WITHDRAWN: Mitochondrial accumulation induced axon dysfunction promotes paranode instability and demyelination in hypoxic-ischemic forms of demyelination

Abstract

Hypoxic-ischemic forms of demyelination, caused by chronic or acute reduction of blood flow in subcortical white matter, is increasingly considered as an important contributor to cognitive decline. However, it remains unclear how hypoxia/ischemia leads to demyelination pathology and no effective drugs clinically. In this study, we aimed to investigate the relationship between axon injuries and demyelination as well as the mechanism in the development of hypoxic-ischemic forms of demyelination. Bilateral common carotid artery stenosis (BCAS) mouse model of whole-brain hypoperfusion was used to observe the pathological changes of hypoperfusion-induced demyelination in vivo, and low glucose-low oxygen (LGLO) treatment in cerebellum slice cultures was used to uncover molecular machinery in vitro. We found that mitochondria were excessively accumulated among axons after BCAS/LGLO, which impaired the retrograde transport of mitochondria for mitophagy and anterograde transport for metabolic supply. This axonal insult occurred prior to demyelination and promoted the progression of demyelination through impairing the paranode stability by mitochondrial ROS. Syntaphilin (SNPH), an axonal specific arching protein of mitochondria, was elevated after hypoperfusion and was responsible for the accumulation of mitochondria. Knockdown of SNPH promoted retrograde transport of mitochondria to alleviate ROS load among axons and enhanced anterograde transport of mito-chondria for synapse signalling, mitigated demyelination and retrieved cognitive function. Our results uncovered a distinctive pathological characteristic of hypoperfusion-induced demye-lination and clarified SNPH as a promising target in the treatment of hypoxic-ischemic forms of demyelination.