Intracellular and Intercellular Mitochondrial Dynamics in Parkinson’s Disease

Abstract

The appearance of alpha-synuclein-positive inclusion bodies (Lewy bodies) and the loss of catecholaminergic neurons are the primary pathological hallmarks of Parkinson’s disease (PD). However, the dysfunction of mitochondria has long been recognized as a key component in the progression of the disease. Dysfunctional mitochondria can in turn lead to dysregulation of calcium homeostasis and, especially in dopaminergic neurons, raised mean intracellular calcium concentration. As calcium binding to alpha-synuclein is one of the important triggers of alpha-synuclein aggregation, mitochondrial dysfunction will promote inclusion body formation and disease progression. Increased reactive oxygen species (ROS) resulting from inefficiencies in the electron transport chain also contribute to the formation of alpha-synuclein aggregates and neuronal loss. Recent studies have also highlighted defects in mitochondrial clearance that lead to the accumulation of depolarized mitochondria. Transaxonal and intracytoplasmic translocation of mitochondria along the microtubule cytoskeleton may also be affected in diseased neurons. Furthermore, nanotube-mediated intercellular transfer of mitochondria has recently been reported between different cell types and may have relevance to the spread of PD pathology between adjacent brain regions. In the current review, the contributions of both intracellular and intercellular mitochondrial dynamics to the etiology of PD will be discussed.

The Emerging Role of RHOT1/Miro1 in the Pathogenesis of Parkinson's Disease

“…This mechanism is extremely important for many neurodegenerative diseases including PD, as it may represent a key neuroprotective approach in stem cell-based regenerative medicine. At the same time, the transfer of damaged mitochondria between different cell types may also trigger the spread of PD pathology to other brain regions and therefore needs to be taken into account for the design of targeted therapies (132).…”

Control of Reactive Oxygen Species for the Prevention of Parkinson’s Disease: The Possible Application of Flavonoids

“…Oxidative stress is frequently referred to as a risk factor of pathogenesis involved with a variety of diseases such as cardiovascular diseases, cancers, and neurodegenerative diseases [ 218 ]. Particularly in the brain, ROS production mainly occurs from catecholaminergic metabolism [ 22 , 23 ], mitochondrial dysfunction [ 14 , 19 , 24 ], and excessive neuroinflammation [ 3 , 8 , 9 , 25 ]. In addition, the DA neurons have striking vulnerability to oxidative stress-related neurotoxicity [ 14 , 20 , 21 ].…”

“…Comprehensive studies on hereditary and sporadic PD suggest that loss of DA neurons in the adult brain can be induced by various neurotoxic events, such as ROS production [ 14 , 24 , 45 ], mitochondrial dysfunction [ 4 , 19 ], protein aggregation [ 11 , 13 ], aberrant apoptosis signaling pathways [ 10 , 12 ], downregulation of neurotrophic factors [ 6 , 15 , 16 , 17 , 46 ], and excessive inflammation [ 3 , 8 , 9 ]; these pathogenic events work together to degenerate DA neurons. Although the fundamental etiology of PD remains unclear, it has been ascertained that the oxidative stress induced by excessive ROS production is widely involved in the pathogenesis of PD [ 5 , 18 ].…”

“…The pathogenic mechanisms of PD causing the degeneration of the nigrostriatal DA system still remain unclear, however, it is well known that the upregulation of risk factors is involved in the pathogenesis and progression of PD [ 4 , 5 , 6 , 7 ], and the following circumstances are highly responsible for the onset of PD: neuroinflammation [ 8 , 9 ], mismanagement of apoptosis [ 10 , 11 , 12 ] and autophagy [ 10 , 11 , 12 , 13 ], genetic mutations [ 5 , 14 ], neurotrophic support failure [ 6 , 8 , 15 , 16 , 17 ], and oxidative stress [ 5 , 18 , 19 ]. In particular, oxidative stress is considered to be a key risk factor of PD due to the vulnerability of DA neurons to oxidative stress caused by the excessive production of reactive oxygen species (ROS; free radicals) [ 14 , 20 , 21 ], resulting from the dopamine metabolism [ 22 , 23 ], mitochondrial dysfunction [ 14 , 19 , 24 ], neuroinflammation [ 3 , 8 , 9 , 25 ], and iron accumulation [ 26 , 27 ] in the SN.…”

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

“…Mediated by enzymes, such as monoamine oxidase (MAO), catechol- O -ethyltransferase (COMT) and aldehyde-dehydrogenase (ALDH), dopamine metabolism involves the production of highly reactive species that oxidize lipids, increases OS and contributes to mitochondrial dysfunction. Dopamine is capable to auto-oxidize at neutral pH, but its reduced sequestration into synaptic vesicles, where the environment is acidic, auto-oxidation is not possible and may represent a neuronal vulnerability factor [ 44 - 46 ]. Dopamine neurons with low dopamine transporter activity in the cell membrane are less susceptible to neurotoxins or dopamine-induced OS and, in turn, are less affected in PD.…”