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Mutations Pervade Mitochondrial DNA

Pathogenic mutations in mitochondrial DNA are common in healthy people, according to a new study.

By | July 7, 2014

ODRA NOELMutations in one or more copies of mitochondrial DNA, known as heteroplasmies, are likely to be much more common in healthy people than previously anticipated. Approximately 90 percent of healthy participants in the 1,000 Genomes Project harbored at least one heteroplasmy, and 20 percent bore mitochondrial genome mutations implicated in diseases, according to the results of a study published today (July 7) in PNAS.

“It’s been known for a long time that lesions in mitochondrial DNA become more prevalent with age,” said metabolic disease specialist Neal Sondheimer of the Children’s Hospital of Philadelphia who was not involved with the work. This study “offers the intriguing possibility that maybe everybody has a little bit of something wrong with their mitochondrial DNA and that might play a role in aging.”

Because a single cell can contain hundreds to thousands of mitochondria, it also carries multiple copies—and, sometimes, variants—of these maternally inherited genomes. Pathogenic mutations can co-exist with healthy mitochondrial DNA (mtDNA) within a cell or group of cells; clinical signs of disease only occur when the frequency of mutations crosses a threshold, which typically ranges from 60 percent to 85 percent of mitochondria.

More than 500 point mutations in mtDNA have been implicated in various diseases so far. Previous studies, which had only examined a control region or subsets of mitochondrial DNA, suggested approximately 25 percent to 65 percent of people harbored heteroplasmy.

The new study, led by Zhenglong Gu of Cornell University, examined nearly 85 percent of the mitochondrial genome in 1,085 healthy participants, drawn from 14 different populations, and detected mutations at frequencies as low as 1 percent. The team identified a total of 4,342 heteroplasmies, 301 of which have been linked to disease. One in five participants carried at least one such pathogenic mutation, according to Gu.

This is the “first study to have used such deep sequencing on so many positions and in this many people, so it’s sort of hit a trifecta,” said Sondheimer.

Severe mtDNA mutations can cause certain myopathies, epilepsy, and other diseases, while less pathogenic variants have been implicated in complex conditions such as type 2 diabetes, aging, and cancer.

Although these results suggest pathogenic mtDNA mutations are more prevalent than previously thought, the low frequency at which they occur is unlikely to have a negative impact on health. However, if the mutations increase in frequency in some fraction of cells as they divide, they could provide a likely source of mitochondrial dysfunction, according to the authors.

“The problem is that mitochondrial DNA isn’t stable, so there’s nothing to say that a 1 percent load of mutation won’t blossom into a different level later,” Sondheimer told The Scientist. Even though a low-frequency mutation “isn’t pathogenic in and of itself, it’s harder to develop a mutation later if you don’t have one, compared to when you start with some level of mutation,” he said. This is especially important when considering the formation of oocytes, which creates a “bottleneck” in which only a few mitochondria from maternal cells are parsed into daughter cells. The process can change the disease-causing potential of a heteroplasmy from one generation to the next, according to Sondheimer.

This difference in mutation frequency between oocytes can mean patients with severe mitochondrial diseases have siblings who carry the disease-causing heteroplasmy, but remain healthy because of its lower frequency. “It is still unknown whether [these] low loads of pathogenic mutations, which are common in siblings, contribute to later-onset phenotypes like neurodegeneration, cancer or aging,” said Sondheimer.

In future studies, Gu and his colleagues plan to study heteroplasmy in single cells and in samples from various tissues, which might have different heteroplasmies than the samples in the 1,000 Genomes Project. “It’s possible that right now our estimates might not reflect the real situation in humans,” Gu told The Scientist

The larger question, according to Gu, is to understand “whether these cells die or [proliferate and] cause degenerative diseases.” Understanding how the frequency of heteroplasmy changes over the course of a person’s life could help manage disease progression or aging, he said.

The mitochondrial genome could be “of ultimate important in aging-related disease,” said Gu. “Hopefully our research will generate more interest.”

K. Ye et al., “Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals,” PNAS, doi:10.1073/pnas.1403521111, 2014. 

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July 8, 2014

Phil. Trans. R. Soc. Lond. B 1988 319, doi: 10.1098/rstb.1988.0040, published 31 May 1988

 

Cell, Vol. 58, 69-76, July 14, 1989, Copyright 0 1989 by Cell Press

See sublimons and cytoplasmic male sterilty in higher plants

Avatar of: barrybarclay

barrybarclay

Posts: 10

July 8, 2014

As a dedicated mitochondriac It is very nice to see some front page attention given to these important organelles. This is a very interesting study. It speaks not only to the near universality of mtDNA polymorphisms in human populations but also to some of the technical challenges faced in testing for those with clinical relevance. I would just add here that our view of mitochondria as simple generators of ATP as energy currency in cells has changed drastically in recent years so we now know that they are centrally important metabolic and bioenergetic regulators. Mitochondria are also very sensitive to environmental insults that cause their dysfunction -like exposure to pesticides heavy metals and the like which are now becoming ubiquitous in water air and food because unlike the nuclear genome mtDNA has limited capacity for repair and lacks protective chromatin found in chromosomes. Such mitochondrial dysregulation plays an important role in tumor formation, disease progression and importantly metastatic potential in many types of cancer. Because such damage is maternally inherited it can be passed from mothers to their children over several generations an important issue in women's health. What I would recommend in any heavily contaminated environment is that both mothers and newborns be screened for mitochondrial DNA damage before such damage manifests clinically commonly after a latency period of months to many years.

