1.2.2. Mitochondrial pathway
The mitochondrial pathway, also called intrinsic pathway, because it is initiated from inside the cell. Various stimuli such as growth factors withdrawal, DNA-damage, hypoxia, and oxidative stress can induce apoptosis through this cascade. These insults cause increasing permeability of the outer mitochondrial membrane and opening of the mitochondrial permeability transition (MPT) pore which is controlled by members of the Bcl-2 family proteins. This large family of proteins is defined by the presence of conserved Bcl-2 homology domains (BH1 to BH4). Up to 30 Bcl-2 family genes have been identified in mammals, which have either pro-apoptotic or anti-apoptotic functions. Some of the anti-apoptotic members include Bcl-2 itself, Bcl-XL, Bcl-w, BAG and Mcl-1 which possess all domains of BH1 to BH4. The pro-apoptotic family proteins can be divided into two subgroups: consists of Bak, Bax, and Bok with possess BH1 to BH3 domains, and Bad, Bid, Bik, BNIP3, Bim, Bmf, Blk, Hrk, Noxa, Puma, and Spike) that only possesses BH3 domain [Cory, 2002; Mund, 2003]. It is believe that BH3-only proteins interfere with the fine-tuned balance of homo- or hetero-oligomerization between pro-apoptotic multidomains (eg., Bax/Bak) and anti-apoptotic members (eg., Bcl-2/Bcl-XL) (Figure 3). In general, oligomers of Bak, Bax, and Bok induce PMT, either by forming channels by themselves or by interacting with components of the PMT [Antonsson, 2000]. Bad can also heterodimerize
Succinate dehydrogenase is an enzyme found in the mitochondrial inner membrane. The enzyme catalyzes the reaction of oxidizing its substrate, succinate, into fumarate via the removal of hydrogen ions from succinate. This oxidation is vital in the Krebs cycle.
Assay of succinate dehydrogenase of after isolation of mitochondria in Cauliflower (Brassica oleracea) using differential centrifugation.
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
Once a upon time, there was a lonely mitochondria named Sophia Mitochondria. Sophia Mitochondria had been alone for a while and she does not know where her parents are. She want to find her parents so she decided to talk someone to help her which is her childhood best friend, David Chloroplast. However, before she called him, she did her normal routine. She took nutrients from one of their cells, breaks it down and turn it into energy. This routine is also known as cellular respiration. After that, she call her David Chloroplast and thirty minutes later, David Chloroplast was in front of her house. David Chloroplast and Sophia Mitochondria came to Bacteria Garden which Sophia Mitochondria’s parents favorite place to go every weekend. When they
Mitochondria are rod-shaped organelles that can be considered the power generators of a cell. They convert oxygen and nutrients into ATP. In turn, ATP powers most of the cell’s chemical reactions that allow the cell to function. Without mitochondria, certain cells would not be able to work and do their job. The cells would not be able to obtain enough energy to survive. A cell’s mitochondria relates to workers because they supply the cell with energy, just like how workers supply their energy to do their job. The mitochondria in a cell are responsible for providing energy so the cell can function, like how workers do certain tasks to keep the business thriving. Mitochondria are found in both plant and animal cells. However, they are found in
The mitochondria has been known as the powerhouse of the cell. What does that even mean? Well, what it means that the mitochondria does all of the cell energy conversion. It takes nutrients from the cell and transforms it into viable ATP. ATP, molecule adenosine triphosphate, is the energy that cells can use. The process in turning nutrients into ATP is called ATP Synthase. The first part of ATP synthase is an ending of cellular respiration. The mitochondria plays a small but large role in the cell. The structure of the mitochondria plays a huge part of cellular respiration. Mitochondrial structure has two membranes an inner and an outer. Inside the inner membrane you have the matrix and the cristae. The first part of cellular respiration is glycolysis, it is made outside of the mitochondria in a gel like fluid called the cytoplasm. Next, is the citric acid cycle, also known as the Krebs cycle, named after the German researcher Hans Krebs, goes in through the outer membrane. Enzyme Acetyl CoA enters and combines the two carbon groups with another four carbon groups. The result is six carbon molecules citrate, which are acidic. The next part in the Krebs cycle is that the hydrogen atoms are stripped and produce NADH molecules. The final Krebs step is; ADP is transferred to ATP the succinate is oxidized forming another four carbon molecule. The two hydrogen carbons react and their electrons transform from FAD to FADH2. The Krebs cycle makes only about 4 ATP and in the
