Tiny Organelles Research Articles

MITOCHONDRIA – AS A TARGET OF ENVIRONMENTAL FACTORS

Mitochondria—tiny organelles in the cell that each possess their own DNA—have come under a growing scientific spotlight. The traditional view of mitochondria as static organelles has been reassessed. Scientists increasingly believe they play a central role in many, if not most, human illnesses. Mitochondria are often target of toxicity of environmental toxicants resulting in multisystem disorders involving different cells, tissues, and organs. The purpose of this review is to discuss the mechanism and consequences of mitochondrial dysfunction caused by environmental factors. Recognition of the key role of mtDNA integrity and mitochondrial function in health has grown greatly in recent years. The environment can influence human health and disease in many harmful ways. One such mechanism for this is through environmental factors increasing oxidative stress in the cell, and this stress can subsequently lead to alterations in DNA molecule. Research shows that mitochondrial DNA is uniquely susceptible to the damaging effects of reactive oxygen species (ROS). These effects are more extensive and longer-lasting in mitochondrial DNA than they are in the nuclear genome. In humans, the most concerning chemicals may be mitochondrial toxins with long half-lives. Examples include lipophilic chemical mixtures such as persistent organic pollutants (POPs) and heavy metals. Other examples of chronic exposure to mitochondrial toxins are air pollution and cigarette smoking. Compared with its nuclear counterpart, mitochondrial DNA generally has less capacity to repair itself. It specifically can’t delete the large DNA helix–distorting adducts formed when mitochondrial DNA bases are damaged by mutagens such as polyaromatic hydrocarbons and ultraviolet radiation. Conclusion - Despite numerous existing researches, the specified question requires further study. it is necessary clearer understanding of what specific environmental factors damage mitochondria and how they do so, this is important way to prevent many diseases induced by mitochondrial dysfunction. Keywords: Mitochondria; Environmental Factors; Mitochondrial dysfunction;

Seriously cilia: A tiny organelle illuminates evolution, disease, and intercellular communication.

The borders between cell and developmental biology, which have always been permeable, have largely dissolved. One manifestation is the blossoming of cilia biology, with cell and developmental approaches (increasingly complemented by human genetics, structural insights, and computational analysis) fruitfully advancing understanding of this fascinating, multifunctional organelle. The last eukaryotic common ancestor probably possessed a motile cilium, providing evolution with ample opportunity to adapt cilia to many jobs. Over the last decades, we have learned how non-motile, primary cilia play important roles in intercellular communication. Reflecting their diverse motility and signaling functions, compromised cilia cause a diverse range of diseases collectively called "ciliopathies." In this review, we highlight how cilia signal, focusing on how second messengers generated in cilia convey distinct information; how cilia are a potential source of signals to other cells; how evolution may have shaped ciliary function; and how cilia research may address thorny outstanding questions.

Skeletal ciliopathy: pathogenesis and related signaling pathways.

Cilia are tiny organelles with conserved structures and components in eukaryotic cells. Ciliopathy is a set of diseases resulting from cilium dysfunction classified into first-order and second-order ciliopathy. With the advancement of clinical diagnosis and radiography, numerous skeletal phenotypes, including polydactyly, short limbs, short ribs, scoliosis, a narrow thorax, and numerous anomalies in bone and cartilage, have been discovered in ciliopathies. Mutation in genes encoding cilia core components or other cilia-related molecules have been found in skeletal ciliopathies. Meanwhile, various signaling pathways associated with cilia and skeleton development have been deemed to be significant for the occurrence and progression of diseases. Herein, we review the structure and key components of the cilium and summarize several skeletal ciliopathies with their presumable pathology. We also emphasize the signaling pathways involved in skeletal ciliopathies, which may assist in developing potential therapies for these diseases.

