Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Institute for Brain and Cognition, Tarbiat Modares University, Tehran, Iran.
Mol Neurobiol. 2024 Jun;61(6):3442-3460. doi: 10.1007/s12035-023-03778-x. Epub 2023 Nov 23.
Multiple sclerosis (MS) is a primary inflammatory demyelinating disease with different clinical courses and subtypes. The present study aimed to determine whether mitochondrial dysfunction and sirtuins 1 and 3, as metabolism and epigenetic modifying factors, might contribute to MS disease progression measured by physical disability and cognitive impairment.The volunteers (n = 20 controls, n = 59 MS) were recruited and assessed for cognitive function and disability scores; then, patients were clinically classified as relapsing-remitting (RR) in remission phase, RR in relapse phase, and secondary progressive MS. We measured sirtuin (SIRT) 1 and 3 levels, mitochondrial complex I, IV, aconitase, and α-ketoglutarate dehydrogenase (α-KGD) activity in the peripheral blood mononuclear cells (PBMCs). Furthermore, SIRT1, pyruvate, lactate, and cytochrome c (Cyt c) were determined in plasma. Finally, we performed postmortem tissue immunohistochemistry to assess the level of SIRT1 and SIRT3 in the brain lesions of patients with MS.Increased disability and cognitive impairment in patients were correlated. Plasma level of lactate showed a correlation with the disability in MS patients; moreover, a trend toward increased Cyt c plasma level was observed. Investigation of PBMCs exhibited decreased SIRT1 during the relapse phase along with a reduced complex IV activity in all MS subgroups. α-KGD activity was significantly increased in the RR-remission, and SIRT3 was elevated in RR-relapse group. This elevation correlated with disability and cognitive impairment. Finally, immunohistochemistry demonstrated increased levels of SIRT1 and 3 in the brain active lesion of patients with MS.Our data suggest that mitochondrial dysfunction and alteration in some epigenetics and metabolism modifying factors in the CNS and peripheral blood cells may contribute or correlate with MS progression.
多发性硬化症（MS）是一种原发性炎症性脱髓鞘疾病，具有不同的临床病程和亚型。本研究旨在确定线粒体功能障碍以及作为代谢和表观遗传修饰因子的 Sirtuins 1 和 3 是否可能导致通过身体残疾和认知障碍来衡量的 MS 疾病进展。志愿者（n=20 名对照组，n=59 名 MS 患者）被招募并进行认知功能和残疾评分评估；然后，根据临床将患者分类为缓解期复发缓解型（RR）、复发期 RR 型和继发进展型 MS。我们测量了外周血单个核细胞（PBMCs）中的 Sirtuin（SIRT）1 和 3 水平、线粒体复合物 I、IV、乌头酸酶和α-酮戊二酸脱氢酶（α-KGD）活性。此外，还测定了血浆中的 SIRT1、丙酮酸、乳酸和细胞色素 c（Cyt c）。最后，我们进行了尸检组织免疫组织化学，以评估 MS 患者脑损伤中 SIRT1 和 SIRT3 的水平。患者的残疾和认知障碍增加与增加相关。MS 患者的血浆乳酸水平与残疾相关；此外，还观察到 Cyt c 血浆水平呈上升趋势。对 PBMCs 的研究表明，在复发期 SIRT1 减少，所有 MS 亚组的复合物 IV 活性降低。RR 缓解期的α-KGD 活性显著增加，RR 复发组的 SIRT3 升高。这种升高与残疾和认知障碍相关。最后，免疫组织化学显示 MS 患者脑活跃病变中的 SIRT1 和 3 水平升高。我们的数据表明，中枢神经系统和外周血细胞中线粒体功能障碍以及某些表观遗传和代谢修饰因子的改变可能与 MS 进展有关或相关。
