Parkin functionally interacts with PGC-1α to preserve mitochondria and protect dopaminergic neuron<i>s</i>

Zheng, Lu; Bernard-Marissal, Nathalie; Moullan, Norman; D’Amico, Davide; Auwerx, Johan; Moore, Darren J.; Knott, Graham; Aebischer, Patrick; Schneider, Bernard L.

doi:10.1093/hmg/ddw418

Cited by 51 publications

(66 citation statements)

References 72 publications

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“…Mfn2 is a key ubiquitination target of Parkin (Matsuda et al, 2010;Nguyen, Padman & Lazarou, 2016), and Parkin mediates the expression of PGC-1α (Shin et al, 2011), which in turn controls Mfn2 expression under stress conditions (see Section IV) (Bach et al, 2003Soriano et al, 2006). Under healthy conditions, Parkin has been proposed to protect dopaminergic neurons by promoting mitochondrial homeostasis in a PGC-1α-dependent manner (Zheng et al, 2017). Furthermore, Mfn2 has been reported to function as a receptor for Parkin in cardiac cells (Chen & Dorn, 2013;Gong et al, 2015), however whether this extends beyond this cell type is unclear (Narendra et al, 2008;Nguyen et al, 2016).…”

Section: (2) Additional Neurodegenerative Diseasesmentioning

confidence: 99%

Structure, function, and regulation of mitofusin‐2 in health and disease

2017

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Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non-neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis. In this review, we summarize the current knowledge of the structural and functional properties of Mfn2 as well as its regulation in different tissues, and also discuss the consequences of aberrant Mfn2 expression.

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Section: (2) Additional Neurodegenerative Diseasesmentioning

confidence: 99%

Structure, function, and regulation of mitofusin‐2 in health and disease

2017

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“…In the first one, Cali et al showed that overexpression of Parkin in neuroblastoma cells increases ER-mitochondria juxtaposition, and enhances IP 3 R-dependent mitochondrial Ca 2+ transients and ATP production; Parkin down-regulation by RNA interference has the opposite effect . Parkin overexpression in nigral neurons also led to a slight increase in the percentage of mitochondria in contact with the ER (Zheng et al, 2017). In contrast, we and others recently associated Parkin and PINK1 dysfunction with an exacerbation of the ER-mitochondria interface (Celardo et al, 2016;Gautier et al, 2016).…”

Section: Parkinson's Diseasementioning

confidence: 53%

“…Of note, Parkin has recently been reported to co-regulate ER-mitochondria juxtaposition together with the transcription factor peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), a key modulator of mitochondrial biogenesis (Zheng et al, 2017). In this study, the overexpression of PGC1α in the mouse substantia nigra by means of an adeno-associated viral vector led to exacerbation of ERmitochondria contacts that was suppressed by the co-expression of Parkin.…”

Section: Parkinson's Diseasementioning

confidence: 82%

“…Controversial observations are not limited to the above mentioned studies, in which the role of Mfn2 in ER-mitochondria tethering was directly addressed by knockdown or knockout approaches in different model systems. They also apply to studies in which the degree of ER-mitochondria juxtaposition was correlated with endogenous Mfn2 levels: Mfn2 abundance was found to be either higher (Arruda et al, 2014;Gautier et al, 2016) or lower (Zheng et al, 2017) in models associated with an exacerbated ER-mitochondria interface.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…Approximately 10% of the cases are due to monogenic mutations . Physical and/or functional association with ER-mitochondria contacts was demonstrated in the case of the PD-related proteins α-synuclein (Cali et al, 2012;Guardia-Laguarta et al, 2014), DJ-1 , PINK1 (Celardo et al, 2016;Gelmetti et al, 2017) and Parkin Celardo et al, 2016;Gautier et al, 2016;Gelmetti et al, 2017;Van Laar et al, 2015;Zheng et al, 2017).…”

Section: Parkinson's Diseasementioning

confidence: 99%

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From dysfunctional endoplasmic reticulum-mitochondria coupling to neurodegeneration

