Pathophysiology of stroke-like episodes in MELAS: neuron–astrocyte uncoupling in neuronal hyperexcitability

Abstract

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a distinct clinical syndrome characterized by fluctuated encephalopathy, migraineous headache, seizure and stroke-like episodes. The molecular mechanism of MELAS mutations has been elucidated; however, the pathogenesis of stroke-like episodes remains largely unknown. Three main hypotheses include ischemic, metabolic and neuronal hyperexcitability hypotheses. Recently, emerging hypotheses include alterations in nitric oxide homeostasis and over-reduction/oxidative stress mechanisms. Although neuron–astrocyte communication is crucial in various physiological functions, it has not been seriously considered in the pathophysiology of stroke-like episodes. This review summarizes what is known about the molecular mechanisms of gene mutation, clinico-radiological, clinico-physiological and pathological features of stroke-like episodes, as well as its pathogenesis. We finally discuss potential mechanisms involved in the pathogenesis of stroke-like episodes based on currently available clinical data and the current understanding of the mechanisms of neuron–astrocyte communications. We propose that neuron–astrocyte uncoupling is a new target of research in mitochondrial disorders.