Tag Archives: mitochondria

What is cellular respiration: from food to ATP

When we breathe, gases are exchanged between blood and tissues. This is known as internal respiration. However, individual cells have their own respiration, known as cellular respiration — the oxidative metabolism of glucose inside the cell’s mitochondria (in the case of eukaryotic cells).

Cellular respiration is critical to any living organism since it is this process that essentially turns food into energy that the body needs to survive.

Thanks to cellular respiration, cells convert the energy stored in glucose and other nutrients into a more usable form, known as adenosine triphosphate (ATP).

Every time you twitch a muscle, breathe, replicate your DNA, or think, you’re using ATP to do all of this work.

However, the process of converting sugar into ATP isn’t as straightforward as it sounds and involves quite a number of steps and complex organic chemistry.

If you ever wondered how a hamburger is turned into energy to power the 75 trillion cells inside the human body, here’s how it all works.

The stages of cellular respiration

During cellular respiration, several oxidation-reduction (redox) reactions transfer electrons from organic molecules to other molecules, eventually converting glucose (life’s basic nutrient) into ATP, the energy currency employed by biological processes. Oxidation refers to electron loss and reduction to electron gain.

Although cellular respiration involves many chemical reactions, the process can be summed up with the following simplified reaction:

C6H12O6 + 6O2 → 6CO2 + 6H2O + Chemical Energy (ATP)

The above chemical reaction tells us that glucose (sugar) is burned (oxidized) by reacting with a lot of oxygen to form water and carbon dioxide, as byproducts, along with ATP. Both sugar and oxygen are delivered to cells through the bloodstream.

The process can be broken down into four steps of cellular respiration.

  1. Glycolysis. This is the first phase of the carbohydrate catabolism, meaning the breaking down of a larger molecule into smaller ones. During glycolysis, sugar is broken down in a cascade of chemical reactions into two molecules pyruvate and two molecules of ATP. Much more ATP, however, is produced later in the cellular respiration cycle. The pyruvate is shuttled into the mitochondria — tubular-shaped organelles that are found in the cytoplasm of every eukaryotic cell — where it is converted into Acetyl coenzyme A (CoA) for further breakdown.
  2. The Tricarboxylic acid cycle. Also known as the TCA cycle, the Krebs cycle, and the citric acid cycle, this stage takes place in the matrix of the mitochondria where all the hydrogen molecules are stripped off the Acetyl CoA to extract electrons required for making ATP. The reaction extracts electrons, releasing CO2 and H2O as waste. Only four ATP molecules are produced, along with a lot of NADH (a crucial coenzyme in making ATP). NADH, along with another molecule called flavin adenine dinucleotide (FADH2) will ultimately transport the electrons to the inner membrane of the mitochondria.
  3. The electron transport chain. The final process of cellular respiration takes place in the cristae of the mitochondria. Electrons carried by NADH and FADH2 are passed along a series of enzymes (the chain), releasing energy that expels protons. The resulting proton gradient enables the synthesis of roughly 32 ATP molecules for every molecule of glucose. Now we’re talking!

Did you count all the ATP molecules? That’s around 38 ATPs for every glucose.

Cellular respiration doesn’t necessarily require sugar. When the body runs out of glucose, it can burn fats and proteins to make ATP instead. This is what actually happens when people are on low-carb diets such as Atkins or Keto.

Anaerobic respiration

What happens if there is no oxygen? Well, humans die, but there are certain bacteria and fungi that can generate ATP in environments with very low levels of oxygen or even none to speak of.

This happens through anaerobic respiration, a process that only goes as far as glycolysis. As such, anaerobic respiration, also known as fermentation, is highly inefficient since it generates only two molecules of ATP.

Cells in the human body can also undergo anaerobic respiration when there is suboptimal O2 intake, such as when you’re working out heavily. This results in the production of lactic acid, which causes muscles to become more acidic. This is why you feel sore and in pain after intense physical exercise.

Bottom line: When the term ‘respiration’ comes to mind, we tend to associate it with breathing and the lungs — but this is only where the process starts. The lungs pull in the oxygen that the mitochondria need to burn sugar and then release the CO2 generated as a byproduct of breaking down the sugar. Though you breathe in through your lungs, the harder work, what keeps your body going, is happening at the cellular level.

Mitochondria and Tesla battery packs work pretty much the same way, study reports

Mitochondria are built up of many individual bioelectric units that generate energy as an array — pretty much like a Tesla electric car battery.

Mitochondria (red) are organelles found in most cells. They generate a cell’s chemical energy. Image credits NICHD / U. Manor via NICHD / Flickr.

The prevailing theory up to now was that mitochondria, the organelles that produce energy for living cells, worked like one of the batteries in your remote: though a chemical reaction inside a single chamber or battery cell.

However, a new study from the University of California, Los Angeles (ULCA) finds that this isn’t the case. Mitochondria, they explain, work like arrays, with many, many battery cells that work to manage energy safely and provide fast access to high-intensity current.

Team effort

“Nobody had looked at this before because we were so locked into this way of thinking; the assumption was that one mitochondrion meant one battery,” said Dr. Orian Shirihai, a professor of medicine in endocrinology and pharmacology at the David Geffen School of Medicine at UCLA and senior author of the study.

