Mitochondrial mutations as determinants of beneficial versus maleficial exercise response in mouse models for mitochondrial diseases (Mitosport)

原发线粒体疾病现在被认为是最常见的代谢性疾病，估计每4200人中就有1人受到影响。此外，线粒体功能障碍与从糖尿病到阿尔茨海默病等一系列常见疾病有关。然而，目前还没有针对线粒体疾病的有效治疗措施。运动被发现对糖尿病和阿尔茨海默氏症有益，这表明适当的运动方案可能对原发性线粒体疾病也有好处。然而，原发性线粒体疾病在遗传上是多样化的，涉及线粒体DNA(MtDNA)和核DNA(NDNA)基因的数百个突变。因此，我假设特定的运动方案对一些线粒体疾病是有益的，但在另一些依赖于潜在的线粒体缺陷的情况下是禁忌的。线粒体和表观基因组医学中心(CMEM)已经开发出一系列独特的线粒体疾病小鼠模型，其中包括线粒体DNA复合体I(ND6P25L)和IV(COIV421A)基因的突变以及腺核苷酸转运体1(ANT1)的突变。这些突变小鼠包括广泛的线粒体功能障碍，因此提供了一个特殊而强大的机会，将不同的线粒体缺陷暴露在受控运动制度下，然后进行详细的生理和生化分析。在分子水平上，运动适应是通过代谢产物和氧化还原变化来调节的，比如NAD/NADH比率，这可以通过高空间分辨率的显微镜下确定。通过结合CMEM的小鼠模型和我在氧化还原成像方面的专业知识，我现在处于一个独特的位置来阐明线粒体突变、运动反应和潜在的分子途径之间的相互关系。这将为线粒体患者提供有关有益体力活动的个性化临床建议，并深入了解运动对常见疾病的治疗基础。我将追求三个具体目标：特定目标1：确定线粒体突变小鼠的运动生理学及其对运动刺激的急性反应。每天的活动和对急性运动应激测试(VO2max)的反应将被评估，并与氧化还原状态、代谢物水平、信号通路变化和炎症反应的变化相关联。具体目标2：根据运动方案评估线粒体突变小鼠的运动适应。小鼠将接受为期6周的运动方案，以评估它们在生理、呼吸复合体活动、代谢产物和信号通路方面的线粒体反应。具体目标3：通过评估烟酰胺核苷和AICAR作为运动模拟物，阐明运动反应的生理学基础。我将通过改变突变小鼠的NAD/NADH比率或ADP/ATP比率来评估其对运动能力的影响。

Primary mitochondrial disorders are now recognized as the most common class of metabolic disorders affecting an estimate 1 in 4200 individuals. Furthermore, mitochondrial dysfunction has been implicated in a wide range of common diseases from diabetes to Alzheimer’s disease. Yet, there are no proven therapeutic interventions for mitochondrial disease. Exercise has been found to be beneficial for diabetes and Alzheimer’s disease indicating that appropriate exercise regimes might be beneficial for primary mitochondrial disease as well. However, primary mitochondrial diseases are genetically diverse involving hundreds of mutations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes. Accordingly, I hypothesize that specific exercise regimes will be beneficial for some mitochondrial disorders but contraindicated in others dependent on the underlying mitochondrial defect.The Center for Mitochondrial and Epigenomic Medicine (CMEM) has developed a unique series of viable mouse models of mitochondrial disease, among which are mutations in the mtDNA complex I (ND6P25L) and IV (COIV421A) genes and in the adenine nucleotide translocator 1 (Ant1). These mutant mice encompass a wide range of mitochondrial dysfunction and thus provide an exceptional and powerful opportunity to expose different mitochondrial defects to controlled exercise regimes followed by detailed physiological and biochemical analyses. On the molecular level, exercise adaptions are mediated via metabolite and redox changes like the NAD/NADH ratio, which can be determined microscopically with high spatial resolution.By combining CMEM’s mouse models with my expertise in redox imaging I am now in a unique position to clarify the interrelation between mitochondrial mutations, exercise response, and the underlying molecular pathways. This will open the possibility of personalized clinical advice for mitochondrial patients regarding beneficial physical activity, as well as obtain deep insight into the therapeutic basis of exercise for common diseases.I will pursue 3 specific aims:Specific Aim 1: Determination of the exercise physiology of the mitochondrial mutant mice and their acute response to an exercise stimulus. The daily activity and the response to an acute exercise stress test (VO2max) will be assessed and correlated with changes in redox state, metabolite levels, signaling pathway changes and inflammatory response.Specific Aim 2: Assess the exercise adaptions of the mitochondrial mutant mice upon an exercise protocol. The mice will be exposed to a 6 week exercise protocol to assess their mitochondrial responses in physiology, respiratory complex activity, metabolites, and signaling pathways.Specific Aim 3: Elucidate the physiological basis of the exercise response by evaluating nicotinamide riboside and AICAR as exercise mimetics. I will evaluate the effects on exercise capacity of the mutant mice by altering their NAD/NADH ratio or ADP/ATP ratio specifically.