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What is Mitochondrial Disease?

Last updated on 3rd May 2023

According to statistics, mitochondrial disease is one of the most common types of genetic disease that occurs in at least 1 in 5,000 people. Each year, around 150 women in the UK are at risk of transmitting mtDNA disease. In this article, we’ll talk in detail about mitochondrial disease, the causes, the different types, signs and symptoms and treatments.

What is mitochondrial disease?

Mitochondrial disease is named after the mitochondria, which are minute organelles present in almost all of our cells. These are responsible for generating around 90% of our energy. Our cells can’t work properly if our mitochondria aren’t healthy, and when these organelles fail, there are wide-ranging and serious consequences.

Mitochondrial disease – or “mito” – will affect patients in different ways as it depends on the function of the affected cells. This means it is difficult to diagnose the disease as the symptoms will resemble other illnesses. For instance, someone with mito might have fatigue, hearing loss, poor vision, seizures, poor growth, respiratory problems or cognitive disabilities, which could all be caused by other, more benign reasons. Mitochondrial disease can affect any organ or system in the body, like the skin, liver, gut, lungs, brain and heart.

Mitochondrial disease is actually more than one disease. The term is used collectively to describe and encompass a group of similar diseases.

What are mitochondria?

Mitochondria exist in 90% of the cells in our bodies. They’re often called the cell “powerhouse” because they turn the energy we consume from food into usable energy. These mitochondria are vital to human survival because they generate a substance called ATP (adenosine triphosphate), which is essentially the cell’s energy currency.

As well as this, they are also needed in other functions. They are used in apoptosis, for example, which is also known as programmed cell death (as opposed to necrosis, which is when cells die because of deprivation or outside trauma).

Mitochondria are tiny and are not visible under a microscope unless a dye is used. They measure somewhere between 0.75 and 3 micrometres (μm). To compare, this is similar to the width of a single strand of spider web silk. Human hair is between 17 and 181 μm.

Unlike all other organelles (a cell’s miniature organs), mitochondria have an inner and an outer membrane that have different functions. The mitochondria are separated into different parts that do different jobs.

Outer membrane

The outer membrane allows small molecules to pass freely through the membrane. The outside contains porins, a type of protein, which encourage proteins to cross the membrane. There are also a variety of enzymes with different functions here.

Intermembrane space

This is the area between the two membranes.

Inner membrane

This holds proteins with different roles. There are no porins here and most molecules cannot get through the membrane. The ones that can cross do so with a special membrane transporter. It is in this inner membrane where the majority of ATP is made.

Cristae

These are inner membrane folds that increase its surface area and, thus, the amount of space for chemical reactions to occur.

Matrix

This is inside the inner membrane and contains hundreds of different enzymes. The matrix is important for producing ATP and the mitochondrial DNA is in this part.

Mitochondria

Different cells and their mitochondria

Each type of cell we have in our bodies has a different number of mitochondria. Mature red blood cells, for instance, have no mitochondria at all, while a liver cell will have over 2,000.

Cells that require a lot of energy will have more mitochondria. Heart muscle cells, for example, have 40% of their cytoplasm as mitochondria.

Though you’ll often see these organelles drawn as an oval, they are linked to one another in a network that is constantly changing through fission (dividing) and fusion (bonding).

In sperm cells, they are spiralled and produce the energy for the motion of the tail.

Despite most human DNA being within a cell’s nucleus, mitochondria are different and have their own DNA (mtDNA), which is much more similar to the DNA of bacteria.

During reproduction, a foetus gets half of its DNA from the mother and half from the father. However, all of the mtDNA will come from the mother. This is why mtDNA is very good at tracing family trees and genetic lines. It was mtDNA analysis that discovered how humans originally came from Africa and descended from one common ancestor, which has been called mitochondrial Eve.

What do mitochondria do?

Although the main role of mitochondria is to produce energy, they also have other roles.

Let’s look at all of these roles:

Energy production

Mitochondria produce ATP, which is a complex chemical that powers the metabolic processes of the cells. Most of this energy is produced via a series of reactions called the Krebs cycle or citric acid cycle.