All cells in our bodies, with the exception of red blood cells, contain one or more mitochondria — sometimes up to several thousands of them. These organelles (cellular organs) are covered in a smooth outer membrane and boast a wrinkled, inner membrane. The folds of this inner membrane (called ‘cristae’) extend all the way to the center of the organelle.

Up to now, it was assumed that the role of this wrinkly texture on the inner membrane was simply to increase the surface area and thus help increase the energy output.

However, the world works in mysterious ways; California has taken a leading role in renewable energy and e-vehicles, and that decision made the current study possible.

“Electric vehicle engineers told me about advantages of having many small battery cells instead of one large one; if something happens to one cell, the system can keep working, and multiple small batteries can provide a very high current when you need it,” Shirihai said.

Tesla vehicles are some of the best-known e-vehicles right now, so let’s take that as an example. Tesla battery packs are an array of 5,000 to 7,000 small battery cells (depending on the exact model). These batteries, while individually small, work in tandem to allow vehicles to charge rapidly, cool down more effectively, and to provide large amounts of power quickly when needed (such as when accelerating).

Using conventional microscopy, Shirihai observed that cells can function well with a small number of very long mitochondria, which didn’t fit in with what the engineers were telling him. So, instead, he started looking for the array inside individual mitochondria. Together with his colleagues, he developed a technique to map the voltage on the membrane of mitochondria in living cells with much better accuracy than ever before. Dane Wolf (first author) and Mayuko Segawa (second author), two UCLA students, optimized a form of high-resolution microscopy to peer into the interior of mitochondria and watch energy production and voltage distribution inside the organelle.

“What the images told us was that each of these cristae is electrically independent, functioning as an autonomous battery,” Shirihai said. “One cristae can get damaged and stop functioning while the others maintain their membrane potential.”

The inner membrane of the mitochondria loops back outward between each cristae, the team reports, and clusters of proteins form in this area and determine the boundaries of individual cristae. Previous research has shown that without these proteins, the mitochondria are more susceptible to damage, but not why; Shirihai’s study found why.

These proteins, the study explains, act as insulators between cristae. In effect, they turn a huge battery into a collection of smaller ones. If these proteins disappear, the mitochondria stop acting like battery arrays.

“The battery experts I had originally talked to were very excited to hear that they were right,” Shirihai said. “It turns out that mitochondria and Teslas, with their many small batteries, are a case of convergent evolution.”

The findings may help broaden our understanding of mitochondria, the roles they play in cells and in aging, and even shed light on new treatments for diseases and medical complications that involve disturbances in mitochondria or cristae structure.

The paper “Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent” has been published in The EMBO Journal.

Researchers find out how cells heat themselves

While we knew that mitochondria somehow generate heat, we didn’t exactly understand how. Researchers at the University of Illinois used a tiny thermometer to find out.

The team reports that mitochondria release heat in quick, powerful bursts using energy stored in internal proton batteries. The findings were made possible through the new tool the researchers built, as previous methods were too slow to pick up on the heat spikes.

a) False-color electron microscope image of the probe, scale bar 100 μm. c) A schematic of the experiment. d) Image of the probe in action, scale bar 100 μm.
Image credits Manjunath C. Rajagopal et al., 2019, Communications Biology.

“Producing heat is part of the mitochondria’s role in the center of metabolism activity,” said mechanical science and engineering professor Sanjiv Sinha. “It needs to produce the energy currency that’s used for the activities in the cell, and heat is one of the byproducts.”

Mitochondria also have a mechanism in place to increase heat output if needed, such as when the body’s overall temperature goes down. In order to get a better understanding of how this heat is generated, the team developed a fast-read thermometer probe measure the internal temperature of living cells. Tab of Rhanor Gillette, professor emeritus of molecular and integrative physiology at Illinois, helped test the probe in a mitochondria-rich strain of neurons.

The team then made the cells produce heat. They recorded very fast changes in temperature inside the neurons, “results that were completely different from what has been published before” according to first author Manjunath Rajagopal.

“We saw a sharp temperature spike that is significantly large and short-lived — around 5 degrees Celsius and less than one second,” he explains.

“The gold standard for measuring has been with fluorescence, but it is too slow to see this short, high burst of heat.”

The findings conflict with previous assumptions that mitochondria break down glucose to generate heat: the temperature spikes, Sinha says, are too large. In order to find the source of energy, the team turned to the mitochondria, and chemically induced them to open up protein channels on their membrane.

“In the mitochondria, one part of the glucose metabolism reaction stores some of the energy as a proton battery. It pushes all the protons to one side of a membrane, which creates an energy store,” Rajagopal said.

“We basically short-circuited the stored energy.”

In the future, the team wants to use their probe on other types of cells. One of their primary focus will be identifying therapeutic targets, they add. Better control over this energy sink could have applications against obesity and cancer.

The paper “Transient heat release during induced mitochondrial proton uncoupling” has been published in the journal Communications Biology.

Mitochondrial DNA can sometimes come from fathers, too

Credit: Pixabay.

