Parkinson's disease: connecting mitochondria to inflammasomes

Lawrence, Grace M.E.P.; Holley, Caroline L.; Schroder, Kate

doi:10.1016/j.it.2022.09.010

Cited by 37 publications

(20 citation statements)

References 74 publications

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“…In the brain, an organ particularly susceptible to mitochondrial dysfunction and thus heavily affected by mitochondriopathies, the mitochondrial transfer might have a very important pathophysiological role. Likewise mitochondria are implicated in neuroinflammation 36 . Accruing evidence shows that astrocytes transfer mitochondria to neurons 17 , and vice versa that damaged mitochondria are transferred from neurons to astrocytes 18 .…”

Section: Discussionmentioning

confidence: 99%

P2X7-dependent exchange of extracellular microparticles and mitochondria by mouse microglia

Falzoni

Chiozzi

Vultaggio-Poma

et al. 2023

Preprint

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Microparticles (MPs) are ubiquitously secreted by all cells and play a fundamental role in numerous biological processes such as cell-to-cell communication, cell differentiation, inflammation, and cell energy transfer. Ligation of the P2X7 receptor (P2X7R) by extracellular ATP (eATP) is the well-known stimulus for MP release, which affects their contents in a cell-specific fashion. We investigated MP release and functional impact in mouse microglial cell lines characterized for high (N13-P2X7RHigh) or low (N13-P2X7RLow) expression of the P2X7R. Stimulation with extracellular ATP triggered a P2X7R-dependent release of a MP population enriched with naked mitochondria. Released mitochondria were taken up and incorporated into the mitochondrial network of the recipient cells in a P2X7R-dependent fashion. Other constituents of the MP cargo, e.g. NLRP3 and the P2X7R itself, were also delivered to the recipient cells. Transfer of mitochondria, NLRP3 and P2X7R increased the energy level of the recipient cells and conferred a pro-inflammatory phenotype. These data show that P2X7R-dependent exchange of MPs and mitochondria modulates energy metabolism and inflammatory responses, pointing to the P2X7R as a master regulator of intercellular organelle and MP trafficking in mouse microglia.

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Section: Discussionmentioning

confidence: 99%

P2X7-dependent exchange of extracellular microparticles and mitochondria by mouse microglia

Falzoni

Chiozzi

Vultaggio-Poma

et al. 2023

Preprint

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“…[18][19][20] In addition, social disconnection can induce mitochondrial dysfunction, and increasing evidence has highlighted the mitochondrial dysfunction as a critical driver of PD pathology. [21][22][23] Finally, social isolation can modulate social inequality and further restrict people from seeking social support and health care resources, which may lead to poor management of risk factors and prodromal symptoms of PD. 24 Nevertheless, more studies are warranted to further illuminate the potential mechanisms through which social isolation plays a role in the development of PD.…”

Section: Discussionmentioning

confidence: 99%

Social Isolation and the Risk of Parkinson Disease: the UK Biobank Study

Geng,

Li,

Peng

et al. 2023

Preprint

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Background Parkinson disease (PD) has become one of the most rapidly growing causes of disability among the older population and social isolation is a major concern in the PD community. However, the relationship between social isolation and future risk of PD remains unclear. Methods This study included 192,340 participants aged 60 or older who were free of dementia and PD at baseline from the UK Biobank study. Social isolation was measured using a composite score derived from three questions on number in household, frequency of friend/family visits, and leisure/social activities. Incident PD cases were identified through electronic health records. Multivariable-adjusted Cox regression models were used to compute the hazard ratio (HR) and 95% confidence interval (CI). Results Among the 192,340 participants (mean [standard deviation] age, 64.2 [2.9] years; 103,253 [53.7%] women), 89,075 (46.3%) participants were in the least isolated group and 26,161 (13.6%) were in the most isolated group. Over a median follow-up of 12.5 years, 2048 incident PD cases were documented. Compared to the least isolated group, the multivariable-adjusted HRs (95% CIs) for PD were 1.00 (0.91–1.10) for the moderately isolated group and 1.19 (1.05–1.36) for the most isolated group (P-trend=0.04). The observed association was independent of the genetic susceptibility to PD and consistent in subgroup analyses. Conclusions Social isolation was associated with a higher risk of PD regardless of genetic risk. Our findings highlighted the importance of developing screening and intervention strategies for social isolation among older adults to reduce the risk of PD.

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“…Several preclinical models, including the DBA/2J mouse (model of secondary glaucoma) and patient data, link mitochondrial loss and inflammation in glaucomatous neurodegeneration [62]. Inducible microglial mitochondrial fission has been reported to promote NLRP3-dependent neuroinflammation in hereditary and idiopathic PD [63]. In postnatal organotypic hippocampal slice cultures, microglia undergo transformation into a discrete phenotype through single toll-like receptor 4 stimulation with LPS (lipopolysaccharide), which is altered in the process of inhibition of the respiratory chain [64].…”

Section: Microglial Mitochondria and Their Significance In Neurodegen...mentioning

confidence: 99%

Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration

Ragupathy,

Vukku,

Barodia

2023

IJMS

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Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which is a well-accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of the neuronal population due to increased oxidative stress leads to neurodegenerative diseases, mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is a key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitute a significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decide the fate of overall brain health; therefore, it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable the diversity and highly synchronized connecting property of non-neuronal cells are in keeping the neurons healthy to control neurodegeneration.

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Parkinson's disease: connecting mitochondria to inflammasomes

Cited by 37 publications

References 74 publications

P2X7-dependent exchange of extracellular microparticles and mitochondria by mouse microglia

P2X7-dependent exchange of extracellular microparticles and mitochondria by mouse microglia

Social Isolation and the Risk of Parkinson Disease: the UK Biobank Study

Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration

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