UQCRC1 engages cytochrome c for neuronal apoptotic cell death

Hung, Yu‐Chien; Huang, Kuan‐lin; Chen, Po‐Lin; Li, Jeng-Lin; Lu, Serena Huei-An; Chang, Jui-Chih; Lin, Hon‐Yi; Lo, Wen-Chun; Huang, Shu‐Yi; Lee, Tai-Ting; Lin, Tai-Yi; Imai, Yuzuru; Liu, Chin‐San; Tsai, Su-Yi; Chen, Chunhong; Lin, Chin‐Hsien; Chan, Chih‐Chiang

doi:10.1016/j.celrep.2021.109729

Cited by 16 publications

(12 citation statements)

References 46 publications

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“…In Drosophila and mouse models, URCRC1 p.Y314S knock-in organisms showed dopaminergic neuronal loss, age-dependent locomotor deficits, and peripheral neuropathy [ 112 ]. Disruption of the Uqcrc1 gene in mice causes embryonic lethality [ 114 ], and deficiency of Uqcrc1 in Drosophila increases the cytochrome c in the cytoplasmic fraction and activates the caspase cascade, thus causing a reduction of dopaminergic neurons and neurodegeneration [ 115 ].…”

Section: Recently Described Parkinson’s Disease Genesmentioning

confidence: 99%

Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

Jia

Fellner

Kumar

2022

Genes

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Parkinson’s disease may be caused by a single pathogenic variant (monogenic) in 5–10% of cases, but investigation of these disorders provides valuable pathophysiological insights. In this review, we discuss each genetic form with a focus on genotype, phenotype, pathophysiology, and the geographic and ethnic distribution. Well-established Parkinson’s disease genes include autosomal dominant forms (SNCA, LRRK2, and VPS35) and autosomal recessive forms (PRKN, PINK1 and DJ1). Furthermore, mutations in the GBA gene are a key risk factor for Parkinson’s disease, and there have been major developments for X-linked dystonia parkinsonism. Moreover, atypical or complex parkinsonism may be due to mutations in genes such as ATP13A2, DCTN1, DNAJC6, FBXO7, PLA2G6, and SYNJ1. Furthermore, numerous genes have recently been implicated in Parkinson’s disease, such as CHCHD2, LRP10, TMEM230, UQCRC1, and VPS13C. Additionally, we discuss the role of heterozygous mutations in autosomal recessive genes, the effect of having mutations in two Parkinson’s disease genes, the outcome of deep brain stimulation, and the role of genetic testing. We highlight that monogenic Parkinson’s disease is influenced by ethnicity and geographical differences, reinforcing the need for global efforts to pool large numbers of patients and identify novel candidate genes.

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Section: Recently Described Parkinson’s Disease Genesmentioning

confidence: 99%

Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

Jia

Fellner

Kumar

2022

Genes

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“…In line with these observations, and the fact that RTP801 induces neuron-death 1,4 , we found that EVs derived from neurons overexpressing RTP801 (RTP801-EVs) contained higher levels of pro-apoptotic proteins (such as cytochrome b-c1, cytochrome c and alpha-internexin) and lower levels of anti-apoptotic proteins (such as core histone macro-H2A, NDRG3 protein, and endophilin). When the apoptotic cascade is initiated, cytochrome c is released to the cytosol 67,143 . Other apoptotic-related proteins, such as alphainternexin 73,74 , phosducin-like protein 3 86 , neogenin 91,92 , and transmembrane protein 2 144 , might be activated also in response to RTP801 to accelerate the cell death.…”

Section: Discussionmentioning

confidence: 99%

RTP801 Mediates Transneuronal Toxicity via Extracellular Vesicles by Affecting Their Protein Cargo and Abrogating Their Trophic Effect