In groundbreaking research set to rewrite textbooks, scientists have found evidence of paternal inheritance of mitochondrial DNA. Until recently, mitochondrial DNA was thought to be inherited solely from the mother’s side.

“This paper profoundly alters a widespread belief about mitochondrial inheritance and potentially opens a novel field in mitochondrial medicine,” the authors wrote.

Living things are made up of millions of tiny units of life called cells which are composed of extremely small functional parts called organelles. A mitochondrion is a cell organelle that has an extremely important role in the proper functioning of the cell.  Also known as the ‘powerhouse of the cell’, mitochondria are responsible for producing chemical energy called ATP (adenosine triphosphate), which is necessary for all biological processes within the body to occur.

Most of our DNA is stored in the cell’s nucleus, but some of it is also stored in the mitochondria, i.e. mitochondrial DNA (mtDNA). While in some species (i.e. flies and lice), mtDNA can also be inherited from the father, in humans, this was known to exclusively come from the mother. Nuclear DNA, on the other hand, is inherited equally from both parents; a child will inherit 50% of their nuclear DNA from the mother and the other 50% from their father.

But this common knowledge has been turned on its head by a new study led by geneticist Taosheng Huang from the Cincinnati Children’s Hospital Medical Centre. The study was spurred by the case of a four-year-old boy, who showed signs of a mitochondrial disorder. When Huang and colleagues tested the boy, they were shocked to find that his mitochondrial DNA also seemed to contain paternal contributions. Of course, that should have been impossible but subsequent tests returned the same results. When the boy’s sister and mother showed evidence of the same heteroplasmy (the co-existence of multiple mitochondrial DNA variants in a single source), Huang knew he was on to something.

When the researchers sequenced the mtDNA of the mother’s parents, they found that the mtDNA had a 60/40 inheritance from her mother and father, respectively. Overall, the researchers identified three unrelated multi-generation families (17 individuals) with mtDNA heteroplasmy, ranging from 24% to 76%. This phenomenon may be present in as many as 1 in every 5,000 people, according to the preliminary investigation published in PNAS.

The authors are careful to note that maternal inheritance of mtDNA is still the norm and that these results signify an exception to the rule. However, it’s not clear how rare these exceptions are. For instance, previous genetic sequencing that turned up a paternal inheritance of mtDNA were discounted as errors. These new findings suggest that there may have been more to these observations than mere errors.

Scientists aren’t exactly sure how this paternal mtDNA infiltrated the embryos. What they know for sure is that this must be a genetic trait, especially since there doesn’t seem to be any defects present in any of the patients’ mitochondria. It’s likely that whatever allows fathers to pass on their mitochondrial DNA to their offspring is due to a mutation in the nucleus — where DNA comes from both mother and father.

In the future, researchers will keep a watchful eye for cases of heteroplasmy in humans. What’s certain is that our view of genetic inheritance has expanded greatly, and there’s no telling just how far this could go, from novel gene therapies to tracing down our species’ evolution.

When mitochondria break down so do our minds, new research shows

Your mind can only work as well as your mitochondria, new research suggests.

Mitochondria.

Mitochondria (red) are organelles found in most cells.
Image credits NICHD / Flickr. Manor

Mitochondria play a much more central role in how we think than scientists had suspected. They supply the energy without which our brain can’t perform its functions, and can ultimately impair the whole organ as they age and become damaged, a new paper suggests.

Keeping the lights on

“Given the multiple first-rate jobs that mitochondria do in the nervous system, it is hardly accidental that their malfunctioning has been associated with virtually every mental or neurological affliction on earth,” wrote authors Peter Kramer and Paola Bressan, researchers at the Università di Padova in Italy.

Mitochondria are former prokaryotic cells (bacteria) that at one point in the distant past decided they’ve had enough of this ‘living alone’ thing, so they joined forces with other cells. This agreement, which involves the cells offering nutrients and protection in exchange for mitochondria’s energy, is one that has endured, pretty much unchanged, up to today; mitochondria still retain their own, separate DNA, and live as organelles behind the membranes of other cells. In many ways, this arrangement is the lynchpin that made eukaryotic cells as we know today possible.

Mitochondria generate energy then chemically store it as adenosine triphosphate (ATP) and ship it out to the cell. ATP is a molecule that virtually all the cells in your body ‘spend’ when they need energy. Without ATP, our bodies would completely stall — it’s not only important, it’s vital to our cells.

Through the process of creating this molecule, however, mitochondria also generate heat and waste products — carbon dioxide, water, and aggressive, corrosive compounds known as free radicals that degrade cells and the mitochondria themselves. Although mitochondria have a number of contingency measures they can employ to deal with this type of damage, they’re only temporary. After a certain amount of time, damage builds up beyond the organelle’s ability to fix — so over time, a certain level of mitochondrial dysfunction is inevitable, the authors write.

The brain, which regularly gulps down around 25% of the body’s energy, bears the brunt of this wear and tear.

