mitochondria

The Mitochondrial Genome The genome of human mitochondria contains 16,569 base pairs of DNA organized in a closed circle. These encode: 2 ribosomal RNA (rRNA) molecules 22 transfer RNA (tRNA) molecules (shown in the figure as yellow bars; two of them labeled) 13 polypeptides The 13 polypeptides participate in building several protein complexes embedded in the inner mitochondrial membrane. 7 subunits that make up the mitochondrial NADH dehydrogenase 3 subunits of cytochrome c oxidase 2 subunits of ATP synthase cytochrome b All these gene products are used within the mitochondrion, but the mitochondrion also needs proteins encoded by nuclear genes. These proteins (e.g., cytochrome c and the RNA and DNA polymerases used within the mitochondrion) are synthesized in the cytosol and then imported into the mitochondrion.

 "The mitochondria are implicated in a multitude of devastating diseases and disabilities, as well as the very process of aging itself ..." "Whenever a cell dies, a trail of clues leads back to the mitochondria ..." "Mitochondrial diseases are notorious masqueraders, [causing] symptoms that are indistinguishable from those caused by common disorders." -- Guy Brown, PhD The Energy of Life

 "Imagine a major city with half its power plants shut down. Now imagine your body with one-half of its energy shut down. The brain would be impaired, vision would be dim, muscles would twitch spastically or would be too weak to allow your body to walk or write

Causes of Mitochondrial Disease

For most people, mitochondrial disease is inherited. While other possibilities exist (such as mitochondrial toxins), the biggest cause of mitochondrial disease is inheritance. While the DNA of the cell receives one copy from the mother and one copy from the father, all (or nearly all) of the mitochondrial DNA is inherited from the mother. This is due to the sheer size of the egg cell, which is significantly larger than the sperm cell. Furthermore, while a regular cell contains two copies of DNA, mitochondria may hold anywhere from five to ten copies of DNA at one time. If a majority of the DNA is defective, it can quickly become a big problem.

Symptoms of Mitochondrial Disease

poor growth muscle weakness, poor coordination sensory (vision, hearing) problems reduced mental functions disease of the organ (heart, liver) dementia respiratory problems.

 Aspyn Remar Block Nov 14, 2001 - July 15, 2002 Hypertrophic Cardiomyopa thy, Mitochondria l Disease

Kayley McManus 16 March 2000 - 23 September 2000 Kayley was diagnosed with Leigh's disease.

Melissa Hope Baker March 30, 2004 to January 7, 2005 Leigh's Disease

Emma Christiansen June 25, 2003 to September 17, 2003 Mitochondrial Disease, Complex I and IV

 Gabriel Thomas Cowan June 3, 1991 to August 22, 1999 Mitochondrial Myopothy, Lactic Acidosis, Stroke Like Episodes, Deficencies I, II, and IV

Rachel Cowan April 19, 1994 to May 24, 2004 Complex Deficiencies .................................

Lochie Jacob Georg-Dent 20 July 2000 - 20 July 2001 Cardiomyopathy & unconfirmed mitochondrial disorder

 Samya Haddad March 17, 1994 to December 10, 2002 Mitochondrial Disease

 Amanda Lauren Owenby December 18, 2000 - December 28, 2003 Mitochondrial Disorder and Complex IV

Connor Trey Sands Irwin June 14th, 2004 - October 6th, 2004 Cox IV (Cytochrome C Oxidaise)

 HunterLynn Schaller December 27, 2003 to March 31, 2004 Leigh's Disease

Kurt William Smith May 1, 1996 to September 14, 1996 Leigh's Disease

 Olivia Lauren Steele May 10, 2000 to November 14, 2000 Mitochondria l Disease

Kaitlin Marie Vasilich September 25, 1986 - February 8 , 2004 Diagnoses: MNGIE

 Lyndsie Wood Born: August 6, 2000 Angel Date: August 11, 2000 Diagnosis: Mitochondrial Disease with partial Defect in electron transport chain complex III and Congenital Heart Disease

 Ty is 31/2 years old and is not able to sit up, speak, or eat table food. He will never be able to walk, talk, or play with his older brother. Ty has a mitochondrial disease called Leighs Disease. It is a degeneration of the central nervous system due to defects in the mitochondria. Patches of brain damage continue to occur as nerve cells die. The prognosis of Leighs Disease is very poor and there is no treatment. Occasionally, patients may live to be 6 or 7 years old.

