Abstract:

The relationships between the molecular abnormalities in mitochondrial respiratory chain complexes and their negative contributions to mitochondrial and cellular functions have been proved to be essential for better understandings in mitochondrial medicine. Herein, we established the method to identify disease phenotypic differences among patients with muscle histopathological cytochrome c oxidase (COX) deficiency, as one of the representative clinical features in mitochondrial diseases, by using patients' myoblasts that are derived from biopsied skeletal muscle tissues. We identified two obviously different severities in molecular diagnostic criteria of COX deficiency among patients: structurally stable, but functionally mild/moderate defect and severe functional defect with the disrupted COX holoenzyme structure. COX holoenzyme disorganization actually triggered several mitochondrial dysfunctions, including the decreased ATP level, the increased oxidative stress level, and the damaged membrane potential level, all of which lead to the deteriorated cellular growth, the accelerated cellular senescence, and the induced apoptotic cell death. Our cell-based in vitro diagnostic approaches would be widely applicable to understanding patient-specific pathomechanism in various types of mitochondrial diseases, including other respiratory chain complex deficiencies and other mitochondrial metabolic enzyme deficiencies.

日本語要旨:

チトクロームｃ酸化酵素欠損症患者の培養細胞を用いて、酵素活性、蛋白量、アッセンブリー状態などの解析を行うことで病態解析が可能であることを示した。