Ye olde, older power plant

In the case of degenerative conditions such as Alzheimer’s or Parkinson’s disease, decreased blood flow to the brain (a consequence of aging) limits the amount of glucose and oxygen that mitochondria there can burn to produce ATP. This shortage of fuel slowly causes neurons to degenerate in energy-intensive regions of the brain, such as those associated with memory (i.e., the hippocampus in Alzheimer’s) or motor planning (i.e., the substantia nigra pars compacta in Parkinson’s).

Several rat studies also seem to indicate that low concentrations of ATP in the nucleus accumbens (caused by mitochondrial degradation) could also prop up the symptoms of depression and anxiety, seen as “submissive” behavior in the animals. Kramer and Bressan explain that the link between the two was established by exposing equally-anxious rats to drugs that either inhibited or promoted mitochondrial energy production: the first were likelier to submit to their peers, while the latter exhibited less anxious behavior.

“Considering all of the above, it should come as no surprise that mental disorders are apt to hinge together,” the duo writes. “For example, schizophrenia patients are often depressed, autism patients are often anxious, Down syndrome patients tend to develop premature dementia, and current depression predicts dementia later on.”

Exactly how mitochondria can contribute to such a wide range of disorders is still poorly understood, they add, but luckily, we know how to keep them healthy: exercise, sufficient sleep, a healthy and nutrient-rich diet, as well as engaging in stress-reducing activity all help, the authors write.

The paper “Our (Mother’s) Mitochondria and Our Mind” has been published in the journal Perspectives on Psychological Science.

Brain sculpture.

Mitochondria in the brain changed by cocaine use — the findings could help us better fight addictions

Exposure to cocaine leads to significant changes in the mitochondria of certain brain cells, new research reports. They are now investigating whether these changes play a hand in shaping addiction, for both cocaine and other classes of drugs.

Brain sculpture.

Image via Pixabay.

We’ve known that mitochondria embedded in brain cells play a role in brain disorders ranging from depression, generalized anxiety, and exaggerated stress responses, all the way to bipolar disorders. New research by scientists at the University of Maryland School of Medicine (UMSOM) has found that cocaine use also brings about changes in the little cellular powerhouses, with currently-unknown effects.

The team discovered the changes while working with mice. After repeated exposure to cocaine, cells in the rats’ reward pathways (nucleus accumbens, NAc) showed an increase in dynamin-related protein-1 (Drp1), the molecule that underpins mitochondrial division (fission). Higher levels of Drp1 in the mice’s NAc area caused mitochondria to divide — and thus multiply — faster.

[Read More] If you want to freshen up on your brain anatomy and see exactly where the NAc is, take a minute to peruse 3D Brain.

Such changes could, in turn, explain the chemical fluctuations we’ve seen in the brains of addicts. They report having successfully blocked these changes using a chemical dubbed Mdivi-1. Furthermore, they also blocked responses to cocaine by genetically manipulating the fission molecule within the mitochondria of brain cells.

“We are actually showing a new role for mitochondria in cocaine-induced behavior, and it’s important for us to further investigate that role,” said Mary Kay Lobo, Associate Professor of Anatomy and Neurobiology and corresponding author on the paper.

The team later harvested post-mortem brain tissue samples from individuals with a documented cocaine addiction to confirm that the changes also take place in human brains. Dr. Lobo says these findings could help us better understand how addiction impacts the brain, both from cocaine and other addictive substances.

“We are interested to see if there are mitochondrial changes when animals are taking opiates. That is definitely a future direction for the lab,” she added.

The paper “Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence” has been published in the journal Neuron.

Exposure to BPA might reprogram the brains of turtles — affecting them genetically

It’s never pleasant to come into contact with a pollutant, but BPA might be even worse for the environment than we thought.

Painted turtle eggs were brought from a hatchery in Louisiana, candled to ensure embryo viability and then incubated at male-permissive temperatures in a bed of vermiculite. Those exposed to BPA developed deformities to testes that held female characteristics. Image credits: Roger Meissen, MU Bond Life Sciences CenterClose.

Bisphenol A (typically abbreviated BPA) is a common chemical used in a variety of consumer products, including food storage containers, water bottles and certain resins. It’s been in commercial use since the late 1950s. BPA exhibits estrogen mimicking, hormone-like properties that raise concern about its effects on the environment, and it also affects the growth, reproduction, and development in aquatic organisms, fish being the most vulnerable. Now, researchers have found yet another negative effect the chemical has on wildlife: it can really mess up the brains of turtles.

Turtles are often regarded as an “indicator species,” being indicative of the environmental health of the entire ecosystem. So if something’s wrong with turtles, it could be that similar things are happening to other species in the same habitat. Cheryl Rosenfeld, an investigator in the Bond Life Sciences Center, along with other researchers at the University of Missouri, Westminster College and the Saint Louis Zoo, set out to see how BPA (a common pollutant) affects the turtles. Startingly, researchers report that the chemical can have a severe effect on their brains and behavior, making male turtles act like females and vice versa.

“Painted turtles lack sex chromosomes, and their gender is primarily determined by the incubation temperature of the egg during development–cooler temperatures yield more males while warmer temperatures yield more females,” said Rosenfeld, who also is an associate professor of biomedical sciences in MU’s College of Veterinary Medicine. “Previously, our research team found that exposure to BPA might override the brain development of male turtles and could induce female type behaviors. Our goal for this research was to determine the genetic pathways that correlate to the behavioral changes we identified.”