Rheana was born on May 5, 2002. She came into the world a very sick little baby. As young as two weeks old the doctors new that something was wrong. Mitochondrial disease was suspected. The confirmation came when Rheana was fourteen months old. She was a "newborn" for over a year and she was so "sick". Rheana's struggles and diagnosis are: seizures, chronic lactic acidosis, chronic vomiting, dysmotility, hypoglycemia, failure to thrive, lesion on her brain, g-tube, J-tube (surgically placed as well), central line, chronic sepsis, blood transfusions, anemia, needs a special chair for ambulatory assistance, muscle pain, nuerogenic bladder, dysautonomia, weakness, sever teeth problems, poor growth with short stature. Rheana is a smart wonderful little princess with such a strong will to live. Rheana has recently had her TPN (Total Parenteral Nutrition) removed! She no longer receives tube feeds 20 hours a day. Keep Rheana in your prayers.

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Depending on which cells of the body are affected, symptoms might include: Poor growth Loss of muscle coordination, muscle weakness Visual and/or hearing problems Developmental delays, learning disabilities Mental retardation Heart, liver, or kidney disease Gastrointestinal disorders, severe constipation Respiratory disorders Diabetes Increased risk of infection Neurological problems, seizures Thyroid dysfunction Dementia (mental disorder characterized by confusion, disorientation, and memory loss)

How are mitochondrial diseases treated? There are no cures for mitochondrial diseases, but treatment can help reduce symptoms, or delay or prevent the progression of the disease. Treatment is individualized for each patient, as doctors specializing in metabolic diseases have found that every child and adult is "biochemically different." That means that no two people will respond to a particular treatment in a specific way, even if they have the same disease.

The Mammalian Mitochondrial Genome. The genome encodes 22 transfer RNAs (single letter code), 2 ribosomal RNAs (16S and 12S rRNA) and 13 proteins.

Mitochondrial Disease in Children

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Kumar M, Verma R, Raghava GPS. (2005) Prediction of mitochondrial proteins using support vector machine and hidden Markov model. J Biol Chem. 281:5357-63.

Mitochondrial oxidative phosphorylation provides the majority of the cells ATP. ATP in turn provides the energy required to synthesize and maintain cells and the organisms they comprise. Mitochondria also produce highly reactive forms of oxygen that are toxic to the cell, as well as to the mitochondria themselves. These reactive oxygen species (ROS) and the damage they cause are believed to underly the cellular dysfunction associated with aging and some disease pathologies.

Figure 1. Ligation of the CTL TCR by antigen induces the activation of signaling cascades that result in the polarization of the Golgi and MTOC, and the docking and release of lytic granules. Surrounded by adhesion molecules that include aL2/LFA-1 and ICAM-1 are separate signaling and secretory domains.

Granzyme A targets components of the SET complex, releasing NM23-H1 to elicit singlestranded DNA nicks. Other Granzyme A substrates include core and H1 histones and the nuclear Lamins A through C.

Granzyme B entry into the cytosol unleashes a cascade of events contributing to apoptosis. Substrates include Bcl-2 family members Mcl-1 and BID, leading to the downstream release of Cytochrome c from the mitochondria and formation of the apoptosome. Also released from the mitochondria are the IAP suppressors SMAC/Diablo and HTRA2/Omi, and mediators of chromatin condensation and DNA fragmentation, AIF and Endo G. Granzyme B may also directly target Lamin B, Procaspase-3, Procaspase-8, and ICAD. The endogenous Serpin PI9 (mouse SPI6), and several viral proteins (US3, L4-100kDa, CrmA) are known to suppress Granzyme B activity.