Avatar of: Alexandru

Alexandru

Posts: 71

July 8, 2014

"The problem is that mitochondrial DNA isn’t stable..." (Neal Sondheimer)

 

When we talk about inheritance mutation and instable evolution of maternal mitochondria, please take into consideration the paternal mitochondria inheritances, which play a very important invisible role in the maternal mitochondria visible stability or instability.

 

To complete Eve mtDNA theory and rationally understand the magnetic influence in the fertility, the immunity and the cardiac pulls, please carefully read "Mitochondrial Adam DNA data transmissions theory - ISBN 978-606-92107-1-0".

In this theory is described the magnetic influence of "the living soul" and "the life giving spirit" (Paul, 1 Corinthians 15.44-47 and Hebrews 4.12), not seen by the "blind" geneticist (Revelation 3.17)

 

Abstract: Brain and soul storming - The necessary and sufficient processes to a well function of the human body are meticulous arranged by specific organizational cells, so called process bio-managers, using inter-conditioned procedures, transmitted through three ways of communication: chemical or “protein channel”, electrical or “ion channel” and mitochondrial or “Electro Magnetic Field wireless channel”. The third type is out of the visible and measurable spectrum and raises a new challenge to the scientist. For this type of bio communication, we bring a new theoretical hypothesis, based on the managerial multidisciplinary analysis of a cybernetic model proposed by us, by simulating the human body function with the virtual computerized system based on the management of its total knowledge and its perfect quality way of function. The main bricks used for this virtual construction are: the brain, as main bio-processor, and Eve mtDNA and Adam mtDNA, as bio-antennas. We call this assembly of the total knowledge, build with brain reasoning, biological feeling, and unlimited spirit feeling, Main Decision Triangle: reason IQ - feeling EQ - conformance with ecological adaptation CQ. The main principle of the management of the total knowledge imposes us to not neglect the information produced by man during the time, even if it seems creasy at the beginning (see brainstorming definition). Because in the natural fertilisation the spermatozoids are naturally equipped with the paternal mtDNA (it looks like reflex klystron power amplifier, a veritable main bio-GPS), we consider that the paternal mitochondria DNA have a very important role in the evolution of the human being life quality and we have developed a new hypothesis, "Adam mtDNA theory", in addition to "Eve mtDNA theory".

Keywords: brain, mitochondria, maternal, paternal

 

Avatar of: barrybarclay

barrybarclay

Posts: 10

Replied to a comment from Alexandru made on July 8, 2014

July 8, 2014

Total nonsense.

 

Avatar of: James V. Kohl

James V. Kohl

Posts: 194

July 8, 2014

Nutrient-dependent/pheromone-controlled adaptive evolution: a model. "In flies, ecological and social niche construction can be linked to molecular-level cause and effect at the cellular and organismal levels via nutrient-dependent changes in mitochondrial tRNA and a nuclear-encoded tRNA synthetase. The enzyme enables attachment of an appropriate amino acid, which facilitates the reaction required for efficient and accurate protein synthesis (Meiklejohn et al., 2013)."

Amino acid substitutions appear to stabilize the organized genomes of species from microbes to man via conserved molecular mechanisms that we detailed in our 1996 Hormones and Behavior review: From Fertilization to Adult Sexual Behavior. " Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans (Adler and Hajduk, 1994; de Bono, Zarkower, and Hodgkin, 1995; Ge, Zuo, and Manley, 1991; Green, 1991; Parkhurst and Meneely, 1994; Wilkins, 1995; Wolfner, 1988). That similar proteins perform functions in humans suggests the possibility that some human sex differences may arise from alternative splicings of otherwise identical genes."

Apparently, all cell type differentiation is nutrient-dependent and pheromone-controlled via the thermodynamics of intercellular signaling that enables amino acid substitutions to stabilize organism-level thermoregulation. Without the thermodynamics and organism-level thermoregulation, all aspects of protein folding might be linked to mutations and natural selection instead of from quantum physics to chemistry and the quantum biology of experience-dependent de novo olfactory receptor gene creation.

Avatar of: Alexandru

Alexandru

Posts: 71

July 10, 2014

Replied to barrybarclay's comment.

