Synergistic Effect of Mitochondrial and Lysosomal Dysfunction in Parkinson’s Disease

Guerra, Flora; Girolimetti, Giulia; Beli, Raffaella; Mitruccio, Marco; Pacelli, Consiglia; Ferretta, Anna; Gasparre, Giuseppe; Cocco, Tiziana; Bucci, Cecilia

doi:10.3390/cells8050452

Cited by 49 publications

(41 citation statements)

References 107 publications

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“…EV cargoes enriched in damaged mitochondria may also be delivered to lysosomes for degradation [66]. In support to this hypothesis, alterations of lysosomal function were described in association with impaired mitochondrial biogenesis in fibroblasts from a young PD patient with Parkin gene (PARK2) mutation [154].…”

Section: Circulating Mitochondrial-derived Vesicles Systemic Inflammmentioning

confidence: 83%

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Picca

Calvani

Coelho-Júnior

et al. 2020

Cells

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Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca 2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson's disease as a prototypical geroscience condition.Cells 2020, 9, 598 2 of 18 instability, telomere attrition, epigenetic alterations, deregulated nutrient sensing, and stem cell exhaustion [3]. According to the geroscience hypothesis, perturbations in these mechanisms increase the susceptibility to most chronic diseases, functional loss, and eventually, death [4]. Hence, these biologic pillars represent ideal targets for interventions to foster healthy aging [5,6].Mitochondrial dysfunction has attracted considerable interest as a target for geroprotective interventions. Indeed, mitochondria play sensor-transducer-effector roles in a multitude of biological processes, including integration of cell death signaling and preservation of cell stemness [7,8]. Albeit long considered to be standalone organelles, a great deal of evidence indicates that mitochondria interact physically and functionally with other cellular compartments via membrane contact sites and tethering molecules [9,10]. In particular, mitochondria establish connections with the endosomal compartment [11,12] and lysosomes [13,14]. These interactions support cytosolic shuttle systems of ions and metabolites across organelles [10,15], and participate to the regulation of cellular housekeeping processes [13,14].The mitochondrial-lysosomal axis is a major actor in mitochondrial quality control (MQC), a hierarchical network of pathways that ensure organellar homeostasis through the coordination of mitochondrial proteostasis, dynamics, biogene...

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Section: Circulating Mitochondrial-derived Vesicles Systemic Inflammmentioning

confidence: 83%

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Picca

Calvani

Coelho-Júnior

et al. 2020

Cells

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“…Damaged MDV cargoes may also be delivered to lysosomes for degradation [41]. In support to this hypothesis, alterations of lysosomal function concomitant with impaired mitochondrial biogenesis have been described in Parkin gene (PARK2) mutated fibroblasts from a young patient with PD [38]. These changes were likely sustained by a mitochondrial genetic defect, blocking mitochondrial turnover and triggering premature cellular senescence [38].…”

Section: Discussionmentioning

confidence: 95%

“…Peripheral processes (e.g., inflammation) and neuronal mitochondrial dysfunction contribute to neurodegeneration in PD [37][38][39][40]. However, the molecular determinants linking the two processes are underexplored.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Signatures in Circulating Extracellular Vesicles of Older Adults with Parkinson’s Disease: Results from the EXosomes in PArkiNson’s Disease (EXPAND) Study

Picca

Guerra

Calvani

et al. 2020

JCM

Self Cite

104

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Systemic inflammation and mitochondrial dysfunction are involved in neurodegeneration in Parkinson’s disease (PD). Extracellular vesicle (EV) trafficking may link inflammation and mitochondrial dysfunction. In the present study, circulating small EVs (sEVs) from 16 older adults with PD and 12 non-PD controls were purified and characterized. A panel of serum inflammatory biomolecules was measured by multiplex immunoassay. Protein levels of three tetraspanins (CD9, CD63, and CD81) and selected mitochondrial markers (adenosine triphosphate 5A (ATP5A), mitochondrial cytochrome C oxidase subunit I (MTCOI), nicotinamide adenine dinucleotide reduced form (NADH):ubiquinone oxidoreductase subunit B8 (NDUFB8), NADH:ubiquinone oxidoreductase subunit S3 (NDUFS3), succinate dehydrogenase complex iron sulfur subunit B (SDHB), and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2)) were quantified in purified sEVs by immunoblotting. Relative to controls, PD participants showed a greater amount of circulating sEVs. Levels of CD9 and CD63 were lower in the sEV fraction of PD participants, whereas those of CD81 were similar between groups. Lower levels of ATP5A, NDUFS3, and SDHB were detected in sEVs from PD participants. No signal was retrieved for UQCRC2, MTCOI, or NDUFB8 in either participant group. To identify a molecular signature in circulating sEVs in relationship to systemic inflammation, a low level-fused (multi-platform) partial least squares discriminant analysis was applied. The model correctly classified 94.2% ± 6.1% PD participants and 66.7% ± 5.4% controls, and identified seven biomolecules as relevant (CD9, NDUFS3, C-reactive protein, fibroblast growth factor 21, interleukin 9, macrophage inflammatory protein 1β, and tumor necrosis factor alpha). In conclusion, a mitochondrial signature was identified in circulating sEVs from older adults with PD, in association with a specific inflammatory profile. In-depth characterization of sEV trafficking may allow identifying new biomarkers for PD and possible targets for personalized interventions.

