The mitochondrion is an organelle which originated from the endosymbiosis of eubacteria and, as a result, contains its own genome which encodes for essential mitochondrial transcriptional machinery proteins and subunits of electron transport chain (ETC) complexes [1, 2]. However, the vast majority of mitochondrial proteins are encoded for by the nucleus [3]. As a result, these two organelles must be able to communicate in order to coordinate protein synthesis and maintain mitochondrial homeostasis [4]. This communication is also particularly important in the cells response to stress. Mitochondria are deemed ‘endogenous stress detectors’ as they can sense stresses induced by high reactive oxygen species (ROS) levels and oxidative stress, membrane depolarisation, cellular energy levels, and an accumulation of unfolded proteins [5]. Therefore, in response to stress, this mitochondrial-to-nuclear communication is essential to bring about a change in nuclear gene expression, which will relieve the stress and protect the cell from damage. This commonly occurs through the activation of specific retrograde stress response pathways from mitochondria to the nucleus, which combat the stress and allow mitochondria to regain homeostasis [6, 7].
It is important that we understand these retrograde stress responses, as many of these pathways have been implicated in lifespan regulation in model organisms [8]. For example, dysregulation of two well characterised stress response pathways, the
Mitochondria, dubbed the ‘powerhouse of the cell’, are a type of organelle present in most human cells. Their primary function is to generate Adenosine Triphosphate (ATP), the cell’s principal source of chemical energy. Unlike most other organelles, mitochondria store their own set of genetic material, distinct from the DNA situated in a cell’s nucleus. Although this ‘mitochondrial genome’ represents only 0.1% of a cell’s genetic information, it often plays a significant role in development.
A. SIGNIFICANCE. Our goal is to screen chemical libraries to identify compounds that modulate mitochondrial transport in hippocampal and cortical neurons. This study is significant in four ways: (1) There is an urgent need to develop CNS (Central Nervous System) active drugs. CNS disorders are not only staggeringly complex but are poorly treated diseases (Palmer and Stephenson, 2005). In the United States alone the annual cost for stroke, depression, Schizophrenia and Alzheimer’s disease are currently estimated to be over $250 billion annually (Pangalos et al., 2007). Despite the advances in translational medicine and pharmaceutical research little progress has been made in developing CNS therapeutics. Improving CNS drug discovery efforts is an urgent goal as an estimated 1.5 billion people suffer from CNS-related diseases worldwide. Unfortunately only a handful of new drugs have been brought to the market with very few in the pharmaceutical pipeline (Kissinger, 2011; Schoepp, 2011; Abbot, 2011). The majority of pharmaceutical companies have recently announced a shift from supporting internal drug discovery efforts in favor of academic and government partnerships (Schoepp, 2011). At Scripps Florida we have close interaction of state of the art high throughput small molecule screening and cutting-edge neuroscience research. Thus we are in a unique position to address the challenges in developing CNS therapeutics. (2) Mitochondrial dysfunction is part of the pathophysiology of
Mitochondria are often referred to as the powerhouses of the cells. They generate the energy that our cells need to do their jobs. For example, brain cells need a lot of energy to be able to communicate with each other and also to communicate with parts of the body that may be far away, to do this substances need to be transported along the cells, which needs lots of energy. Muscle fibres also need a lot of energy to help us to move, maintain our posture and lift objects.
Under normal conditions, the mitochondria maintain cytosolic Ca2+ levels, which is necessary for normal cellular function. However, the mitochondrial uptake of excessive levels of Ca2+ can lead to inhibition of ATP synthesis, disruption of mitochondrial membrane potential, increased ROS production, and generation of the mitochondrial permeability transition (mPT) state, which is thought to occur in response to formation of the mPT pore. As a consequence, cellular demise can occur through necrotic-related mechanisms events, including a loss of energy production and oxidative stress as well as apoptotic-related mechanisms, including the mitochondrial release of pro-apoptotic proteins. Given the central role of the mitochondria in cell
Stress plays an important role in our daily life. Many studies have been conducted to study the effects of stress. The “lifespan hormesis effect” explains that moderate amounts of stress is beneficial to the body and in turn allowing the body to cope with higher stress
Meyer et al 2014 In vertebrates the stress response is an evolutionary conservative process mediated by the HPA access and allows organisms to respond rapidly to unpredictable changes in their environment. It is initiated when higher brain centers perceived and endogenous or exogenous noxious stimuli that are in homeostasis and how many it’s release of good corticoids from the adrenal cortex. Elevated levels of circulating clinical records exert a variety of catabolic and Terry productive anti-gross and immunosuppressive effects that mobilize and repartition under detailed organisms restore homeostatic balance. Other than physiological response to short-term stress is adaptive long-term stress occurring over weeks to months may lead to pathological syndrome of distress characterized by amino suppressive decreased reproduction and diminish growth. According Lee measures of population performance such as survival for productive output and abundance may be reduced as a proportion of distress individuals it a population increases. . (MacBeth et al. 2010) The hypothalamus pituitary digital access to respond rapidly and specifically to wide range of environmental and internal demand half deferred to her stress. Is believed to HP a response to stress plays a pivotal role in our in his
1. Dr. Wahls explains at great length the importance of diet to mitochondrial function, but if you had to simplify her message to fit in a single 140 character "tweet", what would you type?