Bacterial microcompartments

<p indent="0mm">Traditionally, bacteria were considered primitive organisms that lack intracellular organization. However, this knowledge was overturned by studies that showed bacteria have a high level of organization including research on bacterial microcompartments. Microcompartments are self-assembling organelles composed of a protein shell, and internal enzymes encapsulated by the shell. The overall morphology of bacterial microcompartments is similar to viruses. They are polyhedral in shape and about 100 to <sc>200 nm</sc> in size. The common feature of bacterial microcompartments is that they use a protein shell as a diffusion barrier to help channel toxic or volatile pathway intermediates to the next pathway enzyme. Gene clusters of bacterial microcompartments are widespread, and their specific physiological roles are diverse. 68 types were found in the genome of bacteria across 45 phyla. However, the functions of many types of bacterial microcompartments remain unclear, and only several types have been characterized experimentally. One of the best-studied microcompartments is used for 1,2-propanediol catabolism in <italic>Salmonella typhimurium</italic>. Genes encoding enzymes that are responsible for 1,2-propanediol catabolism and shell proteins form a <italic>pdu</italic> operon. Enzymes and shell proteins of <italic>pdu</italic> operon form a Propanediol utilization (Pdu) microcompartment. 1,2-Propanediol is transported into the lumen of the microcompartment, where it is converted to propionaldehyde by propanediol dehydratase. Propionaldehyde is a toxic chemical and high levels of propionaldehyde inhibit the activity of the cell. The shell of the Pdu microcompartment prevents the propionaldehyde transported into the cytoplasm and reduces its toxicity to the cell. Propionaldehyde is converted to propanol, a less toxic chemical, and finally transported into the cytoplasm. The disruption of the Pdu microcompartment increases propionaldehyde levels in the culture broth, and slows the growth of cells. The carboxysome microcompartment is another type of highly investigated microcompartment. It is used to enhance autotrophic CO₂ fixation and is found in nearly all cyanobacteria and some chemoautotrophs. Bicarbonate crosses the protein shell of the carboxysome and enters the lumen, where bicarbonate is converted to CO₂. The protein shell of the carboxysome helps to maintain a high local concentration of CO₂ by inhibiting its outward diffusion. If the shell of the carboxysome is disrupted, cells are unable to grow autotrophically at atmospheric CO₂. levels. Besides these two types of microcompartments, the ethanolamine utilization (Eut) microcompartment, glycyl-radical propanediol (Grp) microcompartment, choline utilization (Cut) microcompartment, <italic>Planctomycete</italic> and <italic>Verrucomicrobia</italic> (PV) microcompartment, taurine metabolism microcompartment, and ethanol utilization (Eut) microcompartment are microcompartments whose specific function is known. Bacterial microcompartments are interesting structures, and they have potential applications in biomedicine and biotechnology. Some heterologous pathways have been encapsulated into microcompartments and shown potential biotechnology advantages. Research on bacterial microcompartments is in its infancy, but these tiny organelles have big potential.

Studying the effects of non-pathogenic mutations of OXPHOS subunits on cellular respiration

Mitochondria are tiny organelles that provide almost all the required energy supply of eukaryotic cells in the form of ATP through a process known as oxidative phosphorylation (OXPHOS). OXPHOS is carried out by five protein complexes (CI-CV) consisting of up to 44 subunits (CI). The majority of the subunits are encoded by nuclear DNA (nDNA), but 13 major subunits are still encoded in mitochondrial DNA (mt-DNA). These two genomes (nDNA and mtDNA) could have different types of genetic variation, which may lead to compatibility problems between the different subunits that need to orchestrate as a unit during the critical steps of oxidative phosphorylation.

MtDNA Haplogroup M5 Associated with Risk of Colorectal Cancer in South India Population

The life on earth is driven by energy, supplied by the tiny organelles of the cell called mitochondria and they are usually stated as the powerhouses of the cell. In population genetics, Mitochondrial DNA (mtDNA) is used extensively to categorize individuals or populations. The mutation sites observed in human mtDNA by comparing with the reference sequence (rCRS) are termed into definite human mtDNA haplogroups. Previous studies showed that mtDNA specific haplogroups and polymorphisms were established to be linked with various human diseases, including cancer in numerous populations. Furthermore, it is also known that several mitochondrial DNA polymorphisms are implicated in enhanced production of Reactive Oxygen Species (ROS) which are known to be an increased risk cause for several cancers, including colorectal cancer in Indian patients. Hence in our study, we made high resolution examination on mtDNA hypervariable region to trace the association of specific mtDNA haplogroup with colorectal cancer in south Indian populations. We report that mtDNA Haplogroup M was observed in 60% of the colorectal cancer patients and around 55% in the studied control samples. Haplogroup M is the most frequent mtDNA cluster found among south Indian populations. We further sub-lineated macro haplogroup M and found sub haplogroups (M8, M7, M6, M5, M3 and M2) in varied frequencies. In particular, we found significant association of haplogroup M5 with colorectal cancer patients (p = 0.026). Haplogroup M5 was observed in 12% of colorectal cancer patients in south Indian patients and in 3.3% of the control populations. These results suggest that individuals with haplogroup M5 may have significant risk to develop colorectal cancer.