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“…Substantia nigra tissue of PARK2 p.Q311* mutant mice displayed a late-stage block in autophagy, an increased PARIS expression and a PARIS-dependent reduced expression of both PGC1α and the lysosomal transcription factor TFEB [312]. Moreover, primary fibroblasts of a patient with juvenile PD with compound heterozygous deletions in PARK2 displayed abnormal abundance, acidification and morphology of the late endocytic compartment and lysosomal dysfunction [123].…”

Section: Endo-lysosomal Dysfunction Caused By Alteration In Genes Primentioning

confidence: 99%

“…The lysosomal defects in the mouse embryonic fibroblasts were partially rescued by treatment with the antioxidants N-acetylcysteine or coenzyme Q10, suggesting that increased ROS from damaged mitochondria mediates lysosomal dysfunction [73]. Treatment of the mouse motor neuron NSC-34 cell line with the mitochondrial complex I inhibitor rotenone causes alterations in lysosomal biogenesis, function and morphology [123]. Interestingly, inducing TFEB via trehalose treatment in iPSC-derived dopaminergic neurons with compromised mitochondrial functioning, caused by longterm treatment with rotenone, restored the mitochondrial membrane potential and ATP production [312].…”

Section: Endo-lysosomal Dysfunction Caused By Alteration In Genes Primentioning

confidence: 99%

Genetic perspective on the synergistic connection between vesicular transport, lysosomal and mitochondrial pathways associated with Parkinson’s disease pathogenesis

Smolders

Broeckhoven

2020

acta neuropathol commun

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Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) are symptomatically characterized by parkinsonism, with the latter presenting additionally a distinctive range of atypical features. Although the majority of patients with PD and APS appear to be sporadic, genetic causes of several rare monogenic disease variants were identified. The knowledge acquired from these genetic factors indicated that defects in vesicular transport pathways, endo-lysosomal dysfunction, impaired autophagy-lysosomal protein and organelle degradation pathways, α-synuclein aggregation and mitochondrial dysfunction play key roles in PD pathogenesis. Moreover, membrane dynamics are increasingly recognized as a key player in the disease pathogenesis due lipid homeostasis alterations, associated with lysosomal dysfunction, caused by mutations in several PD and APS genes. The importance of lysosomal dysfunction and lipid homeostasis is strengthened by both genetic discoveries and clinical epidemiology of the association between parkinsonism and lysosomal storage disorders (LSDs), caused by the disruption of lysosomal biogenesis or function. A synergistic coordination between vesicular trafficking, lysosomal and mitochondria defects exist whereby mutations in PD and APS genes encoding proteins primarily involved one PD pathway are frequently associated with defects in other PD pathways as a secondary effect. Moreover, accumulating clinical and genetic observations suggest more complex inheritance patters of familial PD exist, including oligogenic and polygenic inheritance of genes in the same or interconnected PD pathways, further strengthening their synergistic connection. Here, we provide a comprehensive overview of PD and APS genes with functions in vesicular transport, lysosomal and mitochondrial pathways, and highlight functional and genetic evidence of the synergistic connection between these PD associated pathways.

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Synergistic Effect of Mitochondrial and Lysosomal Dysfunction in Parkinson’s Disease

Cited by 49 publications

References 107 publications

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Mitochondrial Signatures in Circulating Extracellular Vesicles of Older Adults with Parkinson’s Disease: Results from the EXosomes in PArkiNson’s Disease (EXPAND) Study

Genetic perspective on the synergistic connection between vesicular transport, lysosomal and mitochondrial pathways associated with Parkinson’s disease pathogenesis

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