Mitochondrial dynamics, cell death and the pathogenesis of Parkinson’s disease

Abstract

The structure and function of the mitochondrial network is regulated by mitochondrial biogenesis, fission, fusion, transport and degradation. A well-maintained balance of these processes (mitochondrial dynamics) is essential for neuronal signaling, plasticity and transmitter release. Core proteins of the mitochondrial dynamics machinery play important roles in the regulation of apoptosis, and mutations or abnormal expression of these factors are associated with inherited and age-dependent neurodegenerative disorders. In Parkinson's disease (PD), oxidative stress and mitochondrial dysfunction underlie the development of neuropathology. The recessive Parkinsonism-linked genes PTEN-induced kinase 1 (PINK1) and Parkin maintain mitochondrial integrity by regulating diverse aspects of mitochondrial function, including membrane potential, calcium homeostasis, cristae structure, respiratory activity, and mtDNA integrity. In addition, Parkin is crucial for autophagy-dependent clearance of dysfunctional mitochondria. In the absence of PINK1 or Parkin, cells often develop fragmented mitochondria. Whereas excessive fission may cause apoptosis, coordinated induction of fission and autophagy is believed to facilitate the removal of damaged mitochondria through mitophagy, and has been observed in some types of cells. Compensatory mechanisms may also occur in mice lacking PINK1 that, in contrast to cells and Drosophila, have only mild mitochondrial dysfunction and lack dopaminergic neuron loss. A better understanding of the relationship between the specific changes in mitochondrial dynamics/turnover and cell death will be instrumental to identify potentially neuroprotective pathways steering PINK1-deficient cells towards survival. Such pathways may be manipulated in the future by specific drugs to treat PD and perhaps other neurodegenerative disorders characterized by abnormal mitochondrial function and dynamics.

Bioactive l-DOPA induced quinoprotein formation to inhibit root growth of cucumber seedlings

“…24,25) Moreover, quinoproteins from dopaminequinone induced mitochondrial swelling and permeability transition of the mitochondrial membrane and reduced complex I activity and electron transport leading to dysfunction of mitochondria in human and rat brains. 12,26,27) Recent proteomics studies using radiolabeled dopamine showed that dopaminequinone covalently modified critical proteins such as mitochondrial chaperonin, ubiquinol-cytochrome c reductase, mortalin, mitofilin, creatine kinase, and NADH dehydrogenase in animal and human cells. 28,29) The covalent modification of these proteins by dopaminequinone may contribute to cytotoxicity.…”

The role of α-synuclein in neurodegeneration — An update

“…However, the mechanism by which PINK1 or parkin confers neuroprotection is not clear [255]. Both causes of arPD induce mitophagy or defective oxidative phosphorylation [256,257], and GTPase dynamic-related protein (Drp1) is one of the targets of Parkin [258], while PINK1 is involved in mitochondrial trafficking by forming a multiprotein complex with the GTPase Miro and the adaptive protein milton [259].…”

Lecome-backde la mitochondrie dans l’apoptose chez la drosophile

“…Quoi qu'il en soit, certaines différences qui semblent exister aujourd'hui entre les voies de mort mitochondriale chez ces différentes espèces pourraient aussi refléter l'état encore incomplet de nos connaissances. La drosophile est un système modèle de choix pour comprendre les maladies humaines impliquant une voie de mort mitochondriale, ou associées à une altération du fonctionnement mitochondrial [37][38][39]. La poursuite des études sur la contribution de la mitochondrie dans l'apoptose chez la drosophile pourrait bien nous révéler encore d'autres aspects de la mort cellulaire programmée impliqués dans des pathologies.…”