This takes place in the inner membrane’s cristae (folds). The process of converting the energy we take from food into energy the cell can use is called oxidative phosphorylation. The energy produced is stored as chemical bonds and is released when these are broken.

Cell death

As mentioned above, mitochondria are involved in apoptosis, which is otherwise known as programmed cell death and is essential to life. When cells become broken or old, they’re destroyed at it’s the job of the mitochondria to decide when a cell needs to be destroyed.

Mitochondria are also thought to play a role in cancer because this disease involves a problem with normal apoptosis.

Calcium storage

Mitochondria play a key role in storing calcium ready for when we need it. Calcium is vital for many cellular processes, including fertilisation, muscle function, blood clotting, and others.

Producing heat

As humans, we will naturally shiver when we feel cold. Besides this, our bodies can produce heat in other ways. Mitochondria are capable of generating heat. They do this through a process named proton leak, which is known as “non-shivering thermogenesis”.

How common are mitochondrial diseases?

What are the types of mitochondrial disease?

There are lots of different types of mitochondrial disease.

We’ll discuss them here:

  • Alpers disease – this is also called progressive infantile poliodystrophy and its symptoms include seizures, spasticity, dementia, blindness, cerebral degeneration and liver dysfunction. The only treatment available is symptom management.
  • Autosomal dominant optic atrophy – this affects the optic nerves and causes vision impairment, loss or blindness that begins in childhood. This is caused by the mitochondrial dysfunction that deals with optic nerve fibre death.
  • LIC (Lethal Infantile Cardiomyopathy) or Barth syndrome – this is shown in cardiomyopathy, neutropenia, short stature and skeletal myopathy. Treatments are now much more effective than they once were.
  • Beta-oxidation defects – these can be treated with a low fat, high carbohydrate diet alongside administering triglyceride oil and avoiding fasting.
  • Cartinine deficiency/Carnitine deficiency syndromes – this can show up as apnoea, bradycardia, seizures, lethargy, vomiting, coma, limb weakness, enlarged liver and myoglobin in urine. Depending on the type of deficiency, there might also be speech delay, mental retardation and autistic behaviours.
  • Co-enzyme Q10 deficiency – this will show as mental retardation, encephalomyopathy, exercise intolerance, recurrent myoglobin in urine and ragged-red fibres.
  • Complex I deficiency – this is a progressive neuro-degenerative disorder with symptoms present in tissues and organs that need high energy like the heart, brain, skeletal muscles and liver.
  • Complex II deficiency – this manifests itself in symptoms like failure to thrive, developmental delay, hypotonia, respiratory failure, lethargy, ataxia, myoclonus and lactic acidosis.
  • Complex IV deficiency – this has two major symptoms. A child is typically normal for their first six to twelve months of life and then will regress, and have ataxia, lactic acidosis, seizures and other symptoms.
  • Complex V deficiency – this will show as slow and progressive myopathy.
  • CPEO (Chronic Progressive External Ophthalmoplegia syndrome) – this has symptoms like visual myopathy and central nervous system dysfunction.
  • CPT I/II deficiency – problems triggered by illnesses or fasting, enlarged liver (CPT I), muscle pain and stiffness (CPT II).
  • KSS (Kearns-Sayre syndrome) – this is a rare disorder caused by DNA deletions. Onset is around age 20. It causes paralysis of eye muscles, retina degeneration, and often ataxia, elevated cerebrospinal fluid protein, and cardiac conduction defects.
  • LBSL/Leukodystrophy – this involves the spinal cord and brain stem and is slowly progressive. It involves dysfunction of the legs and causes retained tendon reflexes. It usually begins in childhood and many people need to be in a wheelchair by adolescence.
