What is mitochondrial disease?
& The Role of LONP1
What is Mitochondrial (“Mito”) Disease?
Understanding mitochondrial disease
Mitochondrial disease refers to a group of genetic conditions that affect the mitochondria. We all have mitochondria! Mitochondria are the powerhouse of almost every cell of the body and their main function is generating 90% of the energy that our body needs to function. This is achieved by using the oxygen available within the cell to convert food into chemical energy, called ATP (adenosine triphosphate), that can power various cellular functions. For someone with a mitochondrial disease, the cells are not able to produce enough energy (ATP) for organs to function properly.
Essentially, living with mitochondrial disease is hypothetically like running on low battery all the time without the battery being able to be recharged.
Any organ can be affected, especially the ones with high-energy demand such as the brain, muscles and heart.
Impact on the body
Depending on which cells are affected, a wide range of symptoms could appear including muscle weakness, poor growth, developmental delay and learning disabilities, hearing and/or vision loss, neurological problems, heart disease, diabetes, liver disease, kidney disease, gastrointestinal problems and respiratory disorders.
Prevalence and prognosis in children
It’s estimated that about 1 in 4,000 people are affected by a mitochondrial disease. These disorders can appear in infancy, childhood, or adulthood, with symptoms and severity varying widely even among family members carrying the same mutation.
The prognosis varies significantly depending on the type of mitochondrial disease and the severity of the symptoms. Early onset of the disease is related to a poorer prognosis.
Early diagnosis and supportive therapies can improve quality of life, but many mitochondrial diseases currently have no cure.
So what is LONP1 and how is Aria the only one on earth?
Location and function
LONP1 is a protein coding gene located in the nuclear DNA and it is highly conserved throughout evolution from bacteria to humans, which means that it is a really important gene for life. Knockdown of the LONP1 gene is not compatible with life. Mutations in the gene lead to severe disease in humans.
LONP1 is still quite a novel gene and it has been shown to be important for maintaining mitochondrial homeostasis. It is a multifunctional enzyme that regulates crucial mitochondrial functions, including:
- mediating the selective degradation of damaged, impaired proteins in the mitochondria
- folding and assembling proteins inside the mitochondria, for example by constructing the complicated parts that form the production line of energy (so called, the respiratory chain)
- regulating mitochondrial gene expression
- helping maintain the integrity of the mitochondrial genome.
In the recent years, there seems to be an increased interest in knowledge regarding LONP1 as LONP1 dysregulation has been shown to be implicated in heart disease, cancer, diabetes, neurodegeneration diseases (such as Alzheimer’s and Parkinson’s disease) and even human aging.
Role in Disease
Point mutations in the LONP1 gene can be characterised broadly in the following diseases:
- Congenital diaphragmatic hernia ( identified recently in 2021 by Professor Wendy Chung at Harvard Medical School)
- CODAS (Cerebral , Ocular, Dental, Auricular and Skeletal) syndrome, a complex disorder in which both copies of the LONP1 gene contain mutations
- Mitochondrial disorders (Aria’s mutation falls within this category)
Aria’s specific LONP1 mutation
Every person inherits two copies of a gene (from the nuclear DNA), one from each parent. We all have hundreds of “misspellings” (mutations) in genes. Normally, if one copy of a gene does not work properly, the other copy takes over and fulfills the function of that particular gene and thus it does not affect health.
Aria has a heterozygous change in the LONP1 gene that is de novo, not inherited from the parents. This mutation is p.(Tyr565Asn) in LONP1. Heterozygous means that the mutation happens in only one copy of the gene, while the other copy of LONP1 is normal. LONP1 gene is formed by 959 amino acids and Aria’s mutation means that at the location 565, a misspelling happen in which the amino acid Tyrosine (Tyr) is replaced by Asparagine (Asn).
In the case of Aria’s mutation, it is predicted that the mutation is dominant negative, meaning that having one damaged copy of the gene causes problems even when the other copy of the gene is normal.
Aria’s mutation is novel and unique and it has never been uncovered in anyone in the world. Two similar worldwide cases have been reported by our genetic team, mutations that happen at the same location, but with different exchange of amino acids. Both babies have tragically passed away, one at 7 months old and one before reaching 2 years old.
Aria’s symptoms are consistent with those of a mitochondrial disease. The biology of Aria’s mutation and the mechanism of her disease have not been elucidated though.
Therefore, one part of our mission is to fund essential research to understand the biology of her mutation and mechanism of her disease in order to uncover what therapeutic solutions can be developed for her (such as RNA and/or DNA therapeutics). Being such a novel mutation, the work will also advance research being at the frontier of science.