A New Genetic Insight into Mitochondrial DNA Depletion Syndrome
Japanese researchers have identified a novel genetic cause for hepatocerebral mitochondrial DNA depletion syndrome (MTDPS), linking it to variants in the MICOS10 gene. This finding provides valuable insight into the mechanisms of mitochondrial diseases, which impair energy production and often lead to severe multi-organ dysfunction.
Mitochondrial DNA depletion syndrome is a rare disorder characterized by a significant reduction in mitochondrial DNA (mtDNA), with symptoms ranging from muscle weakness and fatigue to liver and brain dysfunction. Hepatocerebral MTDPS, a severe subtype, predominantly affects the liver and central nervous system. With over 400 genes implicated in mitochondrial diseases, many are associated with the mitochondrial contact site and cristae organizing system (MICOS) complex, an essential component of mitochondrial structure and function.
Identifying MICOS10 variants enhances our understanding of mitochondrial function and genetic diagnosis in rare diseases; Image Credit: Yasushi Okazaki from Juntendo University, Japan.
This discovery reportedly marks the first documentation of MICOS10 variants in this context and highlights their role in mitochondrial disease pathology.
Key Findings: Genetic Variants and Mitochondrial Dysfunction
The study investigated a patient presenting with severe liver dysfunction, including cirrhosis, developmental delays, and persistent neurological symptoms post-liver transplantation. Mitochondrial respiratory chain defects and a marked reduction in mtDNA levels — only 23.7% of normal — were identified, confirming a diagnosis of MTDPS.
Through whole genome sequencing, two MICOS10 gene variants were detected:
- A single nucleotide missense mutation, where a single DNA base change results in the substitution of one amino acid for another in a protein, potentially altering its function.
- A deletion in large exon 1, a segment of the gene that contains coding information for protein synthesis. Exons are portions of a gene that are expressed and translated into proteins.
While both copies of the gene were present, only the mutated copy was functional, as the exon 1 deletion inhibited expression of the other copy. This reduced MICOS10 expression disrupted mitochondrial structure and respiration, leading to the observed clinical features.
Functional assays in fibroblast cells derived from the patient revealed that reintroducing normal MICOS10 expression restored mitochondrial respiration and corrected cristae structural abnormalities. The cristae are the inner folds of the mitochondrial membrane where energy production occurs. Disruption in cristae structure can impair the mitochondria’s ability to generate energy efficiently.
“Our functional studies showed that restoring MICOS10 expression can rescue mitochondrial dysfunction,” says Prof. Okazaki. “This confirms the crucial role of MICOS10 in maintaining mitochondrial structure and function.”
These results hint at the essential role of MICOS10 in maintaining mitochondrial integrity.
Implications for Diagnosis and Treatment
This study highlights the importance of the MICOS10 gene in mitochondrial function and its potential role in genetic diagnostics. Identifying such genetic variants could improve diagnostic accuracy for mitochondrial diseases, particularly for those previously undiagnosed due to limitations in genetic testing technologies.
“Clarifying genetic variants that were previously undetectable could greatly improve the efficiency of diagnosis for patients with mitochondrial disorders,” Prof. Okazaki emphasizes. “These insights could unlock targeted treatments, offering hope for restoring mitochondrial function in affected patients.”