Mitochondrial cytopathy is a genetic heritable disorder [5]. It occurs as a result of DNA mutation in the gem-line cells that can be transmitted to the second generation. This type of genetic disorder is often caused by mutations in the mitochondrial DMA versus the nucleic DNA. The mitochondria DNA is 20-30 times more susceptible to acquire mutations secondary to absence of DNA repair mechanisms in the mitochondria, giving rise to frequent point mutations or deletions in the mtDNA during cell division[1]. Such mutations are inherited exclusively from the maternal mitochondria. The paternal mitochondria do not contribute to the fetal mitochondria [6]. When some of the mitochondria in the ovum have mutations in their DNA, some of those defected mitochondria will go to daughter cells upon division. If the cells receiving the defected mtDNA contribute to forming tissues that are actively dividing after birth, they will be eliminated by the natural selection process after successive cell divisions. In contrast, if the cells inheriting the defected mitochondria developed into organs or tissues of limited dividing ability, this will result in problems related to energy metabolism in that organ [6]. Due to the random nature of the process, defected mitochondria may end up randomly in different types of tissue and at different concentration. This explains the variations in the manifestation, progression, prognosis and severity of the disorder.
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?
IOM, Institute of Medicine, held their first meeting, on January 27, 2015, on the topic of ethical and social policies of genetic modification of eggs and zygotes to prevent transmission of mitochondrial disease (Kahn). Mitochondrial transfer is the process of three parent involvement to prevent a mitochondrial disease from occurring in a child before it is ever born. The FDA had requested this topic to be discussed, becuase this topic has alamrily been on the news and increasing number of people are encouraging to do further research. Due to the government implementation of policies from preventing experimenting on IVT procedures, it has become a barrier for progress. Seeing that Mitochondrial transfers will help humans progress even more,
“The world’s first baby to be born from a new procedure that combines the DNA of three people appears...” The online article “DNA of Three People” discusses a procedure and case study of a mitochondrial transfer in Mexico. A young woman carries the genes for the fatal Leigh syndrome and is unable to have healthy children. After having three miscarriages and losing three children, due to the syndrome, she finally reached out to Dr. John Zhang.
As a apoptosis regulator, Bcl-2 is a family of evolutionarily related proteins. Bcl-2 family proteins, including Bcl-2proper, Bcl-xL, and Bcl-w, have been reported to govern mitochondrial outer membrane permeabilization.
Structurally mitochondria are made up of an outer and inner membrane; which are separated by the intermembrane space. The outer membrane is composed of about a 1:1 ratio by weight of protein to phospholipid lipid, similar to the eukaryotic plasma membrane. The outer membrane contains integral membrane proteins called porins that greatly increase the permeability of the membrane by allowing passage of high molecular weight molecules. The inner membrane is composed of a very high ratio of protein to phospholipid (3:1 by weight), a much higher proportion of protein than found in other eukaryotic membranes. The inner membrane is much less permeable and most molecules require special membrane-spanning transport proteins to enter or exit the matrix
Mitochondria mosaicism: Mitochondria mosaicism occurs when there are distinct genetic populations of mitochondria within a cell. A human cell contains several mitochondria, where each contains several dozen circular mitochondrial chromosomes.[1] Since the rate of mutation of mitochondrial DNA is about tenfold higher than nuclear DNA, a cell can have genetically diverse mitochondria- which is termed heteroplasmy.[1] This can affect biochemical processes if frequency mitochondrial DNA mutations is high which can result in defective oxidative phosphorylation.[1] This is associated with pathogenesis in multiple diseases[1], such as those that are age related and affect tissues that are highly dependent ATP such as retina, brain, cardiac