Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection

East, Daniel A.; Campanella, Michelangelo

doi:10.1016/j.biocel.2016.08.019

Cited by 32 publications

(19 citation statements)

References 67 publications

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“…Mitochondrial homeostasis requires a perfect equilibrium between mitophagy and mitochondrial biogenesis. Extensive mitophagy can lead to bioenergetic failure whereas excessive mitochondrial biogenesis can generate detrimental levels of reactive oxygen species (ROS) and promote apoptosis [42]. Consequently, maintenance of a balanced healthy mitochondrial population by both processes is essential for cellular function and survival [43,44,45].…”

Section: Mitophagymentioning

confidence: 99%

Mitochondrial Dynamics in Mitochondrial Diseases

et al. 2016

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Mitochondria are very versatile organelles in continuous fusion and fission processes in response to various cellular signals. Mitochondrial dynamics, including mitochondrial fission/fusion, movements and turnover, are essential for the mitochondrial network quality control. Alterations in mitochondrial dynamics can cause neuropathies such as Charcot-Marie-Tooth disease in which mitochondrial fusion and transport are impaired, or dominant optic atrophy which is caused by a reduced mitochondrial fusion. On the other hand, mitochondrial dysfunction in primary mitochondrial diseases promotes reactive oxygen species production that impairs its own function and dynamics, causing a continuous vicious cycle that aggravates the pathological phenotype. Mitochondrial dynamics provides a new way to understand the pathophysiology of mitochondrial disorders and other diseases related to mitochondria dysfunction such as diabetes, heart failure, or Hungtinton’s disease. The knowledge about mitochondrial dynamics also offers new therapeutics targets in mitochondrial diseases.

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Section: Mitophagymentioning

confidence: 99%

Mitochondrial Dynamics in Mitochondrial Diseases

et al. 2016

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“…The main result of our study is that different treatments causing mTOR inhibition strongly reduce PrP90-231 toxicity, suggesting that boosting autophagy promotes degradation of intralysosomal PrP90-231, preventing cytosolic diffusion of lysosomal enzymes from damaged membranes. Importantly, since it was demonstrated that autophagy may be neuroprotective by clearing cytoplasm from damaged lysosomes or mitochondria 77 , 78 , it is also reasonable that nutrient deprivation or rapamycin protect neurons acting downstream to PrP90-231 accumulation, removing lysosomes filled with PrP90-231. Although we have no clear evidence of lysosomal or mitochondrial entrapment into autophagosomes, such intriguing possibility will be further addressed.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological activation of autophagy favors the clearing of intracellular aggregates of misfolded prion protein peptide to prevent neuronal death

Thellung¹,

Scoti²,

Corsaro³

et al. 2018

Cell Death Dis

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According to the “gain-of-toxicity mechanism”, neuronal loss during cerebral proteinopathies is caused by accumulation of aggregation-prone conformers of misfolded cellular proteins, although it is still debated which aggregation state actually corresponds to the neurotoxic entity. Autophagy, originally described as a variant of programmed cell death, is now emerging as a crucial mechanism for cell survival in response to a variety of cell stressors, including nutrient deprivation, damage of cytoplasmic organelles, or accumulation of misfolded proteins. Impairment of autophagic flux in neurons often associates with neurodegeneration during cerebral amyloidosis, suggesting a role in clearing neurons from aggregation-prone misfolded proteins. Thus, autophagy may represent a target for innovative therapies. In this work, we show that alterations of autophagy progression occur in neurons following in vitro exposure to the amyloidogenic and neurotoxic prion protein-derived peptide PrP90-231. We report that the increase of autophagic flux represents a strategy adopted by neurons to survive the intracellular accumulation of misfolded PrP90-231. In particular, PrP90-231 internalization in A1 murine mesencephalic neurons occurs in acidic structures, showing electron microscopy hallmarks of autophagosomes and autophagolysosomes. However, these structures do not undergo resolution and accumulate in cytosol, suggesting that, in the presence of PrP90-231, autophagy is activated but its progression is impaired; the inability to clear PrP90-231 via autophagy induces cytotoxicity, causing impairment of lysosomal integrity and cytosolic diffusion of hydrolytic enzymes. Conversely, the induction of autophagy by pharmacological blockade of mTOR kinase or trophic factor deprivation restored autophagy resolution, reducing intracellular PrP90-231 accumulation and neuronal death. Taken together, these data indicate that PrP90-231 internalization induces an autophagic defensive response in A1 neurons, although incomplete and insufficient to grant survival; the pharmacological enhancement of this process exerts neuroprotection favoring the clearing of the internalized peptide and could represents a promising neuroprotective tool for neurodegenerative proteinopathies.

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“…Neurodegenerative conditions therefore associate with defective mitochondrial physiology. Impairment in the mechanisms of organelle quality control such as mitophagy are possible predictable targets to prevent reverse, or at least mitigate, the pathomechanism onset of neuronal death ( East and Campanella, 2016 ; Martinez-Vicente, 2017 ; Matic et al, 2017 ). Defective mitochondria underlies the development of neuropathology, by increasing the susceptibility of neurons to auto/paracrine stimulations that will ultimately damage them irreparably, and lead to irreversible demise ( Dias et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms of Pathogenic DJ-1 Mutations in Mitochondrial Quality Control

Strobbe

Robinson

Harvey

et al. 2018

Front. Mol. Neurosci.

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The deglycase and chaperone protein DJ-1 is pivotal for cellular oxidative stress responses and mitochondrial quality control. Mutations in PARK7, encoding DJ-1, are associated with early-onset familial Parkinson’s disease and lead to pathological oxidative stress and/or disrupted protein degradation by the proteasome. The aim of this study was to gain insights into the pathogenic mechanisms of selected DJ-1 missense mutations, by characterizing protein–protein interactions, core parameters of mitochondrial function, quality control regulation via autophagy, and cellular death following dopamine accumulation. We report that the DJ-1M26I mutant influences DJ-1 interactions with SUMO-1, in turn enhancing removal of mitochondria and conferring increased cellular susceptibility to dopamine toxicity. By contrast, the DJ-1D149A mutant does not influence mitophagy, but instead impairs Ca2+ dynamics and free radical homeostasis by disrupting DJ-1 interactions with a mitochondrial accessory protein known as DJ-1-binding protein (DJBP/EFCAB6). Thus, individual DJ-1 mutations have different effects on mitochondrial function and quality control, implying mutation-specific pathomechanisms converging on impaired mitochondrial homeostasis.

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Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection

Cited by 32 publications

References 67 publications

Mitochondrial Dynamics in Mitochondrial Diseases

Mitochondrial Dynamics in Mitochondrial Diseases

Pharmacological activation of autophagy favors the clearing of intracellular aggregates of misfolded prion protein peptide to prevent neuronal death

Distinct Mechanisms of Pathogenic DJ-1 Mutations in Mitochondrial Quality Control

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