for nuclear iron-sulfur proteins is in DNA maintenance. Given their key functions in metabolism, dysfunctions of mutations in iron-sulfur proteins, or in proteins participating in iron-sulfur cluster biogenesis, are associated with serious human diseases.
Topics: Humans; Iron; Iron-Sulfur Proteins; Mitochondria; Sulfur
PubMed: 32851828
DOI: 10.1515/9783110589757-013 -
Nature Cell Biology Nov 2023Mitochondrial export into the extracellular space is emerging as a fundamental cellular process implicated in diverse physiological activities. Although a few studies...
Mitochondrial export into the extracellular space is emerging as a fundamental cellular process implicated in diverse physiological activities. Although a few studies have shed light on the process of discarding damaged mitochondria, how mitochondria are exported and the functions of mitochondrial release remain largely unclear. Here we describe mitopherogenesis, a formerly unknown process that specifically secretes mitochondria through a unique extracellular vesicle termed a 'mitopher'. We observed that during sperm development in male Caenorhabditis elegans, healthy mitochondria are exported out of the spermatids through mitopherogenesis and each of the generated mitophers harbours only one mitochondrion. In mitopherogenesis, the plasma membrane first forms mitochondrion-embedding outward buds, which then promptly bud off and thereby result in the generation of mitophers. Mechanistically, extracellular protease signalling in the testis triggers mitopher formation from spermatids, which is partially mediated by the tyrosine kinase SPE-8. Moreover, mitopherogenesis requires normal microfilament dynamics, whereas myosin VI antagonizes mitopher generation. Strikingly, our three-dimensional electron microscopy analyses indicate that mitochondrial quantity requires precise modulation during sperm development, which is critically mediated by mitopherogenesis. Inhibition of mitopherogenesis causes accumulation of mitochondria in sperm, which may lead to sperm motility and fertility defects. Our findings identify mitopherogenesis as a previously undescribed process for mitochondria-specific ectocytosis, which may represent a fundamental branch of mechanisms underlying mitochondrial quantity control to regulate cell functions during development.
Topics: Animals; Male; Semen; Sperm Motility; Spermatozoa; Fertility; Caenorhabditis elegans; Mitochondria
PubMed: 37945830
DOI: 10.1038/s41556-023-01264-z