The Impact of Mitochondrial Fusion and Fission Modulation in Sporadic Parkinson’s Disease

Abstract

Accumulating data suggests that mitochondrial deficits may underline both sporadic and familial Parkinson's disease (PD) neurodegenerative process. Impairment of mitochondrial dynamics results in reactive oxygen species (ROS) production, decreases mitochondrial membrane potential, and could potentiate the accumulation of dysfunctional mitochondria. Excessive mitochondrial fragmentation is associated with the pathology of sporadic PD. Therefore, we modulated mitochondria fusion and fission in different sporadic PD cellular models. We found alterations in two proteins known to regulate mitochondrial fusion and fission events (OPA1 and Drp1, respectively). OPA1 long isoform cleavage seems to be, at least in part, responsible for mitochondrial fragmented pattern observed in sporadic PD cellular models. Moreover, mitochondrial fragmentation can also occur due to an increase in Drp1 that is translocated into the mitochondria by phosphorylation. To disclose the relevance of these alterations to the fragmentation of the mitochondrial network, we overexpressed OPA1 and knock down Drp1. OPA1 overexpression did not rescue MPP(+)-induced increase in ROS. Nevertheless, Drp1 knockdown due to an increase in mitochondrial elongation and interconnectivity rescued mitochondrial membrane potential and decreased ROS production in sporadic PD cells. Overall, our findings suggest that Drp1-dependent mitochondrial fragmentation plays a crucial role in mediating mitochondrial DNA induced mitochondria abnormalities and cellular dysfunction in sporadic PD.

Ultrastructural evidence for impaired mitochondrial fission in the aged rhesus monkey dorsolateral prefrontal cortex

“…For example, mitochondrial deficits appear early in mouse models of AD (Du et al, 2010; Yao et al, 2009). Consistent with the basic research, deficits in the balance of mitochondrial fusion/fission have been reported in neurodegenerative diseases such as AD and Parkinson's disease (Santos et al, 2015; Wang et al, 2009). Understanding this process and protecting mitochondrial integrity may provide a strategy for improving the health and function of the aging brain.…”

“…A balance between fusion vs. fission is also necessary for limiting the production of toxic reactive oxygen species (ROS) and for normal cellular metabolism, whereas disruptions in these processes affect the cell and may be implicated in neurodegenerative diseases (Santos et al, 2015; Wang et al, 2009; D.B. Wang et al, 2013).…”

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease

“…The original postmortem finding was a decrease in complex I activity in the substantia nigra of PD patients, and subsequently, the activities of other respiratory chain complexes have been shown to be decreased to a variable extent in the platelets and skeletal muscles of PD subjects 115–117. Furthermore, mitochondrial fusion and fission, responsible for the dynamic morphology and functional quality of the organelle, are possibly altered in sporadic PD, as suggested from studies in cell-based models of this disease, including cybrids 5,118,119. Cybrids are created by the fusion of human neuroblastoma cells or teratocarcinoma cells depleted of endogenous mitochondrial DNA (mtDNA) with platelets from PD subjects 119,120.…”

The role of modulation of antioxidant enzyme systems in the treatment of neurodegenerative diseases

“…Typically, the overproduction of amyloid beta (Ab) in the postmortem brains of AD patients was indicated to induce imbalances in mitochondrial fission and fusion processes 42,43 . Finally, imbalances in mitochondrial dynamics were also observed in ALS models 44,45 . Several enzymes in the brain have been shown to contribute to the production of ROS/RNS.…”