Rosenfeld wanted to see exactly how BPA does this, and she found that it basically affects the turtles’ gene expression, altering their mitochondrial and ribosomal pathways. Since the mitochondria are the powerhouse of the cell and convert nutrients into useful energy, BPA can change a lot of things. For instance, increased energy production inside brain cells can affect cognitive flexibility and memory. However, we’re only beginning to understand how this type of substance can damage the environment because we don’t know that much about cellular mechanisms and gene expressions in creatures like turtles.

“Metabolic pathways are not well documented in turtles. We were able to use human metabolic models to infer pathway changes in turtles,” said Scott Givan, associate director of MU Informatics Research Core Facility and a co-author of the study. “After analyzing the genes, we were able to link gene expression changes to behavioral changes.”

This is the first study to find a correlation between pollution, gene expression patterns, and behavioral changes in turtles. Although this is a newly discovered mechanism, researchers were able to show that the effects last for at least a year, and they believe that the damage BPA does to the critters might even be permanent.

Journal Reference: Lindsey K. Manshack, Caroline M. Conard, Sara J. Bryan, Sharon L. Deem, Dawn K. Holliday, Nathan J. Bivens, Scott A. Givan, Cheryl S. Rosenfeld. Transcriptomic alterations in the brain of painted turtles ( Chrysemys picta ) developmentally exposed to bisphenol A or ethinyl estradiol. Physiological Genomics, 2017; 49 (4): 201 DOI: 10.1152/physiolgenomics.00103.2016

Animal mitochondrial diagram. Credit: Wikimedia Commons.

What is Mitochondrial DNA and Mitochondrial Inheritance

Mitochondrial DNA: What are mitochondria?

Animal mitochondrial diagram. Credit: Wikimedia Commons.

Animal mitochondrial diagram. Credit: Wikimedia Commons.

Living things are made up of millions of tiny units of life called cells which are composed of extremely small functional parts called organelles. A mitochondrion is a cell organelle that has an extremely important role in the proper functioning of the cell.  Also known as the ‘powerhouse of the cell’, mitochondria are responsible for producing chemical energy called ATP (adenosine triphosphate), which is necessary for all biological processes within the body to occur. Whilst energy production is the most important function of the mitochondria, scientists have placed too much importance on this function and relegated or neglected other important functions.

To be noted that the mitochondria also help in storing calcium, regulating metabolism, controlling cell death, and cell signalling, and carrying out various other functions.

[panel style=”panel-success” title=”Mitochondria DNA facts at a glance” footer=””]

  • Mitochondria have their own genome of about 16,500 bp that exists outside of the cell nucleus. Each contains 13 protein-coding genes, 22 tRNAs, and 2 rRNAs.
  • They are present in large numbers in each cell, so fewer samples are required to construct an evolutionary tree.
  • They have a higher rate of substitution (mutations where one nucleotide is replaced with another) than nuclear DNA making it easier to resolve differences between closely related individuals.
  • They are inherited only from the mother, which allows tracing of a direct genetic line.
  • They don’t recombine. The process of recombination in nuclear DNA (except the Y chromosome) mixes sections of DNA from the mother and the father creating a garbled genetic history.

[/panel]

What is Mitochondrial Inheritance?

mitochondria inheritance

Credit: Khan Academy

Mitochondrial DNA is a special type of DNA and many people are not even aware this type of DNA actually exists. The human cell has two type of DNA: Nuclear DNA and Mitochondrial DNA. We even have 2 separate genomes – the nuclear DNA genome (which is linear in shape) and the Mitochondrial DNA genome (which is circular). Mitochondrial DNA is pretty basic in that it only contains 37 genes. Compared to nuclear DNA, which contains some 20,000 encoding genes, we can see that MtDNA has limited but important protein-coding functions. 13 of the 37 genes carried on MtDNA are involved in enzyme production.

What is also peculiar to MtDNA is the fact that this DNA is maternally inherited – males and females inherit a copy of MtDNA from their mother. Nuclear DNA, on the other hand, is inherited equally from both parents; a child will inherit 50% of their nuclear DNA from the mother and the other 50% from their father.

A MtDNA copy is passed down entirely unchanged, through the maternal line. Males cannot pass their MtDNA to their offspring although they inherit a copy of it from their mother.

This mode of inheritance is called Matrilineal or Mitochondrial Inheritance. There are a mitochondrial DNA testing services available which can help determine maternal lineage or whether the people tested share the same maternal line. Lineage DNA testing using MtDNA is ideal for testing ancient biogenetic origins and tracing one’s unique lineage. For instance, scientists have used MtDNA to compare the DNA of living humans of diverse origins to build evolutionary trees. MtDNA analyses suggest humans originated in Africa, appeared in one founding population some 170,000 years ago, then migrated to other parts of the world.

