Reduced Adolescent-Age Spatial Learning Ability Associated with Elevated Juvenile-Age Superoxide Levels in Complex I Mouse Mutants

Large-scale, heteroplasmic and generally pathogenic mtDNA defects (as induced by defective mitochondrial DNA polymerase, clonal mutations or DNA deletions) are known to negatively impact on life span and can result in apoptosis and tissue loss in, e.g., skeletal muscle or reduce learning abilities. The functional impact of homoplasmic specific mtDNA point mutations, e.g., in genes coding for the electron transport chain, however, remains a matter of debate. The present study contributes to this discussion and provides evidence that a single point mutation in complex I of the respiratory chain is associated with impairment of spatial navigation in adolescent (6-month-old) mice, i.e., reduced performance in the Morris Water Maze, which goes along with increased production of reactive oxygen species (ROS) in juvenile mice (3 months) but not at the age of phenotype expression. A point mutation in complex III goes along with only a mild and non-significant negative effect on cognitive performance and no significant changes in ROS production. These findings suggest to also consider the ontogenetic development of phenotypes when studying mtDNA mutations and highlights a possible impact of complex I dysfunction on the emergence of neurological deficits.

大规模、异质性 (heteroplasmic) 且通常具有致病性的线粒体DNA (mtDNA) 缺陷——由功能异常的线粒体DNA聚合酶、克隆突变或DNA缺失所诱发——已被证实会对寿命产生负面影响，可引发细胞凋亡与组织丢失（如骨骼肌组织），或导致学习能力下降。然而，针对电子传递链 (electron transport chain) 编码基因的特异性同质性 (homoplasmic) 线粒体DNA点突变，其对机体的功能影响仍存在争议。本研究为该争议话题提供了新的佐证，证实呼吸链 (respiratory chain) 复合物I (complex I) 上的单一点突变，会导致青春期（6月龄）小鼠的空间导航能力受损，具体表现为莫里斯水迷宫 (Morris Water Maze) 实验中表现下滑；该突变在幼年（3月龄）小鼠中会伴随活性氧簇 (reactive oxygen species, ROS) 生成量升高，但在表型显现的年龄阶段则无此现象。而呼吸链复合物III (complex III) 上的点突变，仅会对认知功能产生轻微且无统计学意义的负面影响，且未引起ROS生成量的显著变化。上述研究结果提示，在研究线粒体DNA突变时，也应考虑表型的个体发育 (ontogenetic development) 进程，并凸显了复合物I功能异常对神经功能缺损发生的潜在影响。