Abstract
Mitophagy specifically describes autophagy of damaged or dysfunctional mitochondria and occurs in programmed cell death when mitochondria fragment and remodel their cristae. Cellular bioenergetics is entwined with mitochondrial dynamics, and mitochondrial insults, including depolarization and inhibition of electron transport chain, trigger mitochondrial fragmentation. Here we investigated mitophagy in neurons during manipulation of mitochondrial bioenergetics. Dysfunction of mitochondria was induced by pharmacological inhibition of respiratory chain complexes I-V (rotenone, 3-nitropropionic acid, antimycin A, KCN & oligomycin, respectively) in primary cultures of cerebellar granule cells. The extent of bioenergetic failure was determined by measuring [ATP], depolarization of mitochondrial membrane potential and decrease in oxygen consumption rate in the Seahorse XF24. All stressors produced mitochondrial dysfunction as shown by concentration- and time-dependent decline in [ATP] over 4-24h. Complexes I, III or IV showed rapid loss of mitochondrial membrane potential and decreases in oxygen consumption rate over 4-24h. Autophagolysosomal flux was increased as shown by increased LC3-II and labelling of acidic vacuoles with monodansylcadaverine. Immunocytochemistry for PINK1 showed translocation of PINK1 from cytoplasm to mitochondria after injury, indicating likely involvement of mitophagy during bioenergetic dysfunction. Transfection of fluorescent pH-biosensor Rosella (Rosado CJ et al. Autophagy 4: 205 (2008)) targeting mitochondria indicated the pH of the mitochondrial location dropped with the inhibition of complex I and II, implying acidification of mitochondria, presumably in acidic vesicles undergoing mitophagy. Dieback of neuronal arbor observed here paralleled that seen with a GFP-plasmid. Together these data indicate that bioenergetic dysfunction produces mitophagy in primary neurons and is likely to be involved in neuronal dynamics.
Highlights
Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia
The results of the present study indicate that development of the neuronal hypoxic tolerance induced by the three-trial, in contrast to one-trial, mild hypoxic preconditioning is apparently largely associated with the activation of CREB, as well as brain-derived neurotrophic factor (BDNF) and Bcl-2 overexpression
No significant differences in serum level of Solubile form of RAGE (sRAGE) where found between rapidly progressing and slow progressing subgroup of multiple sclerosis (MS) patients.Our results suggest for the role of sRAGE in MS ethiopathogenesis, but we did not find any association of sRAGE in serum with the rate of MS disability progression
Summary
Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia. The aim of the study was to characterize the effects of streptozocin (STZ)-indced diabetes on learning and memory of 5XFAD and wild-type (WT) mice in Morris water maze (MWM) at ages 2 and 6 months and on brain amyloid load. Existing evidence suggests GABAergic system is involved in pathophysiology of Alzheimer’s disease (AD) via inhibitory interneuron deficits (Verret et al, 2012) and decrease in functional GABAA receptors (Limon et al, 2012). Our concept: low doses of muscimol may prevent learning/memory deficits in intracerebroventricular (icv) streptozocin (STZ)-induced AD nontransgenic rat model. The Sigma-1 receptor is a chaperone protein that modulates intracellular calcium signalling of the endoplasmatic reticulum and is involved in learning and memory processes.The aim of the present study was to compare in vitro Ca2+ concentration modulating activity and in vivo behavioural effects of enantiomers of methylphenylpiracetam, a novel positive allosteric modulator of Sigma-1 receptors
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