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Diagram of a typical animal cell. Organelles are labeled as follows: 1) Nucleolus, 2) Nucleus 3) Ribosome 4) Vesicle 5) Rough endoplasmic reticulum 6)Golgi apparatus 7) Cytoskeleton 8) Smooth endoplasmic reticulum 9) Mitochondrion 10) Vacuole 11) Cytoplasm 12) Lysosome 13) Centriole. Image by Magnus Manske (http://www.argusbio.com/images/mitohondria.jpg )

Mitochondrial Eve All of the mitochondrial haplogroups coalesce into a single founder genome at a time about 160,000 years ago.

Mitochondrial DNA is inherited only from the mother: the fertilized egg destroys the mitochondria of the sperm. Because of this selective matrilineal transmission, mitochondrial DNA sequences can be used to by population geneticists and evolutionary biologists to shed light on the unbroken genetic line connecting us to our maternal ancestors.

Electron Micrograph of Mitochondria Cellular organelles; mitochondria, glycogen, rough endoplasmic reticulum with ribosomes on surface (liver cell).

Magnification:-- x11,160

Cells with a high metabolic rate (heart muscle cells) may contain many thousands of mitochondria. Some cells may contain only dozens.

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mitochondria

Mitochondrial dawn Mitochondria around the nucleus of an ovum There are many mitochondria in an ovum, around 100,000. Many but not messy: they arrange themselves in packed circles around the large nucleus. There they lie in their serried rows, whispering to the nucleus in a language as yet unknown. Once fertilization occurs they will spring into action: some will divide, some will lie dormant, for the coming generation.

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Mitochondria may also be called the "powerhouse" of the cell. It creates most of the energy that is needed to do everything. Mitochondrias burn the fuel (food) that gives the cell energy. Mitochondrias are in both plant and Animal Cells you can see what they look like in the picture below.

This is a cluster of 14 mitochondria (yellow) in the vicinity of a multilayered stack of endoplasmic reticulum (blue-green). The close proximity between mitochondrial and ER membranes may be important for regulation of cellular Ca++ levels.

The role of mitochondria in the induction of apoptosis is summarised in the figure below.

http://www.scripps.edu/mem/biochem/ayagi/images/twomitos.gif

Three-dimensional model was reconstructed by electron tomography. The outer membrane and cristae are shown in purple and yellow, respectively.

SDSU Heart Institute Gets $9.5 Million Grant (Aug. 14, 2006) Mark Sussman sees mitochondria, the energy center for cells, as the potential key for reducing heart attack damage. Also, SDSU researchers mimic cardiac cell defenses for developing treatments to reduce damage from heart attacks.

Transcription of all genes starts with the binding of the enzyme RNA polymerase (RNAP), a DNA-binding protein, to a specific DNA binding site immediately upstream of the genes, the promoter. From this position RNAP proceeds to transcribe all three genes (lacZYA) into mRNA.

The lac operon consists of three structural genes, a promoter, a terminator, and an operator. The three structural genes are:: lacZ, lacY, and lacA. lacZ encodes -galactosidase (LacZ), an intracellular enzyme that cleaves the disaccharide lactose into glucose and galactose. lacY encodes -galactoside permease (LacY), a membrane bound transport protein that pumps lactose into the cell. lacA encodes -galactoside transacetylase (LacA), an enzyme that transfers an acetyl group from acetyl-CoA to -galactosides. Only lacZ and lacY appear to be necessary for lactose catabolism.

The regulatory response to lactose requires an intracellular regulatory protein called the lactose repressor. The lacI gene encoding repressor lies nearby the lac operon and is always expressed (constitutive). If lactose is missing from the growth medium, the repressor binds very tightly to a short DNA sequence just downstream of the promoter near the beginning of lacZ called the lac operator. Repressor bound to the operator interferes with binding of RNAP to the promoter, and therefore mRNA encoding LacZ and LacY is only made at very low levels. When cells are grown in the presence of lactose, a lactose metabolite called allolactose binds to the repressor, causing a change in its shape. Thus altered, the repressor is unable to bind to the operator, allowing RNAP to transcribe the lac genes and thereby leading to high levels of the encoded proteins.