Intraflagellar transport

Cells need to be able to sense different types of signals, such as chemical and mechanical stimuli, from the extracellular environment in order to properly function. Most eukaryotic cells sense these signals in part through a specialized hair-like organelle, the cilium, that extends from the cell body as a sort of antenna. The signaling and sensory functions of cilia are fundamental during the early stages of embryonic development, when cilia coordinate the establishment of the internal left-right asymmetry that is typical of the vertebrate body. Later, cilia continue to be required for the correct development and function of specific tissues and organs, such as the brain, heart, kidney, liver, and pancreas. Sensory cilia allow us to sense the environment that surrounds us; for instance, we see as a result of the connecting cilia of photoreceptors in our retina, we smell through the sensory cilia at the tips of our olfactory neurons, and we hear thanks to the kinocilia of our sensory hair cells. Motile cilia, which themselves have sensory functions, also work as propeller-like extensions that allow us to breathe because they keep our lungs clean, to reproduce because they propel sperm cells, and even to properly reason because they contribute to the flow of cerebrospinal fluid in our brain ventricles. Not surprisingly, defects in the assembly and function of these tiny organelles result in devastating pathologies, collectively known as ciliopathies (Box 1). Thus, the proper function of cilia is fundamental for human health.

Live cell imaging of dynamic behaviors of motile cilia and primary cilium.

The cilium is a tiny organelle, with a length of 1-10 μm and a diameter of ~200 nm, that projects from the surface of many cells and functions to generate fluid flow and/or sense extracellular signals from the environment. Abnormalities in cilia may cause a broad spectrum of disease, i.e. the so-called ciliopathies. Multiple imaging approaches have been implemented to understand the structure, motion and function of the tiny cilium. In this review, we focus on the microscopic observations and analyses of the dynamic behaviors of both motile cilia and primary cilium. Motile cilia repeat reciprocal motions at 15-25 Hz with a clear asymmetry of effective and recovery strokes. Observing the fast movement of motile cilia requires a high-speed camera with a frame rate of more than 100 fps. The labeling of cilia tips enables the detailed analysis of the asymmetric beating motion of motile cilia. The primary cilium, which is imagined to be 'static,' is also dynamic, i.e. it elongates, shrinks and disassembles, although this behavior is quite slower than that of motile cilia. The specific fluorescent labeling of primary cilium and time-lapse imaging are required to observe and analyze the slow behaviors of the primary cilium. We present some approaches, including some tips for successful procedures, in the successful imaging of the dynamic behaviors of motile cilia and primary cilium.

