Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.
Brain. 2012 Dec;135(Pt 12):3627-34. doi: 10.1093/brain/aws223. Epub 2012 Oct 12.
Mitochondrial dysfunction and disease may arise as a result of mutations in either the mitochondrial genome itself or nuclear encoded genes involved in mitochondrial homeostasis and function. Irrespective of which genome is affected, mitochondrial encephalopathies share clinical and biochemical features suggesting common pathophysiological pathways. Two common paradigms of mitochondrial encephalopathy are mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes caused by maternally transmitted mutations of mitochondrial DNA and mitochondrial spinocerebellar ataxia and epilepsy caused by recessively inherited mutations of the nuclear-encoded DNA polymerase gamma, which replicates and repairs the mitochondrial genome. We studied and compared the disease mechanisms involved in these two syndromes. Despite having different genetic origins, their pathophysiological pathways converge on one critical event, damage to the respiratory chain leading to insufficient energy to maintain cellular homeostasis. In the central nervous system, this appears to cause selective neuronal damage leading to the development of lesions that mimic ischaemic damage, but which lack evidence of decreased tissue perfusion. Although these stroke-like lesions may expand or regress dynamically, the critical factor that dictates prognosis is the presence of epilepsy. Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death. We believe that it is this cycle of events that determines outcome and which provides us with a mechanistic structure to understand the pathophysiology of acute mitochondrial encephalopathies and plan future treatments.
线粒体功能障碍和疾病可能是由于线粒体基因组本身的突变或参与线粒体动态平衡和功能的核编码基因的突变引起的。无论受影响的基因组是哪一个，线粒体脑病都具有共同的临床和生化特征，提示存在共同的病理生理途径。两种常见的线粒体脑病模式是由母系传递的线粒体 DNA 突变引起的线粒体脑肌病、乳酸酸中毒和卒中样发作，以及由核编码 DNA 聚合酶 γ 的隐性遗传突变引起的线粒体小脑共济失调和癫痫，该突变复制和修复线粒体基因组。我们研究并比较了这两种综合征所涉及的疾病机制。尽管它们具有不同的遗传起源，但它们的病理生理途径集中在一个关键事件上，即呼吸链的损伤导致不足以维持细胞动态平衡的能量。在中枢神经系统中，这似乎导致了选择性神经元损伤，导致类似于缺血性损伤的病变的发展，但缺乏组织灌注减少的证据。尽管这些卒中样病变可能会动态地扩张或消退，但决定预后的关键因素是癫痫的存在。癫痫发作增加了代谢上已经受损的神经元的能量需求，从而建立了一个恶性循环，导致能量衰竭和神经元死亡的恶化。我们认为，正是这种事件循环决定了结局，并为我们提供了一种机制结构来理解急性线粒体脑病的病理生理学，并计划未来的治疗方法。
