Study Sheds Light on Molecular Processes Behind Mitochondrial DNA Diseases

Study Sheds Light on Molecular Processes Behind Mitochondrial DNA Diseases

A team of researchers at Children’s Hospital of Philadelphia (CHOP), the University of Pennsylvania, and Drexel University have provided insights into the molecular mechanisms behind mitochondrial disease and how small changes to mitochondrial DNA can have a major impact on human health.

Mitochondria are the powerhouses of cells. Each cell contains thousands of mitochondria in the cytoplasm which are responsible for generating energy. Mitochondria are responsible for producing around 90% of the energy required by the body. DNA is contained in the nuclei of cells, but mitochondria also have their own DNA which is different from the DNA contained in the nucleus.  Mitochondrial DNA (mtDNA) can include many mutations along with normal DNA, and the mutations vary considerably from individual to individual. The ratio of normal DNA and mutant DNA can even differ considerably in different tissues in the same patient.

Mutations in mtDNA affect energy production. The more mutations that are present, the less effective the mitochondria are at producing energy. If the number of mutations increases past a certain point, there will be insufficient energy and symptoms of mitochondrial disease will be experienced. If many mitochondria are affected by the mutations, the lack of energy production will prove fatal.

Mitochondrial disease is usually inherited, although it can occur at any age. Since mitochondria are found in almost all cells, the disease affects virtually all parts of the body.  The disease affects around one in 5,000 individuals.

The research team was led by Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at CHOP, a pioneer in the field of mitochondrial genetics. Wallace’s previous research has shown how mtDNA regulates the expression of genes in nDNA and how small changes can have a major impact on human health.

For instance, a single base change in a mtDNA transfer RNA gene can have a profound impact on clinical symptoms. If that single base mutation occurs in 10-30% of mtDNA it will cause diabetes or autism. If the mutation is present in 50%-80% of mtDNA, it will cause disease in multiple organs in the body, and if the number of cells with the mutation is 90% or more, it will lead to death in infancy.

Typically, a genetic mutation in nDNA will cause one specific disease – Muscular dystrophy is caused by a mutation that results in the production of a defective protein, dystrophin. However, a mutation in mtDNA can have a wide range of clinical manifestations, but for years it has been unclear why that is the case.  “We’ve been searching for the mechanisms to explain this broad variability of clinical symptoms of mtDNA disorders for the past thirty years,” explained Wallace.

In addition to producing energy, mitochondria produce metabolites that enter the cell nucleus and activate enzymes that make changes to proteins that surround the DNA – histones – which control the expression of genes in nuclear DNA (nDNA).

Wallace and his team studied the metabolites produced by mitochondria that affect signaling between mtDNA and nDNA and investigated the molecular changes that affect expression of genes in nDNA. The researchers showed that the metabolic products produced by the mitochondria modify the tails of histones by adding or removing methyl or acetyl groups. That affects the coiling of chromosomes, which regulates the structure of nDNA and affects gene expression. Those metabolites determine which genes are expressed in nDNA, which can have a major impact on bioenergetics and human health. The metabolites that cause these histone changes were found to be only produced by mitochondria and that even subtle changes to the ratios of mutant and normal mtDNA affects the production of these metabolites and thus the expression of genes in nDNA.

“No one had previously showed how the mitochondria determine the gene expression state of the cell nucleus,” explained Wallace. “These findings open a new avenue for investigating and understanding many common complex [metabolic and degenerative] diseases.”

The study is detailed in the paper – Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy – which was recently published in the journal Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.1906896116

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