Homozygous mutation in MIC13 disrupts cristae structure andcausesmitochondrial DNA depletion syndrome Yoshihito Kishita1,2, Masakazu Kohda1,2, Masumi Akita3, Yosuke Mizuno2, Yukiko Yatsuka2, Tomoko Hirata2, Hiroko Harashima4, Masaru Shimura5, Kei Murayama5, Akira Ohtake4, Yasushi Okazaki1,2 1Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University, Graduate School of Medicine, Japan,.2 Research Center for Genomic Medicine, Saitama Medical University, Japan, 3Division of Morphological Science, Biomedical Research Center, Saitama Medical University, Japan, 4Deptartment of Pediatrics, Saitama Medical University, Japan, 5Deptartment of Metabolism, Chiba Children's Hospital, Japan
Mitochondrial DNA depletion syndrome (MTDPS) is part of a group of mitochondrial diseases and characterized by a reduction in mitochondrial DNA copy number. Most of MTDPSs are caused by mutations in genes involved in maintenance of mtDNA replication machinery or in mitochondrial dNTP pool availability. Here, the whole exome sequencing of one MTDPS patient identified homozygous frameshift mutation in MIC13. MIC13 (also known as QIL1 or C19orf70) is a component of the MICOS (mitochondrial contact site and cristae organizing system) complex which plays crucial roles in the maintenance of cristae junctions at the mitochondrial inner membrane. In the present study, we found apparent loss of MIC13 protein probably due to the non-sense mediated decay. The reduced cristae structures in mitochondria of the patient-derived fibroblasts were observed by transmission electron microscopy. The wild type cDNA of MIC13 was introduced into fibroblast cells from the patient by lentivirus systems. Stable expression of MIC13 in fibroblasts restored mitochondrial respiratory chain complex deficiencies. Our findings indicate that mutation in MIC13 causes mitochondrial respiratory chain complex deficiency, MTDPS and defects in cristae organization.
Funding The work was supported by a Strategic Research Center in Private Universities grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) and by a Grants-in-Aid for Scientific Research (C) Grant Number 16K09973 from the Japan Society for the Promotion of Science (JSPS).
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