Optical Imaging Demonstrates Tissue-Specific Metabolic Perturbations in Mblac1 Knockout Mice

Objective: Metabolic changes have been extensively documented in neurodegenerative brain disorders, including Parkinson’s disease and Alzheimer’s disease (AD). Mutations in the C. elegans swip-10 gene result in dopamine (DA) dependent motor dysfunction accompanied by DA neuron degeneration. Recently, the putative human ortholog of swip-10 (MBLAC1) was implicated as a risk factor in AD, a disorder that, like PD, has been associated with mitochondrial dysfunction. Interestingly, the AD risk associated with MBLAC1 arises in subjects with cardiovascular morbidity, suggesting a broader functional insult arising from reduced MBLAC1 protein expression and one possibly linked to metabolic alterations. Methods: Our current studies, utilizing Mblac1 knockout (KO) mice, seek to determine whether mitochondrial respiration is affected in the peripheral tissues of these mice. We quantified the levels of mitochondrial coenzymes, NADH, FAD, and their redox ratio (NADH/FAD, RR) in livers and kidneys of wild-type (WT) mice and their homozygous KO littermates of males and females, using 3D optical cryo-imaging. Results: Compared to WT, the RR of livers from KO mice was significantly reduced, without an apparent sex effect, driven predominantly by significantly lower NADH levels. In contrast, no genotype and sex differences were observed in kidney samples. Serum analyses of WT and KO mice revealed significantly elevated glucose levels in young and aged KO adults and diminished cholesterol levels in the aged KOs, consistent with liver dysfunction. Discussion/Conclusion: As seen with C. elegans swip-10 mutants, loss of MBLAC1 protein results in metabolic changes that are not restricted to neural cells and are consistent with the presence of peripheral comorbidities accompanying neurodegenerative disease in cases where MBLAC1 expression changes impact risk.

目的：神经退行性脑部疾病（包括帕金森病和阿尔茨海默病）中的代谢变化已有大量文献记载。秀丽隐杆线虫swip - 10基因的突变会导致多巴胺（DA）依赖性运动功能障碍，并伴有DA神经元变性。最近，swip - 10的假定人类同源基因（MBLAC1）被认为是阿尔茨海默病的一个风险因素，阿尔茨海默病和帕金森病一样，与线粒体功能障碍有关。有趣的是，与MBLAC1相关的阿尔茨海默病风险出现在有心血管疾病的受试者中，这表明MBLAC1蛋白表达降低会导致更广泛的功能损伤，且可能与代谢改变有关。 方法：我们目前利用Mblac1基因敲除（KO）小鼠进行的研究，旨在确定这些小鼠的外周组织中线粒体呼吸是否受到影响。我们使用3D光学低温成像技术，对野生型（WT）小鼠及其同窝纯合KO雄性和雌性小鼠的肝脏和肾脏中的线粒体辅酶、NADH、FAD及其氧化还原比（NADH/FAD，RR）水平进行了定量。 结果：与WT相比，KO小鼠肝脏的RR显著降低，且无明显性别差异，主要是由NADH水平显著降低所致。相比之下，在肾脏样本中未观察到基因型和性别差异。对WT和KO小鼠的血清分析显示，年轻和老年KO成年小鼠的血糖水平显著升高，老年KO小鼠的胆固醇水平降低，这与肝脏功能障碍相符。 讨论/结论：正如在秀丽隐杆线虫swip - 10突变体中所见，MBLAC1蛋白的缺失会导致代谢变化，这种变化不限于神经细胞，并且与在MBLAC1表达变化影响风险的情况下神经退行性疾病伴随的外周合并症的存在是一致的。