2024-06-05 ワシントン大学セントルイス校
◆ミトコンドリア病はエネルギー生成に影響を与えますが、研究チームはタンパク質がどのようにエネルギー生成複合体を形成するかを明らかにしました。遺伝的変異に敏感な領域を特定し、ニューカッスル大学のロバート・テイラー教授と協力して、病気関連変異の関連性を解明しました。さらに、5,000以上の追加変異を特定し、病因遺伝的変異を特定する臨床診断ツールの開発に貢献しました。
<関連情報>
- https://source.wustl.edu/2024/06/analysis-reveals-function-of-mitochondrial-disease-related-protein/
- https://www.nature.com/articles/s42255-024-01039-2
複合体Iの構築とミトコンドリア病におけるNDUFAF6の系統的解析 Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease
Andrew Y. Sung,Rachel M. Guerra,Laura H. Steenberge,Charlotte L. Alston,Kei Murayama,Yasushi Okazaki,Masaru Shimura,Holger Prokisch,Daniele Ghezzi,Alessandra Torraco,Rosalba Carrozzo,Agnès Rötig,Robert W. Taylor,James L. Keck & David J. Pagliarini
Nature Metabolism Published:08 May 2024
DOI:https://doi.org/10.1038/s42255-024-01039-2
Abstract
Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding interpretation of potential disease-causing genetic variants. To address these challenges, we devised a deep mutational scanning approach to systematically assess the function of thousands of NDUFAF6 genetic variants. Guided by these data, biochemical analyses and cross-linking mass spectrometry, we discovered that the CIAF NDUFAF6 facilitates incorporation of NDUFS8 into CI and reveal that NDUFS8 overexpression rectifies NDUFAF6 deficiency. Our data further provide experimental support of pathogenicity for seven novel NDUFAF6 variants associated with human pathology and introduce functional evidence for over 5,000 additional variants. Overall, our work defines the molecular function of NDUFAF6 and provides a clinical resource for aiding diagnosis of NDUFAF6-related diseases.
