Docosahexaenoic Acid Alleviates Brain Damage by Promoting Mitophagy in Mice with Ischaemic Stroke

Abstract

Mitophagy, the selective removal of damaged mitochondria through autophagy, is crucial for mitochondrial turnover and quality control. Docosahexaenoic acid (DHA), an essential omega-3 fatty acid, protects mitochondria in various diseases. This study aimed to investigate the neuroprotective role of DHA in ischaemic stroke models in vitro and in vivo and its involvement in mitophagy and mitochondrial dysfunction. A mouse model of ischaemic stroke was established through middle cerebral artery occlusion (MCAO). To simulate ischaemic stroke in vitro, PC12 cells were subjected to oxygen–glucose deprivation (OGD). Immunofluorescence analysis, western blotting (WB), electron microscopy (EM), functional behavioural tests, and Seahorse assay were used for analysis. DHA treatment significantly alleviated the brain infarction volume, neuronal apoptosis, and behavioural dysfunction in mice with ischaemic stroke. In addition, DHA enhanced mitophagy by significantly increasing the number of autophagosomes and LC3-positive mitochondria in neurons. The Seahorse assay revealed that DHA increased glutamate and succinate metabolism in neurons after ischaemic stroke. JC-1 and MitoSox staining, and evaluation of ATP levels indicated that DHA-induced mitophagy alleviated reactive oxygen species (ROS) accumulation and mitochondrial injury. Mechanistically, DHA improved mitochondrial dynamics by increasing the expression of dynamin-related protein 1 (Drp1), LC3, and the mitophagy clearance protein Pink1/Parkin. Mdivi-1, a specific mitophagy inhibitor, abrogated the neuroprotective effects of DHA, indicating that DHA protected neurons by enhancing mitophagy. Therefore, DHA can protect against neuronal apoptosis after stroke by clearing the damaged mitochondria through Pink1/Parkin-mediated mitophagy and by alleviating mitochondrial dysfunction.

Local production of reactive oxygen species drives vincristine-induced axon degeneration

“…Mdivi-1 has recently been shown to act not by inhibiting DRP1, but instead by inhibiting ROS production in mitochondria [28, 35–37]. We therefore evaluated whether mdivi-1 treatment resulted in a decrease in axonal ROS levels.…”

The role of free fatty acid receptor-1 in gastric contractions in Suncus murinus

“…DHA (20 mg kg −1 ) was injected with IG 10–15 min after the onset of phase I contractions, and saline was administered as a vehicle at different phase I contractions using the same suncus. 25…”

“…DHA (20 mg kg −1 ) was injected with IG 10-15 min after the onset of phase I contractions, and saline was administered as a vehicle at different phase I contractions using the same suncus. 25 In order to observe the effect of OA through FFAR1, suncus was IP injected with the FFAR1 antagonist (GW1100) (2.5 mg kg −1 ) within 5 min of the onset of phase I contractions, followed by the administration of OA (160 mg kg −1 , IG) 15 min later. 26 The same suncus received an injection of the same quantity of 2.5% DMSO/saline as a vehicle.…”

Nutrition and autophagy deficiency in critical illness

“…However, docosahexaenoic acid and other (omega-3) polyunsaturated fatty acids (PUFAs) may induce neuroprotection against palmitate-induced lipotoxicity via enhanced autophagy [118]. Also, docosahexaenoic acid alleviated brain damage and behavioral dysfunction in mice with ischemic stroke, with neuroprotection abrogated by mitophagy inhibition [119]. Autophagy induction has further been implicated in neuroprotection by omega-3 PUFA supplementation after TBI in rats [120] and protection from lipopolysaccharide-induced cardiac dysfunction or ischemia-reperfusion renal injury in transgenic mice with high endogenous omega-3 PUFAs [121,122].…”