title: Voltage-dependent anion channels (VDACs) promote mitophagy to protect neuron from death in an early brain injury following a subarachnoid hemorrhage in rats.
abstract: The term mitophagy is coined to describe the selective removal of mitochondria by autophagy but the process itself is still contentious, especially in the early period following subarachnoid hemorrhage (SAH). In the present study, we investigated the role of mitophagy following 48h after SAH injury in rats. Specifically evaluating whether mitophagy, through voltage dependant anion channels (VDACs) interacting with microtubule-associated protein 1 light chain 3, could orchestrate the induction of apoptotic and necrotic cell death in neurons, a VDAC1siRNA and an activitor Rapamycian (RAPA), were engaged. One hundred and twelve male Sprague-Dawley rats were randomly divided into 4 groups: Sham, SAH, SAH+VDAC1siRNA, and SAH+RAPA. Outcomes measured included mortality rate, brain edema, BBB disruption, and neurobehavioral testing. We also used western blotting techniques to analyze the expressions of key mitophagic/autophagic proteins and pro-apoptotic protein such as ROS, VDAC1, LC-3II and Caspase-3. Rapamycin treatment significantly improved the mortality rate, cerebral edema, and neurobehavioral deficits; apoptotic and necrotic cell death in neurons were reduced by Rapamycin following SAH injury. However, VDAC1siRNA worsened the brain injury following SAH. Immunohistochemical staining and western blot analysis demonstrated a decreased expression of VDAC1, LC3II, and an increase of ROS and Caspase-3 followed by VDAC1siRNA administration. In conclusion, mitophagy induced by VDAC1 following SAH injury may in fact play a significant role in neuroprotection, the mechanism which may be through the attenuation of the apoptosic and necrosic molecular pathways. This translates a preservation of functional integrity and an improvement in mortality.
authors.affiliation: Department of Anatomy, Chengdu Medical College, Chendu, Sichuan 610500, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Anatomy and Histology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Anatomy, Chengdu Medical College, Chendu, Sichuan 610500, China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Department of Anatomy, Chengdu Medical College, Chendu, Sichuan 610500, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Anatomy and Histology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology and Critical Care, Hospital of University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.affiliation: Department of Anatomy, Chengdu Medical College, Chendu, Sichuan 610500, China; Department of Anatomy and Histology, Peking University Health Science Center, Beijing 100191, China. Electronic address: changmanzhou@hotmail.com.
authors.forename: Changman
authors.initials: C
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects / Q000502:physiology*; D009336:Necrosis / Q000188:drug therapy / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D050994:Voltage-Dependent Anion Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D020123:Sirolimus; D050994:Voltage-Dependent Anion Channels; C000595225:FUNDC1 protein, rat; C526109:Anxa3 protein, rat
keywords: Early brain injury; Mitophagy; Neuroprotection; Subarachnoid hemorrhage; Voltage-dependent anion channel (VDAC)