Biophotonics LaboratoryDepartment of Electrical Engineering and Computer Science, College of Engineering and Computer ScienceFlorida Atlantic University Boca Raton FL 33431 USA.
Department of Biomedical ScienceCharles E. Schmidt College of MedicineFlorida Atlantic University Boca Raton FL 33431 USA.
IEEE J Transl Eng Health Med. 2024 Jan 15;12:298-305. doi: 10.1109/JTEHM.2024.3355962. eCollection 2024.
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.
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.
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.
代谢变化在神经退行性脑疾病中已有广泛的记载，包括帕金森病和阿尔茨海默病（AD）。秀丽隐杆线虫 swip-10 基因突变导致多巴胺（DA）依赖性运动功能障碍，并伴有 DA 神经元变性。最近，swip-10 的假定人类同源物（MBLAC1）被认为是 AD 的一个风险因素，这种疾病与帕金森病一样，与线粒体功能障碍有关。有趣的是，MBLAC1 与 AD 相关的风险出现在有心血管疾病的患者中，这表明由于 MBLAC1 蛋白表达减少而导致的更广泛的功能损伤，并且可能与代谢改变有关。
我们目前的研究利用 Mblac1 敲除（KO）小鼠，试图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 光学冷冻成像技术，在雄性和雌性 WT 小鼠及其纯合 KO 同窝仔鼠的肝脏和肾脏中定量测定线粒体辅酶、NADH、FAD 及其氧化还原比（NADH/FAD，RR）的水平。
与 WT 相比，KO 小鼠肝脏的 RR 显著降低，没有明显的性别效应，主要是由于 NADH 水平显著降低。相比之下，在肾脏样本中没有观察到基因型和性别差异。WT 和 KO 小鼠的血清分析显示，年轻和年老的 KO 成年鼠的血糖水平显著升高，年老的 KO 鼠的胆固醇水平降低，这与肝功能障碍一致。
讨论/结论：与 C. elegans swip-10 突变体一样，MBLAC1 蛋白的缺失导致代谢变化不仅限于神经细胞，并且与神经退行性疾病伴随的外周合并症一致，在这种情况下，MBLAC1 表达变化影响风险。