Mitochondrial Diseases

The severity of a mitochondrial disease in a child depends on the percentage of abnormal (mutant) mitochondria in the egg cell that formed him or her. Credit: MDA.org

The severity of a mitochondrial disease in a child depends on the percentage of abnormal (mutant) mitochondria in the egg cell that formed him or her. Credit: MDA.org

If there are any abnormalities in the mother’s mitochondria, they will be inherited by her offspring but if the father has abnormal mitochondria, he will not pass on the defect to his children since males do not pass on their MtDNA. Mitochondrial DNA plays such a pivotal role in providing the cell with energy that ineffective MtDNA functioning can lead to the cell malfunctioning or cellular death altogether. The areas that are mainly affected by MtDNA diseases include brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems.

Cause:

Around 15% of mitochondrial diseases are due to a defect in the mitochondrial DNA itself. This defect can arise due to any number of external factors like exposure to harmful radiation, toxins, etc. or due to internal mix up by the cell. The majority of mitochondrial diseases are due to a defect in the nuclear DNA that controls the synthesis of mitochondrial proteins. A small but significant percentage of mitochondrial diseases are not inherited but acquired.

Since mitochondria are present in all types of cells, except red blood cells, a defect in one type of mitochondrial gene may produce an abnormality in the brain whereas, in another individual, it may produce a disease in the kidneys.

Types:

Since mitochondria are so widespread in the body and control incredibly diverse functions, the diseases of the mitochondria are just as diverse.

They most commonly cause neuromuscular diseases called mitochondrial myopathies that have typical symptoms of muscular weakness, loss of tone and restricted movement as well as sensory loss and loss of motor control.

Others include:

  • Leigh Syndrome: It presents with seizures, memory loss, and respiratory failure.
  • Leber’s Hereditary Optic Neuropathy: There is a progressive loss of vision due to nerve damage. It leads to blindness in both eyes.
  • Wolff-Parkinson-White Syndrome: It is a disease of the heart in which conduction defects occur.
  • Diabetes and Deafness- This is a combination of both diabetes mellitus and deafness that occurs due to mitochondrial disease.
  • Other diseases include abnormalities of the muscles in the gastrointestinal tract, limbs, heart, lungs, etc.

Overall, there is muscle weakness, poor growth, and visual and memory loss. Other organ systems may also be involved resulting in heart diseases, lung diseases, kidney diseases, disturbed bowel movements and liver problems, brain damage and hearing loss. Studies have also found links between certain cancers and MtDNA – they have linked the two via by-products known as reactive oxygen species (ROS) produced by MtDNA. Mitochondrial diseases are an intensive and diverse group of inherited or acquired defects that cause mild to severe organ damage and dysfunction resulting in a poor quality of life. They do not have a cure and are progressive, often leading to death.

 

UK scientists inch closer to three-parent babies

In 2014, we wrote that three-parent babies might become a reality in only two years. Well, a three-parent baby was recently born in Mexico, but that’s still in a legal gray area. Now, the UK is on track to legalize the practice as scientists say the technology is ready for clinical tests and we can’t afford to wait any longer.

A pipette pulls out the nuclear genetic material from an unfertilized egg — a step in mitochondrial-replacement therapy. Image credits: Center for Embryonic Cell and Gene Therapy of Oregon Health & Science Univ.

The United Kingdom might become the first country to explicitly allow babies with DNA from three people. Scientists advising the UK Human Fertilisation and Embryology Authority (HFEA) said that after 20 years of research and non-human tests, they’re finally ready to start working on the real deal. Basically, what this technique does is exchange a mother’s faulty mitochondria for healthy ones from another woman’s egg. So in the end, the baby won’t just have the DNA from the parents – the DNA from the egg donor will also be included.

Mitochondria are found in every cell of the human body except red blood cells, and convert the energy of food molecules into the ATP that powers most cell functions. When a large percentage of these organelles malfunction, cells can’t do their jobs properly causing various illness, from weakness to death. This is a major problem for many people, preventing them from giving birth to healthy children.

“We’ll be ready, I hope, to press the button if we get the green light,” says Mary Herbert, a reproductive biologist who is part of a team at Newcastle University, UK, seeking to offer the treatment to women.

So far, UK government legalized mitochondrial-replacement therapy in 2015, but the technique still has to be regulated for live births. The support from researchers has been quite strong. If nothing else, they say that regulation is vital because people will start doing this technique whether it’s regulated or not. Dieter Egli, a stem-cell scientist at the New York Stem Cell Foundation who has studied mitochondrial-replacement therapies said:

“Maybe it’s not the best choice, but they will go elsewhere, even if it means greater risk, less oversight and less expertise. I think we can’t blame them for that.”

Indeed, there are valid concerns with this technique. Particularly, it’s not always effective, as recent research has shown. Basically, it might not prevent mitochondrial disease. According to Nature, a recently published study led by mitochondrial geneticist Shoukhrat Mitalipov, at Oregon Health & Science University in Portland, further supports that concern. His study suggests that picking donors that have similar mitochondrial DNA is important and reduces the chance of complications.

But Herbert believes that not only is this not the case, but it would make the donor-finding process much more cumbersome, making the whole process more difficult.