The hub of energy metabolism, the mitochondrion, is found in virtually all eukaryotic cells, with the exception being erythrocytes. The mitochondrion generates cellular energy in the form of adenosine triphosphate (ATP), mostly by means of the oxidative phosphorylation (OXPHOS) system that is located in the inner mitochondrial membrane. The respiratory chain (CI-CIV) and ATP synthase (CV) is collectively known as the OXPHOS system, encoded by both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). The number of mitochondria per cell, ranging from hundreds to thousands, is controlled by the energy requirements of specific tissues with the greatest abundance of mitochondria found in metabolic active tissue (Pieczenik and Neustadt, 2007). Mitochondrial disease is caused when there is a defect in any of the numerous mitochondrial pathways, due to spontaneous or inherited mutations. Respiratory chain deficiencies (RCDs) are the largest subgroup of mitochondrial disease and occur when one of the four respiratory chain complexes become impaired. RCDs are considered to be one of the most common
Each cell contains hundreds to thousands of mitochondria (1), which are located in the fluid that surrounds the nucleus called cytoplasm. Mitochondria are organelles within cells that convert the energy from food into a form that cells can use. Mitochondria produce energy through a process called oxidative phosphorylation which is the final stage of cellular respiration. During oxidative phosphorylation, an electron transport chain works in conjunction with chemiosmosis to create energy molecules named adenosine triphosphate (ATP) using oxygen and simple sugars. In the electron transport chain, an electrochemical gradient is formed by the chemical gradient from the inside to the outside of a mitochondrion counteracting with the electrical gradient from the outside to the inside of the mitochondrion. During chemiosmosis, the energy stored in the gradient is used to make ATP.
Based on the above-mentioned close relationship, a strict communication between mitochondria, chloroplasts and the nucleus is indispensible. Hundreds of genetic diseases in humans and thousands of phenotypic variations in plants and other organisms are known to be the result of alterations affecting nuclear-mitochondrial (NM) communication. These communication mechanisms include both nucleus to organelle (antrograde) and organelle
Many physiological processes in the cells require the participation of both intra- and extra-mitochondrial enzyme reactions. A link between mitochondria and cytosol is provided by a group of proteins known as the mitochondrial carriers (MCs) family (Arco & Satrustegui, 2005; F. Palmieri, 2004). MCs comprise a family of about 40-50 proteins, depending on the organism, and provide the main communication between mitochondrial matrix and extra-mitochondrial spaces by transporting a wide range of metabolites, nucleotides and cofactors.
Mitochondria are a major source of cell superoxide generation that in turn yields a spectrum of secondary reactive species. They serve multiple functions, including regulation of intracellular calcium stores, ATP production, activation of caspases, and regulation of redox signaling. The outer mitochondrial membrane is porous and allows for passage of low molecular substances between the cytosol, the inter-mitochondrial compartment, and the matrix. Mitochondrial dysfunction is characterized by a decreased ATP production, decreased membrane potential, decreased expression of mitochondrial complexes I, III, IV and increased mitochondrial respiration and ROS production, has been observed in the inflamed airways of asthmatic subjects. Excessive
Previously mitochondria were considered to be static and isolated organelles. However, it has now been established that mitochondria form a complex, interconnected, and highly dynamic network. Mitochondria dynamics also involves changes in mitochondrial morphology, number in the cell and movement along the cytoskeleton. Mitochondrial dynamics is said to be tightly regulated by mitochondrial fusion and fission.
The way God created us as humans is a life cycle where eventually late adulthood comes with the biology of aging. Santrock (2013) describes five different theories of why humans age (p. 541). The evolutionary theory explains that aging is more of a natural selection process, and diseases occur in the elderly because they “would have been eliminated” if they were in younger people (Santrock, 2013, p.541). Cellular clock theory describes how cells get tired of dividing after they have been reproducing for so long (Santrock, 2013, p.541). Free-radical theory explains when “cells metabolize energy the by-products include unstable oxygen molecules known as free radicals” (Santrock, 2013, p.541). The unstable oxygen molecules can damage DNA and other structures inside the cell (Santrock, 2013, p.541). Mitochondrial theory describes how aging occurs because of the mitochondria essentially wearing out and becoming less efficient (Santrock, 2013, p.542). Mitochondria are the cell’s “power house,” and they convert energy inside the cell (Bailey, 2008). The last theory, hormonal stress theory, illustrates the effects of stress, especially long term stress, on aging (Santrock, 2013, p.542). Stress released hormones which depress the immune system making people more susceptible to disease (Santrock, 2013, p.542). There are many theories about why human’s age, and all of them may be true, but regardless aging is inevitable and so are its effects.
Chronic cellular stress often leads to cell dysfunction and many mechanisms for how these processes