Mitochondria, lysosomes, and dysfunction: their meaning in neurodegeneration

Audano, Matteo; Schneider, Anja; Mitro, Nico

doi:10.1111/jnc.14471

Cited by 88 publications

(51 citation statements)

References 161 publications

(138 reference statements)

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“…Interestingly, mitochondrial dysfunction induced by rotenone treatment alters the expression of lysosomal genes, perhaps because mitophagy induction regulates mitochondrial and lysosomal biogenesis through nuclear translocation of transcription factors 22,23 . Recent studies have documented mitochondria-lysosome membrane contact sites, which enable bidirectional regulation of mitochondrial and lysosomal dynamics, and have demonstrated how mitochondrial impairment supresses autophagic flux, suggesting a complex mutual relationship between these two cellular compartments [24][25][26][27][28] .…”

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confidence: 99%

Lysosomal perturbations in human dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Okarmus

Bogetofte

Schmidt

et al. 2020

Sci Rep

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Mutations in the PARK2 gene encoding parkin, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset parkinson's disease (pD). While parkin has been implicated in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration in both sporadic and familial pD upon parkin loss-of-function remains unknown. cultures of isogenic induced pluripotent stem cell (ipSc) lines with and without PARK2 knockout (Ko) enable mechanistic studies of the effect of parkin deficiency in human dopaminergic neurons. We used such cells to investigate the impact of PARK2 KO on the lysosomal compartment and found a clear link between parkin deficiency and lysosomal alterations. PARK2 Ko neurons exhibited a perturbed lysosomal morphology with enlarged electron-lucent lysosomes and an increased lysosomal content, which was exacerbated by mitochondrial stress and could be ameliorated by antioxidant treatment. We also found decreased lysosomal enzyme activity and autophagic perturbations, suggesting an impairment of the autophagylysosomal pathway in parkin-deficient cells. Interestingly, activity of the GBA-encoded enzyme, β-glucocerebrosidase, was increased, suggesting the existence of a compensatory mechanism. In conclusion, our data provide a unique characterization of the morphology, content, and function of lysosomes in PARK2 Ko neurons and reveal an important new connection between mitochondrial dysfunction and lysosomal dysregulation in pD pathogenesis.

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confidence: 99%

Lysosomal perturbations in human dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Okarmus

Bogetofte

Schmidt

et al. 2020

Sci Rep

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“…Although the punctate structures cannot be attributed to the mitochondrial network, we consider that it is functionally linked to the mitochondria as they are colocalized around the cell nucleus. Lysosomes are membrane-enclosed organelles that function as the digestive system of the cell, and these are thought to have membrane contact sites with mitochondria, allowing mutual regulation of their functions [18,19]. In fluorescence imaging, lysosomes and mitochondria have often been observed to colocalize [20].…”

Section: Resultsmentioning

confidence: 99%

“…However, their mechanism and functional roles are still not well known. It has also been suggested that dysfunction of mitochondria and lysosome causes various human diseases including neurodegenerative diseases, for example Parkinson's and Alzheimer's diseases [18,19]. The distinctive lysosome motion observed using PT microscopy may be related to inter-organelle communication between mitochondria and lysosomes.…”

Section: Discussionmentioning

confidence: 98%

Label-free dynamic imaging of mitochondria and lysosomes within living cells via simultaneous dual-pump photothermal microscopy

Miyazaki

Toumon

2019

Biomed. Opt. Express

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The dynamic activities of mitochondria and lysosomes, which play important roles in maintaining cellular homeostasis, were observed without labeling by using highly sensitive photothermal (PT) microscopy. This imaging modality allows for the direct observation of cellular organelles that contain endogenous chromophores, with high temporal and spatial resolution. We identified mitochondria and lysosomes inside living mammalian cells via simultaneous dual-color imaging. Moreover, dynamic imaging revealed that the lysosomes make contact with mitochondria and move between sites within the dynamic mitochondrial network. Since mitochondrial and lysosomal functions are intricately connected, PT microscopy should provide in-depth understanding of cellular functions associated with mitochondria-lysosome communication as well as insights into various human diseases caused by dysfunction of these organelles.

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“…In fact, some of the first insights into the relevance of mitophagy for neurologic disease were derived from patients with Parkinson's patients who were found to have mutations in PINK1 and parkin (PARK2) (Kitada et al, 1998;Matsumine et al, 1997;Valente et al, 2004a;Valente et al, 2004b). These studies have greatly expanded our knowledge of the role of mitochondrial quality control in various neurodegenerative syndromes, both rare and common (Audano et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Lysosomal dysfunction impairs mitochondrial quality control and predicts neurodegeneration in TBCKE

Tintos-Hernández

Santana

Keller

et al. 2020

Preprint

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Biallelic variants in TBC1-domain containing kinase (TBCK) cause intellectual disability in children. It remains unclear how variants in TBCK lead to a neurodevelopmental disorder and what biological factors modulate the variability of clinical severity. Previous studies showed increased autophagosomes in patients sharing the truncating (p.R126X) Boricua homozygous TBCK variant, who exhibit a severe and progressive neurodegenerative phenotype. Since defects in mitophagy are linked to neurodegenerative disorders, we tested whether mitophagy and mitochondrial function are altered in TBCK -/fibroblasts. Our data shows significant accumulation of mitophagosomes, reduced mitochondrial respiratory capacity, and mtDNA depletion. Furthermore, mitochondrial dysfunction correlates with the severity of the neurological phenotype. Since effective mitophagy and degradation of mitophagosomes ultimately depends on successful lysosomal degradation, we also tested lysosomal function. Our data shows that lysosomal proteolytic function is significantly reduced in TBCK -/fibroblasts. Moreover, acidifying lysosomal nanoparticles rescue the mitochondrial respiratory defects, suggesting that impaired mitochondrial quality control secondary to lysosomal dysfunction, may play an important role in the pathogenicity of this rare neurodevelopmental disorder and predict the degree of disease progression and neurodegeneration.

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Mitochondria, lysosomes, and dysfunction: their meaning in neurodegeneration

Cited by 88 publications

References 161 publications

Lysosomal perturbations in human dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Lysosomal perturbations in human dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Label-free dynamic imaging of mitochondria and lysosomes within living cells via simultaneous dual-pump photothermal microscopy

Lysosomal dysfunction impairs mitochondrial quality control and predicts neurodegeneration in TBCKE

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