2016 Winner: Viswanadh Madugula.

We are pleased to announce that the winner of the 2016 JCS prize is Viswanadh Madugula for his paper entitled ‘The ciliary membrane targeting by a ternary complex comprising transportin 1, Rab8 and the ciliary targeting signal’ (Madugula and Lu, 2016).The prize, $1000, is awarded annually to a junior researcher who is the first author of the paper that is judged by the Editors and Editorial Board to be the best eligible paper published in Journal of Cell Science that year. To be considered for the prize, the first author must be a student or a postdoc of no more than five years’ standing.Viswanadh was born in Kakinada of Andhra Pradesh, India. He obtained his Master of Biotechnology from the Jawaharlal Nehru Technological University (Hyderabad, India), under the guidance of Rajkumar Ratinavelu at the Indian Tobacco Company (ITC), R&D center. For his master study, Viswanadh researched the pollen gene flow in Eucalyptus camaldulensis Dennh by using paternity analysis.In 2011, Viswanadh was awarded a research scholarship from the Nanyang Technological University (Singapore) and joined the School of Biological Sciences. He then became fascinated by the subcellular world and decided to start his PhD in the newly set-up lab of Lei Lu, who studies biogenesis and trafficking of cellular organelles by using multidisciplinary approaches. His supervisor encouraged him to explore new research avenues in the field of membrane trafficking. One of the outstanding questions in cell biology then (and now) is how proteins are targeted to the cilium, a tiny protrusion from the plasma membrane that functions as an environment sensor. Around that time, the laboratories of Kristen Verhey and Benjamin Margolis published articles about the role of transportin 1 in ciliary targeting (Dishinger et al., 2010; Hurd et al., 2011). Despite the fact that this meant a new research direction for the Lu lab, Viswanadh decided to embark on a project, in which to test whether importins provide a generic and unified mechanism for ciliary targeting of membrane cargos.For the next five years, Viswanadh was the only one in Lei Lu's lab, who worked on ciliary trafficking. He had to overcome unknown technical hurdles but, through all the challenges, his fascination with this tiny organelle grew. Although ciliary localization was considered to be a trait of ciliary proteins, one of the most difficult tasks for Viswanadh was to find a plasma membrane protein that was not within or on the cilium. CD8a, for example – which had been commonly used as a negative control for ciliary localization – always displayed a significant presence at the cilium. A puzzling observation, until he concluded that the ciliary membrane diffusion barrier must be leaky. Viswanadh realized that ciliary localization was quantitative instead of simply a ‘yes’ or ‘no’. He, therefore, developed an imaging tool, the cilium-to-plasma-membrane-intensity-ratio (CPIR), that allowed him to quantitatively describe the ciliary localization of ciliary membrane proteins. He demonstrated that importin-binding motifs and -binding domains can promote the ciliary localization of reporters.Viswanadh subsequently asked whether bona fide ciliary membrane residents utilize importins for ciliary targeting. He cloned the best-known ciliary membrane proteins or their ciliary targeting signal and tested each one for possible interactions with importin β1 and transportin 1. Several ciliary membrane proteins were found to interact with transportin 1. Interestingly, Gregory Pazour and colleagues found that the ciliary targeting signal of fibrocystin, which displayed positive interaction with transportin 1 in his screen, specifically binds to Rab8-GDP (Follit et al., 2010). Viswanadh, therefore, expanded his scope of interaction study to include Rab8 and found that transportin 1, Rab8 and the ciliary cargo of fibrocystin assemble as a complex to mediate fibrocystin ciliary translocation. Inspired by the better-known nucleocytoplasmic trafficking mechanism, he proposed a new model, whereby the guanine nucleotide exchange of Rab8 within the cilium provides the retention mechanism for ciliary membrane cargos (Madugula et al., 2016).Viswanadh also developed a single-molecule-based imaging tool to quantify the stoichiometry of the nuclear pore complex (Tie et al., 2016). He was recently awarded his PhD and is currently continuing to work in the same lab as a postdoctoral research fellow, pursuing to study the role of importins and Rabs in ciliary targeting.

Loss of a primary cilium in PDAC

Most cells in the human body possess a primary cilium, which is singularly expressed at the cell surface.1 This tiny organelle serves as a cellular “antenna” for the perception of its surrounding e...

Incredibly close-A newly identified peroxisome-ER contact site in humans.

Peroxisomes are tiny organelles that control important and diverse metabolic processes via their interplay with other organelles, including the endoplasmic reticulum (ER). In this issue, Costello et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201607055) and Hua et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201608128) identify a peroxisome-ER contact site in human cells held together by a tethering complex of VAPA/B (vesicle-associated membrane protein-associated proteins A/B) and ACBD5 (acyl Co-A binding protein 5).

Integrating mitochondriomics in children's environmental health.

The amount of scientific research linking environmental exposures and childhood health outcomes continues to grow; yet few studies have teased out the mechanisms involved in environmentally-induced diseases. Cells can respond to environmental stressors in many ways: inducing oxidative stress/inflammation, changes in energy production and epigenetic alterations. Mitochondria, tiny organelles that each retains their own DNA, are exquisitely sensitive to environmental insults and are thought to be central players in these pathways. While it is intuitive that mitochondria play an important role in disease processes, given that every cell of our body is dependent on energy metabolism, it is less clear how environmental exposures impact mitochondrial mechanisms that may lead to enhanced risk of disease. Many of the effects of the environment are initiated in utero and integrating mitochondriomics into children's environmental health studies is a critical priority. This review will highlight (i) the importance of exploring environmental mitochondriomics in children's environmental health, (ii) why environmental mitochondriomics is well suited to biomarker development in this context, and (iii) how molecular and epigenetic changes in mitochondria and mitochondrial DNA (mtDNA) may reflect exposures linked to childhood health outcomes.