  • LCHAD/LCAD (Long-Chain Acyl-CoA Dehydrogenase) deficiency – a fatal syndrome that appears in infancy as failure to thrive, enlarged heart and liver, hypotonia and metabolic encephalopathy.
  • Leigh disease – this is a progressive disorder that comes on in infancy often after a virus. Children often appear normal when born but begin to display symptoms during infancy. There is no cure. The symptoms involve loss of skills like head control, suckling, talking and walking. Eventually, there are problems with breathing, vision, kidneys and heart.
  • LHON (Leber’s Hereditary Optic Neuropathy) – this is a rare disorder that causes painless, sudden and profound central vision loss. It is most common in men around the age of 20.
  • LHON Plus – as well as the vision problems of LHON, there could be symptoms in the ears, heart, central nervous system, endocrinological organs, arteries, bone marrow, kidneys and peripheral nervous system.
  • Luft disease – this is an inherited condition but an unknown cause that comes with resting tachycardia, polyphagia, polydipsia, profuse perspiration, heat intolerance, hypermetabolism, mild weakness and exercise intolerance.
  • MAD (Multiple Acyl-CoA Dehydrogenase deficiency)/Glutaric Aciduria Type II.
  • MCAD (Medium-Chain Acyl-CoA Dehydrogenase deficiency) – affects young children and shows fatty degeneration of the liver and an enlarged liver.
  • MELAS (Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes) – this is progressive and the typical onset is during childhood and adolescence. Symptoms include recurrent vomiting, migraines, seizures and stroke-like episodes.
  • MEPAN (Mitochondrial Enoyl CoA Reductase Protein Associated Neurodegeneration) – this is caused by two gene mutations and comes on in childhood with speech problems, vision loss and walking difficulties.
  • MERRF (Myoclonic Epilepsy and Ragged-Red Fibre disease) – this is a progressive syndrome that typically starts in childhood and involves muscle spasms and epileptic seizures as well as ataxia.
  • MIRAS (Mitochondrial Recessive Ataxia Syndrome) – this comes with balance problems, ataxia, cognitive impairment, epilepsy, psychiatric symptoms and others.
  • Mitochondrial Cytopathy.
  • Mitochondrial DNA Depletion – this has no cure and death is usually between birth and two years old.
  • Mitochondrial Encephalopathy.
  • MNGIE (Myoneurogatointestinal Disorder and Encephalopathy) – symptoms include progressive ophthalmoplegia, limb weakness, digestive tract disorders, and peripheral neuropathy, among others.
  • NARP (Neuropathy, Ataxia and Retinitis Pigmentosa).
  • Pearson syndrome – this shows as pancreas and bone marrow dysfunction.
  • Pyruvate Carboxylase Deficiency – common symptoms include spasticity and seizures.
  • Pyruvate Dehydrogenase Deficiency – symptoms include ataxia, cerebellar and spinal degeneration, lactic acidosis.
  • PDCD (Pyruvate Dehydrogenase Complex Deficiency) – this is characterised with a metabolism error and children can’t convert food energy into energy. Symptoms include respiratory failure, lethargy, lactic acidosis, coma, seizures, developmental delay, and more.
  • POLG Mutations.
  • SCAD (Short-Chain Acyl-CoA Dehydrogenase Deficiency) – symptoms are developmental delay, hypoglycaemia and failure to thrive.
  • SCHAD – this comes with encephalopathy, cardiomyopathy and liver disease as associated problems.
  • VCLAD (Very Long-Chain Acyl-CoA Dehydrogenase Deficiency) – this has varying symptoms, including infantile encephalopathy.

Other conditions

Other conditions are also thought to have some level of mitochondrial dysfunction involved.

These include:

  • Alzheimer’s disease.
  • Bipolar disorder.
  • Parkinson’s disease.
  • Schizophrenia.
  • Chronic fatigue syndrome/ME.
  • Huntington’s disease.
  • Autism.
  • Diabetes.
mitochondrial disease

Why would mitochondria malfunction?

The understanding of the mitochondria is still in its developmental stages and there is so much that we don’t know. What we do know is that mitochondrial diseases are inherited. A person’s mitochondrial can also be affected by environmental factors and other genetic disorders too.

What are the signs and symptoms of mitochondrial disease?