“You’re setting up an arms race between the two mitochondrial genotypes and keeping your fingers crossed. I think a better use of time and money would be to redouble our efforts to get the carry-over as close to zero as we possibly can,” she says, addressing this idea.

So we’re still taking things well into the realm of the unknown, and the most important thing is to reduce health hazards as much as possible, which is why the decision to regulate this technology is so important.

“It’s not perfect. There’s this chance of something going wrong,” says Robin Lovell-Badge, a developmental biologist at the Francis Crick Institute in London who was part of the HFEA panel. People considering the treatments, he adds, “must understand it’s impossible to ensure total safety until clinical trials have taken place”.

However, we also can’t afford to wait, as Mitalipov himself stresses.

“The more we hold off, patients will seek treatments elsewhere,” says Mitalipov. He hopes that the techniques can also be tested in the United States, where the Food and Drug Administration would have to approve any use. “The whole idea of conducting it in the UK and US is that we do it in a few clinics under strict oversight as a clinical trial, so we can evaluate these clinical outcomes.”

Either way, UK’s decision is expected to be decisive.

hourglass aging

New research challenges aging consensus by reversing mitochondrial anomalies in 97-year-old cells

A team led by Professor Jun-Ichi Hayashi from the University of Tsukuba in Japan, known as the white lion to his students given his white hair and powerful voice, challenges the current consensus surrounding the mitochondrial theory of aging, proposing epigenetic regulation, and not genetic mutation, may be responsible for the age-related effects seen in mitochondria. When Hayashi and colleagues tested their theory, they reversed the age defects in cell lines collected from 97-year-old Japanese participants. They then singled out two genes involved in glycine production which they believed are responsible for the mitochondria reversal. The findings thus suggest that a glycine supplementation could help curb aging or age-related diseases.

hourglass aging

Image: Huff Post

Mitochondria are popularly known as the “cell’s powerhouse”, since they’re responsible for producing energy through cellular respiration. One of the unique features of mitochondria is that they contain their own DNA – mitochondrial DNA (mtDNA). All the other DNA of a cell is found in the nucleus (nDNA). Most scientists claim that the mitochondria through mutations sustained in its DNA is involved in aging, since the mutations cause abnormal functions.

The mitochondrial theory of aging (MTA) was first proposed in 1972 by Denham Harman, the “father” of the free radical theory of aging (FRTA). Basically, as we age these mutations add up and the mitochondria is less efficient at producing energy, reducing lifespan and triggering aging-related characteristics such as weight and hair loss, curvature of the spine and osteoporosis. The brain is perhaps the most important organ affected by aging, since it consumes more energy than any other organ of the body. An energy deficit in the brain and central nervous system affects the activities of all organs throughout the body as well as mental acuity and mood.

Professor Hayashi. Credit: Image courtesy of University of Tsukuba

Professor Hayashi. Credit: Image courtesy of University of Tsukuba

Hayashi’s team, however, claims that the MTA has one severe flaw: it’s not DNA mutation, but epigenetic regulations that cause the mitochondrial defects. They collected  human fibroblast cell lines derived from young people (ranging in age from a fetus to a 12 year old) and elderly people (ranging in age from 80-97 years old). Then mitochondrial respiration and the amount of DNA damage in the mitochondria of the two groups was studied. Hayashi  expected to see reduced mitochondrial respiration and more DNA damage in the older cells, but while the elderly group indeed showed reduced respiration, there DNA differences between the two groups was minute. This is when they got the idea that epigenetics – environmental changes that alter the structure of DNA, without affecting its sequence – may have a part to play.

If they were right, then changing cells by genetically reprogramming them into an embryonic stem cell-like state would cancel any epigenetic effects. So, they put it to the test and the human fibroblast cell lines from both young and old participants were then converted into a stem-like state, then turned back into fibroblasts and their mitochondrial respiratory function examined. In an amazing twist of events, all of the resulting mitochondria had respiration rates comparable to those of the fetal fibroblast cell line, irrespective of whether they were derived from young or elderly people. This provides significant evidence to back their claim that mitochondria anomalies, and subsequently human cell aging, are governed by epigenetics.

They then identified two genes that might be controlled epigenetically and cause the age-related defects. The genes, CGAT and SHMT2, regulate glycine production in mitochondria. Glycine is the smallest of the amino acids. It is ambivalent, meaning that it can be inside or outside of the protein molecule.

Moreover, by changing the expression of these two genes, the team showed they could induce defects or restore mitochondrial function in the fibroblast cell lines. For instance, adding glycine for 10 days to the culture medium of the 97 year old fibroblast cell line restored its respiratory function, as reported in Scientific Reports. But could it work for other types of cells? If so, then human aging could be slowed down or even hampered using something like glycen supplements. Of course, this is but a part of the aging puzzle. There are also other things we need to worry about like telomerase length, stem cell death, cancer, transcription error to name but a few.

