3. Iworima, DG; Pasqualotto, BA; Rintoul, GL. (2016) Kif5 regulates mitochondrial movement, morphology, function and neuronal survival.Molecular and Cellular Neuroscience 72: 22-33 Kif5 regulates mitochondrial movement, morphology, function and neuronal survival
kif5; Mitochondrial dynamics; Mitochondrial remodelling excitotoxicity; Mitochondrial trafficking; ro-GFP; ATeam
Due to the unique architecture of neurons, trafficking of mitochondria throughout processes to regions of high energetic demand is critical to sustain neuronal health. It has been suggested that compromised mitochondrial trafficking may play a role in neurodegenerative diseases. We evaluated the consequences of disrupted kif5c-mediated mitochondrial trafficking on mitochondrial form and function in primary rat cortical neurons. Morphological changes in mitochondria appeared to be due to remodelling, a phenomenon distinct from mitochondrial fission, which resulted in punctate-shaped mitochondria. We also demonstrated that neurons displaying punctate mitochondria exhibited relatively decreased ROS and increased cellular ATP levels using ROS-sensitive GFP and ATP FRET probes, respectively. Somewhat unexpectedly, neurons overexpressing the dominant negative form of kif5c exhibited enhanced survival following excitotoxicity, suggesting that the impairment of mitochondrial trafficking conferred some form of neuroprotection. However, when neurons were exposed to H2O2, disruption of kif5c exacerbated cell death indicating that the effect on cell viability was dependent on the mode of toxicity. Our results suggest a novel role of kif5c. In addition to mediating mitochondrial transport, kif5c plays a role in the mechanism of regulating mitochondrial morphology. Our results also suggest that kif5c mediated mitochondrial dynamics may play an important role in regulating mitochondrial function and in turn cellular health. Moreover, our studies demonstrate an interesting interplay between the regulation of mitochondrial motility and morphology. (C) 2016 Elsevier Inc. All rights reserved. DOI
2. Deheshi, S; Pasqualotto, BA; Rintoul, GL. (2013) Mitochondrial trafficking in neuropsychiatric diseases.Neurobiology of Disease 51: 66-71 Mitochondrial trafficking in neuropsychiatric diseases
CULTURED HIPPOCAMPAL-NEURONS; CHILDHOOD-ONSET SCHIZOPHRENIA; IMPAIRED AXONAL-TRANSPORT; ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASES; AMYLOID-BETA; CALCIUM UNIPORTER; MONOAMINE OXIDASE; FOREBRAIN NEURONS; CORTICAL-NEURONS
Mitochondria have numerous roles in healthy neuronal functioning and in neuronal injury mechanisms. They are quite dynamic organelles in that they fuse, divide and move throughout axons and dendrites. The mechanisms of mitochondrial motility have received much attention, however the significance of the dynamic nature of mitochondria in neurons is unclear. Nonetheless, deficits in mitochondrial trafficking have been implicated in numerous neurodegenerative disorders. The role of aberrant mitochondrial trafficking in neuropsychiatric disorders is not as well understood, but may involve similar mechanisms. In this review we examine the evidence which implicates changes in mitochondrial trafficking in the pathogenesis of neuropsychiatric disorders and hypothesize how defective mitochondrial transport may contribute to disease mechanisms. (C) 2012 Elsevier Inc. All rights reserved. DOI
1.Rintoul, GL; Reynolds, IJ. (2010) Mitochondrial trafficking and morphology in neuronal injury.Biochimica et Biophysica Acta-Molecular Basis of Disease 1802: 143-150 Mitochondrial trafficking and morphology in neuronal injury
Mitochondria; Neurodegeneration; Fission; Fusion
Alterations in mitochondrial function may have a central role in the pathogenesis of many neurodegenerative diseases. The study of mitochondrial dysfunction has typically focused on ATP generation, calcium homeostasis and the production of reactive oxygen species. However, there is a growing appreciation of the dynamic nature of mitochondria within cells. Mitochondria are highly motile organelles, and also constantly undergo fission and fusion. This raises the possibility that impairment of mitochondrial dynamics could contribute to the pathogenesis of neuronal injury. In this review we describe the mechanisms that govern mitochondrial movement, fission and fusion. The key proteins that are involved in mitochondrial fission and fusion have also been linked to some inherited neurological diseases, including autosomal dominant optic atrophy and Charcot-Marie-Tooth disease 2A. We will discuss the evidence that altered movement, fission and fusion are associated with impaired neuronal viability. There is a growing collection of literature that links impaired mitochondrial dynamics to a number of disease models. Additionally, the concept that the failure to deliver a functional mitochondrion to the appropriate site within a neuron could contribute to neuronal dysfunction provides an attractive framework for understanding the mechanisms underlying neurologic disease. However, it remains difficult to clearly establish that altered mitochondrial dynamics clearly represent a cause of neuronal dysfunction. (C) 2009 Elsevier B.V. All rights reserved. DOI
