Novel Genetic Variant Associated with Severe Mitochondrial Dysfunction

The rare hereditary condition known as mitochondrial DNA depletion syndrome (MTDPS) involves a significant reduction in mitochondrial DNA (mtDNA). Symptoms of this illness can include weariness, physical weakness, and neurological problems; in cases of hepatocerebral MTDPS, the liver and brain are most affected.

Multiple organ systems may fail as a result of mitochondrial diseases, which are among the most prevalent forms of metabolic disorders. Currently, more than 400 genes have been connected to these illnesses.

The complexity of the genetic mechanisms is shown by the notable association of several of these genes with the mitochondrial contact site and cristae organizing system (MICOS) complex.

Researchers from the Division of Diagnostics and Therapeutics of Intractable Diseases at Juntendo University in Japan, under the direction of Professor Yasushi Okazaki, made significant strides in their understanding of MTDPS in a study published in the journal Liver International.

The research team, which included Drs. Kei Murayama, Yoshihito Kishita, and Ayumu Sugiura, used a mix of whole genome sequencing and RNA sequencing techniques to find a particular mutation in the MICOS10 gene in a patient with the illness.

This is the first report of MICOS10 variants in hepatocerebral MTDPS. Understanding how defects in this complex affect cristae formation and mitochondrial function could provide new insights into the molecular pathogenesis underlying this disease.”

Yasushi Okazaki, Professor, Juntendo University

A young kid with significant liver disease, including cirrhosis and developmental disabilities, was the subject of the investigation. The patient's neurological issues persisted even after receiving a liver transplant.

Defects in the mitochondrial respiratory chain and a substantial decrease in mtDNA levels were found in laboratory studies. The diagnosis of MTDPS was made after it was discovered that the amount of mtDNA in the liver tissue removed during the transplant was only 23.7% of the usual level.

Subsequent whole genome sequencing identified two MICOS10 gene variants: a deletion in big exon 1 and a single nucleotide missense mutation that most likely accounted for the patient's symptoms.

The exon 1 deletion inhibited the expression of the second copy of the gene, thus only the copy with the missense mutation was active despite the presence of both copies. The patient's disease was probably exacerbated by the restricted expression of a single harmful version of MICOS10, which interfered with mitochondrial function.

Restoring MICOS10 expression improved mitochondrial respiration, as seen by increased oxygen consumption, and corrected defects of the cristae structures in patient-derived fibroblast cells, according to functional tests. This study validated the critical function of MICOS10 in preserving mitochondrial structure and function.

The results of this investigation mark a significant advancement in our knowledge of mitochondrial disorders. By shedding light on the function of MICOS10, the study opens new possibilities for genetic testing and treatment development.

Clarifying genetic variants that were previously undetectable could greatly improve the efficiency of diagnosis for patients with mitochondrial disorders.”

Yasushi Okazaki, Professor, Juntendo University

These novel discoveries may open the door to focused therapies, giving afflicted patients hope for mitochondrial function restoration. This study opens the door to a better future by expanding the knowledge of MTDPS and emphasizing the potential of sophisticated genetic diagnostics, giving those dealing with these complicated illnesses fresh hope.