The symptoms of mitochondrial disease very much depend on the type of mitochondrial disease you have. People’s symptoms can be mild or severe, they can occur at any age, and can involve more than one bodily function or organ.

Generally speaking, most mitochondrial diseases have some of the following symptoms:

  • Poor growth/failure to thrive.
  • Muscle pain or weakness, poor muscle tone, intolerance to exercise.
  • Hearing and vision problems.
  • Developmental delays or learning disabilities.
  • Autism spectrum disorder.
  • Kidney, heart or liver problems.
  • Diabetes.
  • Swallowing or gastrointestinal problems.
  • Neurological symptoms like migraine, seizures and stroke.
  • Thyroid problems.
  • Movement problems.
  • Respiratory problems.
  • Lactic acidosis.
  • Dementia.

What causes mitochondrial disease?

For most people, mitochondrial disease is an inherited condition. A child who has mito doesn’t receive a normal copy of genes from his/her parents. Instead, they have a mutated gene.

The child can inherit the disease in one of four ways:

Random mutations

Sometimes a foetus will develop a random genetic mutation that isn’t inherited.

Mitochondrial inheritance

As previously mentioned, mitochondria contain their own DNA and this can only be inherited from the mother.

Autosomal dominant inheritance

This is when the foetus receives a single mutated copy of the gene from one parent.

Autosomal recessive inheritance

This is when the child receives a mutated copy from both parents.

How does mitochondrial disease affect the body?

The body is affected most in the places where it needs the most energy. This is the heart, muscles and brain.

There is a spectrum of symptoms and body parts affected:

The brain

The brain can be affected by dementia, developmental delays, migraines, seizure, stroke, atypical cerebral palsy, autistic features and learning disabilities.

The muscles

Muscles can be weaker and they might cramp. This also might mean constipation, diarrhoea, hypotonia, vomiting, reflux and dysmotility.

The nerves

This might mean poor reflexes, fainting episodes, intolerance to heat or cold and pain.

Pancreas

This might mean parathyroid failure, pancreatic failure or diabetes.

Kidneys

This might mean renal tube failure.

Heart

Heart problems include cardiomyopathy, blockage and defects in the heart.

Liver

This could be low blood sugar and liver failure.

Eyes

This could occur as ptosis, optic atrophy, vision loss, strabismus, retinitis pigmentosa and ophthalmoplegia.

Ears

This could manifest as hearing loss.

Systematic problems

This could be failure to gain weight, short stature, fatigue, respiratory problems and unexplained vomiting.

Systematic problem from mitochondrial disease

How is mitochondrial disease diagnosed?

Since there are so many different mitochondrial diseases and they each affect the body in a different way, it is very difficult to diagnose them. There are no single diagnostic or laboratory tests to confirm mitochondrial disease.

Typically, a diagnosis will begin with tests. There will usually be:

  • A detailed history taken of the patient and family.
  • A physical examination.
  • A neurological examination.
  • A metabolic test – blood/urine tests and possibly a spinal fluid test.

There might be other tests dependent on symptoms. These could include:

  • An MRI.
  • An EKG (Electrocardiogram).
  • ABER – auditory-brainstem evoked responses.
  • Blood tests for genetic testing.

How is mitochondrial disease treated?

Mitochondrial diseases cannot be cured. However, there are treatments available to reduce symptoms and slow progression. The treatment given will depend on the severity of the disease and which one the patient has. Even if the treatment for two people with the same condition is the same, the outcomes might not be the same.

Some treatments prescribed for mitochondrial diseases include:

  • Vitamins and supplements.
  • Exercises.
  • Strength and resistance training.
  • Conserving energy.
  • Other treatments like therapies.

Final thoughts

There is so much to learn about mitochondrial disease that we’ve barely scratched the surface. Though mitochondrial diseases are typically progressive conditions, treatments are getting better all of the time and, depending on the disease type, they are not an immediate death sentence.

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About the author

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Louise Woffindin

Louise is a writer and translator from Sheffield. Before turning to writing, she worked as a secondary school language teacher. Outside of work, she is a keen runner and also enjoys reading and walking her dog Chaos.



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