The genome of human mitochondria contains 16,569 base pairs of DNA organized in a closed circle

The genome of the chloroplasts found in Marchantia polymorpha (a liverwort, one of the Bryophyta) contains 121,024 base pairs in a closed circle. These make up some 128 genes

The Chloroplast Genome The genome of the chloroplasts found in Marchantia polymorpha contains 121,024 base pairs in a closed circle. These make up some 128 genes which include: duplicate genes encoding each of the four subunits (23S, 16S, 4.5S, and 5S) of the ribosomal RNA (rRNA) used by the chloroplast 37 genes encoding all the transfer RNA (tRNA) molecules used for translation within the chloroplast. Some of these are represented in the figure by black bars (a few of which are labeled). 4 genes encoding some of the subunits of the RNA polymerase used for transcription within the chloroplast (3 of them shown in blue) a gene encoding the large subunit of the enzyme RUBISCO (ribulose bisphosphate carboxylase oxygenase) 9 genes for components of photosystems I and II 6 genes encoding parts of the chloroplast ATP synthase genes for 19 of the ~60 proteins used to construct the chloroplast ribosome All these gene products are used within the chloroplast, but all the chloroplast structures also depend on proteins encoded by nuclear genes translated in the cytosol, and imported into the chloroplast. RUBISCO, for example, the enzyme that adds CO2 to ribulose bisphosphate to start the Calvin cycle, consists of multiple copies of two subunits: a large one encoded in the chloroplast genome and synthesized within the chloroplast, and a small subunit encoded in the nuclear genome and synthesized by ribosomes in the cytosol. The small subunit must then be imported into the chloroplast.

Three-Dimensional Model of a Fully Segmented Mitochondrion

 0,5 . Tomogram . cristae , , endoplasmic reticulum . cristal . cristal 30 nm crista.

Chemically Fixed Brown Fat Mitochondrion Reconstructed by Electron Tomography

The outer and inner membranes were segmented and surface-rendered.

Cryofixed Brown Fat Mitochondrion Reconstructed by Electron Tomography

Vesicular Mitochondria have unergone a transformation from the normal morphology with an inner boundary membrane connected to lamellar cristae via crista junctions into a form with multiple vesicular matrix compartments. This facilitates membrane fission or fragmentation as the matrix is fragmented at this stage, so fragmentation of the mitochondrion requires only outer membrane fission. Vesicular mitochondria begin to appear during the release of cytochrome c initiating apoptosis.

Normal mitochondria contain and inner membrane with two topologically distinct components. The inner boundary membrane (rendered in white/gray) lies closely apposed to the outer membrane (rendered in translucent blue) and is connected to the lamellar cristae (rendered in various colors) through circular crista junctions of relatively uniform size. Most of the cytochrome c in mitochondria is found in the intracristal compartments which communicate with the intermembrane space between the outer membrane and the inner boundary membrane via the crista junctions.

Swollen Mitochondria represent the last stage of mitochondrial structural transformation, and in examples such as this one the matrix has swollen to an extent that the outer membrane (rendered in translucent blue) has ruptured.

Vesicular/Swollen Mitochondria are found after the loss inner mitochondrial membrane potential, which follows release of cytochrome c.

Normal/Vesicular mitochondria are in the process of a dramatic transformation from normal morphology with an inner boundary membrane closely apposed to the outer membrane connected to lamellar crista compartments via circular crista junctions. In this example the normal morphology with cristae rendered in green and surrounded by an inner boundary membrane rendered in white/gray appears at one end, while at the other end the inner membrane has transformed into numerous vesicular matrix compartments. Mitochondria in this class begin to appear during the release of cytochrome c from mitochondria initiating apoptosis.