Erpapazoglou

Mouton-Liger

Corti

2017

Neurochemistry International

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Over the last years, contact sites between the endoplasmic reticulum (ER) and mitochondria have attracted great attention in the study of cell homeostasis and dysfunction, especially in the context of neurodegenerative disorders. This is largely due to the critical involvement of this subcellular compartment in a plethora of vital cellular functions: Ca 2+ homeostasis, mitochondrial dynamics, transport, bioenergetics and turnover, ER stress, apoptotic signaling and inflammation. An increasing number of disease-associated proteins have been reported to physically associate with the ERmitochondria interface, and cause structural and/or functional perturbations of this compartment. In the present review, we summarize current knowledge about the architecture and functions of the ER-mitochondria contact sites, and the consequences of their alteration in different neurodegenerative disorders. Special emphasis is placed on the caveats and difficulties in defining the nature and origin of the highlighted defects in ER-mitochondria communication, and their exact contribution to the neurodegenerative process.

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Association of Mitochondrial Biogenesis With Variable Penetrance of Schizophrenia

Tran

Crowley

et al. 2021

JAMA Psychiatry

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that underlie variable penetrance for neuropsychiatric illness in the context of genetic variants that carry elevated risk can advance novel treatment approaches for these disorders.OBJECTIVE To test the hypothesis that mitochondrial compensation is associated with the variable penetrance of schizophrenia in the 22q11.2 deletion syndrome (22q11DS). DESIGN, SETTING, AND PARTICIPANTSThis case-control study compared measures of mitochondrial function and the expression of related genes in 14 induced pluripotent stem cell-derived neurons from typically developing control individuals (6 lines) and from adults with 22q11DS (8 lines). The individuals with 22q11DS included 2 groups, those carrying a diagnosis of schizophrenia and those without this diagnosis (4 lines each). Similar measures were made of lymphoblastic cells lines (LCLs) from a separate group of adults with 22q11DS with (10 lines) or without (8 lines) schizophrenia. The study included samples derived from a clinical setting. The induced pluripotent stem cell lines were derived from individuals with 22q11DS with or without a diagnosis of schizophrenia at Stanford University. The LCLs were from adults within the 22q and You Center at the Children's Hospital of Philadelphia. Data were analyzed between July 1, 2019, and January 24, 2021.MAIN OUTCOMES AND MEASURES Total adenosine triphosphate (ATP), oxidative phosphorylation (OXPHOS) complex activity, and messenger RNA expression via reverse transcription-polymerase chain reaction of selected genes encoding for mitochondrial proteins.RESULTS Study participants included men and women aged 18 to 37 years. Of 32 participants, the mean (SD) age of men was 27 (1.9) years and of women was 29 (1.2) years. Replicating a previous study, neurons from the 22q11DS and schizophrenia (22q+Sz) group had reduced ATP levels (mean [SD], 15.6 [1.5] vs 21.9 [1.4]; P = .02) and reduced OXPHOS activity (ie, complex I; 1.51 [0.1] vs 1.89 [0.1]; P = .01). These deficits were not present in neurons from individuals with 22q11DS without schizophrenia (22q[−]Sz). In this group, the expression of multiple genes encoding OXPHOS subunits was significantly upregulated. For example, compared with control individuals, NDUFV2 expression was increased by 50% in the 22q(−)Sz group (P < .001) but not significantly changed in the 22q+Sz group. Expression of genes driving mitochondrial biogenesis, including PGC1α, showed a similar pattern of upregulation in the 22q(−)Sz group compared with the control and the 22q+Sz groups. Stimulation of mitochondrial biogenesis normalizes the ATP deficit seen in 22q+Sz neurons. Finally, using LCLs from a separate group of adults with 22q11DS, evidence for enhanced mitochondrial biogenesis was again found in the 22q(−)Sz group. CONCLUSIONS AND RELEVANCEIn this study, an increase in mitochondrial biogenesis and function was associated with the absence of schizophrenia in neurons and LCLs from individuals with 22q11DS, but the deficit in the 22q+Sz group was reversible by agents that enhance mitochondrial biogenesis....

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Parkin functionally interacts with PGC-1α to preserve mitochondria and protect dopaminergic neurons

Cited by 51 publications

References 72 publications

Structure, function, and regulation of mitofusin‐2 in health and disease

Structure, function, and regulation of mitofusin‐2 in health and disease

From dysfunctional endoplasmic reticulum-mitochondria coupling to neurodegeneration

Association of Mitochondrial Biogenesis With Variable Penetrance of Schizophrenia

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