A Rogue gone Good: Mitochondria was initially an Energy Parasite

A new milestone study found that mitochondria – the energy factories in animal and plant cells – were initially very similar to parasitic bacteria some two billion years ago, and only later did they become energy sources. Very little is known about the origins of mitochondria, but by probing the genomes of bacteria closely related to the energy cell scientists at University of Virginia (UV) found early mitochondria were parasitic, and only became beneficial after switching the direction of their ATP (adenosine triphosphate) transport years down the road. The findings could help efforts seeking to treat human mitochondrial dysfunctions that cause diseases such as Alzheimer’s disease, Parkinson’s disease and diabetes.

A parasite at first

Image: knowingneurons.com

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. This energy is supplied by mitochondria in the form of ATP.

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The leading theory regarding their origin is that they were formed in an ancient symbiosis between a nucleated cell and an aerobic prokaryote.  The engulfed cell came to rely on the protective environment of the host cell, and, conversely, the host cell came to rely on the engulfed prokaryote for energy production. In time, descendants of the engulfed prokaryote developed into mitochondria which became essential to eukaryotic evolution since – or so the theory goes. UV scientists found, however, that mitochondria’s past isn’t that nice and dandy. Their findings suggest mitochondria was an energy parasite by leaching energy from the host cell. It is not known what turned mitochondria from an energy parasite into the host cells’ power source, but it is believed that ATP is related to the switch.

“We believe this study has the potential to change the way we think about the event that led to mitochondria,” Martin Wu, a biologist at the University of Virginia (UV) and the study’s lead author, said in a statement. “We are saying that the current theories – all claiming that the relationship between the bacteria and the host cell at the very beginning of the symbiosis was mutually beneficial – are likely wrong.”

Image: knowingneurons.com

That’s a bold statement, but will it hold up? Wu and colleagues sequenced the genomes of 18 bacterial species which are closely related to mitochondria. This way, the UV researchers were able to pinpoint human genes that were derived from mitochondria, which could help them gain insight into the genetic basis of human mitochondrial dysfunctions contributing to several diseases like Alzheimer’s or Parkinson’s.

“We reconstructed the gene content of mitochondrial ancestors, by sequencing DNAs of its close relatives, and we predict it to be a parasite that actually stole energy in the form of ATP from its host – completely opposite to the current role of mitochondria,” Wu said.

The findings were published in the journal PLOS ONE.

 

Oldest human DNA ever found – 400.000 years old

The recent discovery of DNA of a 400,000-year-old human thigh bone could provide valuable insight into the evolution of humans; researchers explain this is easily the oldest human genetic material ever found.

When it comes to being a mountain, the Atapuerca Mountains in Spain don’t really have much going for them. It’s an ancient karstic region of Spain comprising mostly of limestone, looking really craggy and run down. But even though they may not impress geologists, the situation is very different with archaeologists. The area is home to a treasure trove of buried archaeological riches: fossils and tools belonging to the earliest known species of ancient humans. The most famous site is called Sima de los Huesos — “The Pit of Bones”, and this is where this femur also came from.

The remains of at least 28 people are there, and archaeologists have so far discovered over 5.500 bones. Now, working in the area, Matthias Meyer, a lead researcher at the Max Planck Institute for Evolutionary Anthropology, and a team of colleagues have recovered and analyzed the earliest known human DNA.

Everything about this discovery is special. First of all, archaeologists had to crawl for hundreds of metres through narrow cave tunnels; then, they had to go down, in the dark, while hanging on to a rope, Indiana Jones style. They believe that the bones (probably bodies at the time) were deposited in inaccessible areas. After they recovered the bones, they carefully drilled into them, obtained about two grams worth of bone, then isolated the DNA using a recently discovered method (in 2013) that employs silica to make the process more efficient.

“Years ago, geneticists said they wouldn’t be able to find DNA that was older than 60,000 years old,” said co-author Jose Bermudez de Castro, from the National Research Centre for Human Evolution (CENIEH), a member of the team that excavated the fossils.

They focused on mitochondrial DNA (the cells’ energy factories), for two reasons:
mitochondrial DNA contains way fewer genes than does nuclear DNA
– because mitochondrial DNA is passed on exclusively from mothers, there are usually no changes from parent to offspring – which makes it a very useful tool for tracking down ancestry.

After sequencing 98% of the mitochondrial DNA genome, Meyer and his team estimated the age of the sample using the length of the DNA branch as a proxy. They estimated the age to be around 400.000 years, which would put it in the Middle Pleistocene and make it by far the oldest human DNA sample ever found. The previous record was a 100.000 year old Neanderthal sample.

The sample comes from Homo heidelbergensis, a group of extinct humans related in many ways to Neanderthals. However, genetic analysis showed that the owner did not share a common ancestor with Neanderthals, but instead with the Denisovans, a mysterious subspecies discovered only in 2008 that last shared an ancestor with Neanderthals and Homo sapiens about one million years ago. This is even more interesting because the Denisovans were initially found in Siberia, which is, needless to say, quite a long way from Spain. Meyer presented three possibilities:

“First, the Sima de los Huesos hominins may be closely related to the ancestors of Denisovans.”

“Second, it is possible that the Sima de los Huesos hominins represent a group distinct from both Neanderthals and Denisovans that later perhaps contributed the mtDNA to Denisovans.”

“Third, the Sima de los Huesos hominins may be related to the population ancestral to both Neanderthals and Denisovans.”