Solana‐Balaguer

Martín‐Flores

Garcia-Segura

et al. 2023

Preprint

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Background Extracellular vesicles (EVs) play a crucial role in intercellular communication, participating in the paracrine trophic support or in the propagation of toxic molecules, including proteins. RTP801 is a stress-regulated protein, whose levels are elevated during neurodegeneration and induce neuron death. However, whether RTP801 toxicity is transferred trans-neuronally via EVs remains unknown. Methods We overexpressed or silenced RTP801 protein in cultured cortical neurons and isolated the neural-derived EVs (RTP801-EVs, or shRTP801-EVs respectively). We characterized their protein content by mass spectrometry (MS) and western blotting (WB). RTP801-EVs toxicity was assessed by treating cultured neurons with these EVs and quantifying apoptotic neuron death and branching. We also tested shRTP801-EVs functionality in the pathologic in vitro model of 6-Hydroxydopamine (6-OHDA) by biochemical analyses. Results Expression of RTP801 increased the number of EVs released by neurons. Moreover, RTP801 led to a distinct proteomic signature of neural-derived EVs, containing more pro-apoptotic markers. Hence, we observed that RTP801 toxicity was transferred to neurons via EVs, activating apoptosis and impairing neuron morphology complexity. In contrast, EVs derived from neurons where RTP801 was silenced were able to increase the arborization of recipient neurons. We also showed that 6-OHDA neurotoxin elevated protein levels of RTP801 in both cell lysates and EVs. Furthermore, neural-derived EVs induced phosphorylation of Ser473-Akt and Ser235/236-RPS6 in recipient neurons, and this effect was lost when EVs were derived from neurons treated with 6-OHDA. Interestingly, EVs derived from neurons where RTP801 was silenced prior to exposing them to 6-OHDA maintained Akt and RPS6 transactivation in recipient neurons. Conclusion Taken together, these results suggest that RTP801 toxicity can be spread via EVs and therefore, it could contribute to the progression of neurodegenerative diseases in which RTP801 is involved.

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“…Recently, ubiquinol‐cytochrome c reductase core protein 1 (UQCRC1), an evolutionarily conserved core subunit of mitochondrial respiratory chain complex III, was shown to prevent neuronal demise by engaging Cyt‐c, which is conserved in flies and humans (Hung et al. , 2021).…”

Section: Introductionmentioning

confidence: 99%

The appearance of cytoplasmic cytochrome C precedes apoptosis during Drosophila salivary gland degradation

et al. 2023

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Apoptosis is an important process for organism development that functions to eliminate cell damage, maintain homeostasis, and remove obsolete tissues during morphogenesis. In mammals, apoptosis is accompanied by the release of cytochrome C (Cyt‐c) from mitochondria to the cytoplasm. However, whether this process is conserved in the fruit fly, Drosophila melanogaster, remains controversial. In this study, we discovered that during the degradation of Drosophila salivary gland, the transcription of mitochondria apoptosis factors (MAPFs), Cyt‐c, and death‐associated APAF1‐related killer (Dark) encoding genes are all upregulated antecedent to initiator and effector caspases encoding genes. The proteins Cyt‐c and the active caspase 3 appear gradually in the cytoplasm during salivary gland degradation. Meanwhile, the Cyt‐c protein colocates with mito‐GFP, the marker indicating cytoplasmic mitochondria, and the change in mitochondrial membrane potential coincides with the appearance of Cyt‐c in the cytoplasm. Moreover, impeding or promoting 20E‐induced transcription factor E93 suppresses or enhances the staining of Cyt‐c and the active caspase 3 in the cytoplasm of salivary gland, and accordingly decreases or increases the mitochondrial membrane potential, respectively. Our research provides evidence that cytoplasmic Cyt‐c appears before apoptosis during Drosophila salivary gland degradation, shedding light on partial conserved mechanism in apoptosis between insects and mammals.

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UQCRC1 engages cytochrome c for neuronal apoptotic cell death

Cited by 16 publications

References 46 publications

Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

RTP801 Mediates Transneuronal Toxicity via Extracellular Vesicles by Affecting Their Protein Cargo and Abrogating Their Trophic Effect

The appearance of cytoplasmic cytochrome C precedes apoptosis during Drosophila salivary gland degradation

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