Inter and intracellular mitochondrial transfer: Future of mitochondrial transplant therapy in Parkinson’s disease

Jain, Rachit; Begum, Nusrat; Tryphena, Kamatham Pushpa; Singh, Shashi Bala; Srivastava, Saurabh; Nand, Sachchida; Vamanu, Emanuel; Khatri, Dharmendra Kumar

doi:10.1016/j.biopha.2023.114268

Cited by 27 publications

(17 citation statements)

References 114 publications

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“…Highly polarized neurons, with their complex axon extending over hundreds of centimeters in length, demand extraordinarily high amounts of energy. Hence, constant mitochondrial commute within a neuron is cardinal to meet the local energy demand and its overall survival [ 31 ]. The mitochondria undergo long-distance bidirectional transport along the microtubule cytoskeleton toward the plus end (anterograde transport) as well as the minus end (retrograde transport).…”

Section: Mt-mediated Axonal Traffickingmentioning

confidence: 99%

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Naren

Samim

Tryphena

et al. 2023

Transl Neurodegener

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The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule (MT)-mediated axonal transport system. This mechanistically regulated system delivers cargos (proteins, mRNAs and organelles such as mitochondria) back and forth from the soma to the synapse. Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde (from the soma to the synapse) and retrograde (from the synapse to the soma) commute of the cargos, respectively. Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications (PTMs) of α- and β-tubulin heterodimers, core components constructing the MTs. Occurring within the lumen of MTs, K40 acetylation of α-tubulin via α-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible, which in turn promotes their lifespan. The movement of various motor proteins, including kinesin-1 (responsible for axonal mitochondrial commute), is enhanced by this PTM, and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions, including Alzheimer’s disease and Parkinson’s disease (PD). PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels. Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question, our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD. The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored. Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it. Graphical abstract

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Section: Mt-mediated Axonal Traffickingmentioning

confidence: 99%

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Naren

Samim

Tryphena

et al. 2023

Transl Neurodegener

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“…TNTs are a significant focus of current research and have been found to play a crucial role in the transfer of mitochondria, which are vital for cell survival [7,74,75]. Dysfunctional mitochondria have been associated with various neurodegenerative diseases such as AD and PD [7,76,77]. Factors such as reduced respiratory chain activity, accumulation of mtDNA mutations, and increased oxidative stress can all contribute to a decline in cellular bioenergetics [74][75][76][78][79][80][81].…”

Section: Mitochondrial Transfer Via Tntsmentioning

confidence: 99%

“…Dysfunctional mitochondria have been associated with various neurodegenerative diseases such as AD and PD [7,76,77]. Factors such as reduced respiratory chain activity, accumulation of mtDNA mutations, and increased oxidative stress can all contribute to a decline in cellular bioenergetics [74][75][76][78][79][80][81]. Therefore, mitochondria have become prime targets for therapeutic interventions.…”

Section: Mitochondrial Transfer Via Tntsmentioning

confidence: 99%

Tunneling Nanotube: An Enticing Cell–Cell Communication in the Nervous System

Dagar,

Subramaniam

2023

Biology

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The field of neuroscience is rapidly progressing, continuously uncovering new insights and discoveries. Among the areas that have shown immense potential in research, tunneling nanotubes (TNTs) have emerged as a promising subject of study. These minute structures act as conduits for the transfer of cellular materials between cells, representing a mechanism of communication that holds great significance. In particular, the interplay facilitated by TNTs among various cell types within the brain, including neurons, astrocytes, oligodendrocytes, glial cells, and microglia, can be essential for the normal development and optimal functioning of this complex organ. The involvement of TNTs in neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, has attracted significant attention. These disorders are characterized by the progressive degeneration of neurons and the subsequent decline in brain function. Studies have predicted that TNTs likely play critical roles in the propagation and spread of pathological factors, contributing to the advancement of these diseases. Thus, there is a growing interest in understanding the precise functions and mechanisms of TNTs within the nervous system. This review article, based on our recent work on Rhes-mediated TNTs, aims to explore the functions of TNTs within the brain and investigate their implications for neurodegenerative diseases. Using the knowledge gained from studying TNTs could offer novel opportunities for designing targeted treatments that can stop the progression of neurodegenerative disorders.

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“…11−14 Mitochondria are highly dynamic organelles and the powerhouse of the cells for their significant contribution to ATP production. 15,16 Mitochondrial fusion and fission are necessary to maintain the optimal number of mitochondria to meet the neuron's energy requirement. 17−20 A disturbance in mitochondrial functioning has been demonstrated in various preclinical disease models and the post-mortem brain samples of PD patients.…”

Section: Introductionmentioning

confidence: 99%

“…ultimately contributing to the demise of dopaminergic neurons. − Dopaminergic neurons of SN have their projections toward the striatum to form the nigrostriatal pathway, which plays an essential role in controlling motor function. They are characterized by their long axonal arbor, less myelinated axons, and intrinsic pace-making activity, which impose a high energy burden on them, making them more vulnerable to mitochondrial dysfunction. − Mitochondria are highly dynamic organelles and the powerhouse of the cells for their significant contribution to ATP production. , Mitochondrial fusion and fission are necessary to maintain the optimal number of mitochondria to meet the neuron’s energy requirement. − A disturbance in mitochondrial functioning has been demonstrated in various preclinical disease models and the post-mortem brain samples of PD patients . Mitochondrial dysfunction manifests as increased generation of reactive oxygen species (ROS), decreased mitochondrial complex I (MCI, Figure ) activity, the release of cytochrome c , caspase-3 activation, and ATP depletion.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Complex I as a Pathologic and Therapeutic Target for Parkinson’s Disease

Tryphena

Nikhil

Pinjala

et al. 2023

ACS Chem. Neurosci.

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The prevalence of Parkinson’s disease (PD) continues to increase despite substantial research. Mounting evidence states that dysfunctional mitochondrial bioenergetics play a vital role in PD etiology. A disturbance in the electron transport chain, more precisely, disruption of the mitochondrial complex I (MCI), is the most detrimental factor. Due to increased susceptibility toward MCI damage, the dopaminergic neurons experience oxidative stress and a compromise in ATP production, leading to neurodegeneration and PD. This article reviews the association of MCI with pathological mechanisms like α-synucleinopathy, neuroinflammation, oxidative stress, and ER stress and also describes the potential therapeutic options explored to overcome MCI dysfunction and related consequences.

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Inter and intracellular mitochondrial transfer: Future of mitochondrial transplant therapy in Parkinson’s disease

Cited by 27 publications

References 114 publications

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Tunneling Nanotube: An Enticing Cell–Cell Communication in the Nervous System

Mitochondrial Complex I as a Pathologic and Therapeutic Target for Parkinson’s Disease

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