Even you are skeptic I have a genetically certitude that God exist, because only using Adam mtDNA theory I certified genetically the Genesis.

Only in The Bible I found the logical information about where exist the bio-transducers couple of the living soul" and "the life giving spirit": Paul, Hebrews 4.12.

Even you believe or not, the divine mitochondrial couple Adam mtDNA and Eve mtDNA exists only in the xifoid process of the naturally born people, at "the division of the soul and the spirit, of the joints also and the marrow, and is a discerner of the thoughts and intents of the heart."

"Mitochondrial DNA isn’t stable..." (Neal Sondheimer) because this unknown feedback of the invisible wireless communication with the Earth Soul and the Universal Spirit.

The genetically modified people develops a different feedback and wireless data transmission works different because the paternal mitochondria elimination.

Have a nice day!

Avatar of: barrybarclay

barrybarclay

Posts: 10

Replied to a comment from Alexandru made on July 10, 2014

July 10, 2014

You too my friend. Go in peace. You win. I just can't argue with such batshit crazy logic.

 

Avatar of: Alexandru

Alexandru

Posts: 71

July 11, 2014

Replied to barrybarclay's comment.

Maybe my logic appears crazy because I use all the data presented by the humanity as impose the logic analyze of the total knowledge management.

What do you think about the "crazy logic" of thousands of geneticists that eliminate paternal mitochondria during artificial fertilization because they neglect its presence in the sperm of naturally borne boys?

Do you know that the in vitro made boys are infertile because missing of paternal mitochondria in the sperm and they have incurables cardiac maladies?

Ok my friend.

I go in peace waiting for the maternal mitochondria instable feedback.

Avatar of: Roy Niles

Roy Niles

Posts: 63

Replied to a comment from James V. Kohl made on July 8, 2014

July 12, 2014

Total nonsense as well.

Avatar of: Roy Niles

Roy Niles

Posts: 63

Replied to a comment from Alexandru made on July 11, 2014

July 12, 2014

The bible was never meant to be logical, was it?

Avatar of: Alexandru

Alexandru

Posts: 71

July 13, 2014

Thank you to The Scientist that gives us the permissions for a free dialogue!

 

My dear friends put aside the Bible and, please, answer to my logical question on genetic:

Who bring back at the puberty the paternal mitochondria in the sperm of natural borne boy and not in vitro made?

"To be, or not to be: that is the question." (William Shakespeare)

"Some of us think maybe otherwise. Are free to believe. What is beautiful in a democracy (as we hope to become) is that each is free on the beliefs, ideals and his illusions. Not imposed on it by means of a pressure more or less dialectic, but I repeat, no matter what we think, we hope or dream to us." (Against desperation - Mircea Eliade, author of History of Religious Ideas)

 

I am electronically engineer specialized in satellite communication and I never read the Bible before 2006 when my boy, student in medicine, shows me the mitochondria structure because I worked fives years in medical electronically devices.

Than I started my studies in genetics and I observed that the paternal mitochondria are eliminating in the artificial fertilizations.

I elaborate the brochure Adam mtDNA theory and I presented to:

- Science and Theology, 8-12 September 2007, Sibiu, Romania

- First EMBO Conference on Centrosomes and Spindle Pole Bodies, 12-16 September 2008 Heidelberg, Germany

- The 2009 edition of BES meeting hosted by Romanian Society of Pure and Applied Biophysics (RSPAB), 10-14 May 2009 Sibiu, Romania.

- 2010 AAAS Annual Meeting, Bridging Science and Society - 18-22 February 2010 San Diego, USA.

??????????????????????

Because nobody was capable to answer and I am sure that God perfect creates the man, I look in all the world religion books.

In the Voodoo Haitian tradition is presented the soul dualism that is compatible with my theory and in the Bible I found the same soul dualism with a very precise location of the place where exists the booth soul magnetic biosensors.

Because all the geneticists consider that paternal mitochondria is not present in the human body, if they bring another logical demonstration for the presence of the paternal mitochondria in the sperm I put aside my theory and all religions books and I stop my research in Biophysics.

Avatar of: cwldoc

cwldoc

Posts: 1

July 17, 2014

As former vice president Dan Quayle was quoted as saying, when addressing the NAACP, "A mind is a terrible thing to lose."

Avatar of: James V. Kohl

James V. Kohl

Posts: 194

Replied to a comment from Roy Niles made on July 12, 2014

November 15, 2014

Without the thermodynamics and organism-level thermoregulation, all aspects of protein folding might be linked to mutations and natural selection instead of from quantum physics to chemistry and the quantum biology of experience-dependent de novo olfactory receptor gene creation.

The new field of quantum biology applies the craziness of quantum physics to biology's most fundamental processes.

Roy Niles is not very bright, is he? Unfortunately, he attempts to apply what he knows to questions about biology's most fundamental processes.

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