Less than perfect divorces: dysregulated mitochondrial fission and neurodegeneration

Oettinghaus, Björn; Licci, Maria; Scorrano, Luca; Frank, Stephan

doi:10.1007/s00401-011-0930-z

Cited by 56 publications

(44 citation statements)

References 126 publications

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“…This dynamics seems indispensable for proper cellular function as many examples have shown. Reduced dynamics accompanies the process of ageing [41], is associated with the development of neurodegenerative diseases [42][43][44] and plays an important role in the execution of apoptosis [45,46]. Repetitive fusion and fission of mitochondria during the cell cycle has to be regulated [47][48][49][50]; otherwise, the continuity of the mitochondrial genome is not properly guaranteed [51,52], resulting in mitochondrial heterogeneity and malfunction [53].…”

Section: The Measurement Of Mitochondrial Dynamics and Its Applicatiomentioning

confidence: 99%

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

Busch

Kowald

Spelbrink

2014

Phil. Trans. R. Soc. B

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Mammalian mtDNA encodes for 13 core proteins of oxidative phosphorylation. Mitochondrial DNA mutations and deletions cause severe myopathies and neuromuscular diseases. Thus, the integrity of mtDNA is pivotal for cell survival and health of the organism. We here discuss the possible impact of mitochondrial fusion and fission on mtDNA maintenance as well as positive and negative selection processes. Our focus is centred on the important question of how the quality of mtDNA nucleoids can be assured when selection and mitochondrial quality control works on functional and physiological phenotypes constituted by oxidative phosphorylation proteins. The organelle control theory suggests a link between phenotype and nucleoid genotype. This is discussed in the light of new results presented here showing that mitochondrial transcription factor A/nucleoids are restricted in their intramitochondrial mobility and probably have a limited sphere of influence. Together with recent published work on mitochondrial and mtDNA heteroplasmy dynamics, these data suggest first, that single mitochondria might well be internally heterogeneous and second, that nucleoid genotypes might be linked to local phenotypes (although the link might often be leaky). We discuss how random or site-specific mitochondrial fission can isolate dysfunctional parts and enable their elimination by mitophagy, stressing the importance of fission in the process of mtDNA quality control. The role of fusion is more multifaceted and less understood in this context, but the mixing and equilibration of matrix content might be one of its important functions.

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Section: The Measurement Of Mitochondrial Dynamics and Its Applicatiomentioning

confidence: 99%

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

Busch

Kowald

Spelbrink

2014

Phil. Trans. R. Soc. B

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“…Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy metabolism [269]. The fascinating interplay of Parkin, PINK1, Drp1 and mitochondrial dysfunction has been discussed recently [34,270].…”

Section: It Improves Mitochondrial Dysfunction Altersmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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“…T he progressive loss of structure and function of neurons in neurodegenerative diseases, including Parkinson's disease (PD), involves mitochondrial dysfunction and early axonal degeneration [1][2][3] . Accordingly, agents that could protect mitochondrial functions may have broad therapeutic implications, especially considering that we still lack efficient therapies to block neuronal demise in the early stages of neurodegeneration.…”

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confidence: 99%

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

et al. 2014

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Mitochondrial dysfunction is a common feature of many neurodegenerative disorders, notably Parkinson's disease. Consequently, agents that protect mitochondria have strong therapeutic potential. Here, we sought to divert the natural strategy used by Borna disease virus (BDV) to replicate in neurons without causing cell death. We show that the BDV X protein has strong axoprotective properties, thereby protecting neurons from degeneration both in tissue culture and in an animal model of Parkinson's disease, even when expressed alone outside of the viral context. We also show that intranasal administration of a cellpermeable peptide derived from the X protein is neuroprotective. We establish that both the X protein and the X-derived peptide act by buffering mitochondrial damage and inducing enhanced mitochondrial filamentation. Our results open the way to novel therapies for neurodegenerative diseases by targeting mitochondrial dynamics and thus preventing the earliest steps of neurodegenerative processes in axons.

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Less than perfect divorces: dysregulated mitochondrial fission and neurodegeneration

Cited by 56 publications

References 126 publications

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

The role of α-synuclein in neurodegeneration — An update

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

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