Regulation of mitophagy in ischemic neurons

Cerebral ischemia remains the top causes of mortality and disability worldwide.The pathological mechanisms underlying ischemic brain injury are not fully illustrated.Cerebral ischemia induces massive mitochondrial damage,which are cleared by mitochondrial autophagy(mitophagy).Our previous studies indicated mitophagy is critical for neuronal survival after ischemic injury,thus raise the conception of rescuing ischemic brain injury by regulating neuronal mitophagy.We further explored the molecular mechanisms underlying ischemia-induced mitophagy,in particular with the regulations of Nix.Our ongoing study focuses on the spatial features of neuronal mitophagy after ischemic insult.Distinct from other cell types,neurons are highlypolarized cells with elaborate dendrites and axons,in which extensive mitochondrial are distributed.Despite the facts that neuronal mitophagy is promptly activated by ischemia,the intracellular locations of mitophagy in neuron,however are largely unknown.The primary cultured mice cortical neurons were treated with oxygen-glucose deprivation(OGD),which mimics ischemia.We confirmed mitochondrial loss both in neuronal cell bodies and axons.However,we found that axonal mitochondria elimination was not compromised in autophagy deficient neurons,suggesting the absence of direct mitophagy in axons.We unexpectedly found that axonal mitochondria underwent a prompt retrograde transportation upon reperfusion while the anterograde mitochondrial mobility was irreversible lost after OGD.We labelled the axonal mitochondria and found they were degraded by autophagic machin-ery in neuronal soma.Inhibition of axonal mitochondria retrograde transportation by expression Syntaphilin,an anchoring protein,blocked neuronal mitophagy.Conversely,chimeric expression of a fusion protein targets mitochondria to dynein complex reinforced mitochondrial retrograde transport and enhanced mitophagy.These evidences indicated a somatic autophagy of axonal mitochondria in ischemic neurons.This pattern may facilitate neuronal mitophagy in the scenario of acute ischemia.Taken together,we found that axonal mitochondria are not cleared locally in axons but are retrograde transported to neuronal soma for mitophagy in ischemic neurons.The present study identified a novel pattern for neurons to eliminate damaged mitochondria and provided the missing link between mitochondrial mobility and mitophagy in ischemic neurons.