Direct Recording and Molecular Identification of the Calcium Channel of Primary Cilia

Primary cilia are solitary, tiny organelles that project from the membrane of most mammalian cells. Housing components of the cell division apparatus between cell divisions, they also serve as specialized compartments for calcium signaling and Hedgehog signaling pathways. The ionic permeability of the primary cilia membrane, the ionic concentrations within the cilia, and the diffusion barrier created by the cilia neck are unknown. Here, we report the first direct measurements and identification of ion channels from intact primary cilia. We demonstrate that a channel composed of two TRP channel proteins, PKD1-L1 and PKD2-L1. This channel richly populates cilia at a density that rival those of voltage-gated ion channels in nerve and muscle. This heteromeric channel conducts a moderately calcium-selective current that is regulated by second messengers of the Gαq/11 pathway. We developed a transgenic mouse in which only cilia express a fluorophore and employ it to measure currents in the cilia of diverse tissues. In conjunction with cilia-specific ratiometric Ca-sensor, we show that the PKD1-L1/PKD2-L1 heteromeric channel establishes the cilia as a unique calcium compartment within cells that regulates established Hedgehog pathways.

New IVF techniques put mitochondrial diseases in focus

New IVF techniques put mitochondrial diseases in focus

Centrosome Dysfunction and Senescence: Coincidence or Causality?

Centrosomes are the tiny organelles found in most eukaryotic systems. By virtue of their ability to anchor, organize and nucleate microtubules, they play a crucial role in establishing spindle bipolarity and in ensuring the fidelity of cell division. Defects in centrosome structure and function often result in mitotic catastrophe, cell cycle arrest, cell death, genomic instability and/or aneuploidy, leading to human disorders such as primary microcephaly, cancer and ciliopathies. Interestingly, genomic instability and aneuploidy are also hallmarks of aging and cellular senescence, but our understanding of the connection between centrosome dysfunction and senescence remains rudimentary. In this review, we focus on existing evidence suggesting that these two phenomena are indeed related, along with the emerging view that centrosome aberrations represent a form of cellular stress that is necessary and sufficient to trigger a permanent cell cycle arrest and senescence. The molecular mechanisms underlying cellular senescence as a consequence of centrosome aberrations and the involvement of p53 will be discussed.

Centrosome Dysfunction Contributes to Chromosome Instability, Chromoanagenesis, and Genome Reprograming in Cancer

The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker’s precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered. Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegregated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies.

Rational design of organelle compartments in cells

Rational design of organelle compartments in cells

The Ultimate Catch-22: Will Life be the Death of Us?

Whatever it is that you live, eat and breathe, the point is you eat and breathe. Remarkably, these two simple (and occasionally pleasurable) activities are all that’s needed to keep the biology of your body ticking over. By getting oxygen into your lungs and food into your stomach you are providing all the raw materials required for aerobic respiration: the chemical reaction that is constantly firing away in every cell of your body to give you energy. This fantastic life-giving reaction comes courtesy of a tiny organelle in your cells called the mitochondrion. But don’t be fooled by their apparently selfless nature - they might just be the death of you.

Unraveling Environmental Effects on Mitochondria

Look into any cell today, and you’ll see remnants of ancient bacteria by the thousands. These mitochondria—tiny organelles in the cell that each possess their own DNA—have come under a growing scientific spotlight; scientists increasingly believe they play a central role in many, if not most, human illnesses. Exquisitely sensitive to environmental threats, mitochondria convert dietary sugars into a high-energy molecule—adenosine triphosphate (ATP)—that cells use as fuel. And when mitochondria falter, cells lose power, just as a flashlight dims when its batteries weaken. Now scientists are linking environmental interactions with the mitochondria to an array of metabolic and age-related maladies, including cancer, autism, type 2 diabetes, Alzheimer disease, Parkinson disease, and cardiovascular illness.

Interaction proteomics of synapse protein complexes

The brain integrates complex types of information, and executes a wide range of physiological and behavioral processes. Trillions of tiny organelles, the synapses, are central to neuronal communication and information processing in the brain. Synaptic transmission involves an intricate network of synaptic proteins that forms the molecular machinery underlying transmitter release, activation, and modulation of transmitter receptors and signal transduction cascades. These processes are dynamically regulated and underlie neuroplasticity, crucial to learning and memory formation. In recent years, interaction proteomics has increasingly been used to elucidate the constituents of synaptic protein complexes. Unlike classic hypothesis-based assays, interaction proteomics detects both known and novel interactors without bias. In this trend article, we focus on the technical aspects of recent proteomics to identify synapse protein complexes, and the complementary methods used to verify the protein–protein interaction. Moreover, we discuss the experimental feasibility of performing global analysis of the synapse protein interactome.