Mitochondrial Diseases

What are mitochondria?

Mitochondria are small organelles found in nearly every cell in the body. Often referred to as the “powerhouses” of the cell, their primary function is to process oxygen and convert the nutrients from the foods we eat into energy. This energy is vital for supporting all cellular activities and is essential for our survival.

key roles of mitochondria...

Mitochondria generate most of the cell’s supply of adenosine triphosphate (ATP), the molecule that carries energy within cells. This energy is crucial for powering various cellular processes and functions.

By converting food into usable energy, mitochondria play a central role in cellular metabolism, which is the set of chemical reactions that occur in living organisms to maintain life.

Mitochondria are involved in regulating the cell cycle and cell growth, as well as initiating the process of programmed cell death (apoptosis) when necessary.

What is mitochondrial disease?

Mitochondrial diseases refer to a group of disorders that affect mitochondrial function. When  several functions are disrupted, less energy is produced which leads to organ dysfunction. Depending on which cells in the body suffer from mitochondrial dysfunction, different symptoms may arise. These may include fatigue, heart and kidney issues, problems with speech and sight, digestion and kidney function failures, seizures, metabolic strokes, developmental or cognitive disabilities, and more. The symptoms may present themselves at any age and affect any organ.

So what is that causes mitochondrial dysfunction in the first place?

Mitochondria have their own DNA (mtDNA) that is highly prone to mutations from both inherited and acquired factors. They produce significant amounts of reactive oxygen species (ROS), which, along with limited repair mechanisms, make mtDNA particularly vulnerable to damage. External factors like chemicals and certain drugs can also harm mtDNA, leading to genetic mutations, deletions, and mismatches. These defects can result in mitochondrial diseases and are linked to ageing, cancers, and other conditions.

Challenges in diagnosing mitochondrial diseases

Diagnosing mitochondrial diseases is challenging due to the varied and severe symptoms. Diagnosis typically starts with genetic testing of mtDNA and nuclear DNA (nDNA), followed by biochemical tests of body fluids, muscle biopsies, and organ-specific examinations. Over 350 types of mitochondrial diseases have been identified through genetic testing, stemming from changes in either mtDNA or nDNA.

Different types of mitochondrial diseases

Leigh syndrome mainly affects young children, showing symptoms within the first years of life. It is characterised by severe neurological problems affecting movement, posture and cognitive abilities, and is usually caused by genetic mutations in either mtDNA or nDNA.

MDDS is characterised by a significant reduction in the amount of mtDNA in the tissues of muscle, liver and brain. Both children and adults can be affected by MDDS. 

NARP results from the mutations in the MT-ATP6 gene, which is present in the mtDNA.  This condition begins in childhood or early adulthood and the symptoms can worsen over time. Most patients experience peripheral neuropathy (pain in arms and legs) and ataxia (problems with balance and coordination) along with vision loss (retinal issue).

Patients affected by MELAS present with a common mutation in the MTTL1 mitochondrial gene. MELAS is inherited by children from their mothers. This mutation exists in a heteroplasmic form, a mixture of healthy and defective mtDNA within the body.  Therefore, the symptoms and signs of the disease may appear during childhood, and range from asymptomatic to severe cases.

Pearson syndrome primarily affects infants and children. It is characterised by abnormalities in the development of blood cells, pancreatic dysfunction, and problems with the nervous system. Pearson syndrome is caused by a single, large deletion of mtDNA that impairs the function of mitochondria to provide enough energy to the cell.

Meet mitochondria patient representative

What is the current stage of theapies?

MAT* (Mitochondrial Augmentation Technology)

At present, there is no cure for mitochondrial disease. Current treatment methods of the diseases largely focus on preventing and/or relieving the symptoms and providing supportive care to patients. The treatment for mitochondrial diseases often varies based on the type and severity of the symptoms, whereas the most common treatments usually involve taking vitamins or supplements, physical therapy, use of assistive devices, and nutritional management.

Minovia, a beneficiary of MITGEST, is testing a treatment platform called MAT* for mitochondrial diseases. The first version (MNV-101) treated Pearson Syndrome patients with personalised therapy using healthy mitochondria, showing positive results in a Phase I/II clinical trial and compassionate use cases. The second version (MNV-201) aims to treat both inherited and non-inherited mitochondrial diseases using a patient’s own cells enhanced with donor mitochondria.

A deep understanding of the mitochondrial gene expression system and new methods to analyse RNA and DNA metabolism in mitochondria are thus urgently needed to develop treatments for the full panoply of mitochondrial disorders. 

 

Within the MITGEST project, we aim to understand the quality control and homeostasis of mitochondrial DNA and its expression and develop novel approaches and disease intervention/therapy. These findings will provide essential insights for the development of effective treatment and disease biomarkers.

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