Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila

Andreazza, Simonetta; Samstag, Colby L; Sánchez-Martínez, Álvaro; Fernández-Vizarra, Erika; Gómez-Durán, Aurora; Lee, Juliette J.; Tufi, Roberta; Hipp, Michael J.; Schmidt, Elizabeth K.; Nicholls, Thomas J.; Gammage, Payam A.; Chinnery, Patrick F.; Minczuk, Michal; Pallanck, Leo J.; Kennedy, Scott R.; Whitworth, Alexander J.

doi:10.1038/s41467-019-10857-y

Cited by 27 publications

(30 citation statements)

References 49 publications

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“…In a final effort to assess whether the Drosophila Pink1/parkin-Sting axis acts in an analogous fashion to mice, we sought to recapitulate the conditions assessed by Sliter et al 10 and test the role of Sting when an additional mitochondrial stress is combined with parkin loss-of-function. To do this, we used our previously established mtDNA mutator model (mito-APOBEC1), which generates high levels of deleterious mtDNA mutations in somatic tissues, disrupting mitochondrial function and causing motor defects and shortened lifespan 27 . Notably, the loss of parkin or Sting did not exacerbate the impact of mito-APOBEC1 alone on locomotor function (Fig.…”

Section: Resultsmentioning

confidence: 99%

The STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/parkin or mtDNA mutator models

Lee

Andreazza

Whitworth

2020

Sci Rep

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Mutations in PINK1 and Parkin/PRKN cause the degeneration of dopaminergic neurons in familial forms of Parkinson’s disease but the precise pathogenic mechanisms are unknown. The PINK1/Parkin pathway has been described to play a central role in mitochondrial homeostasis by signalling the targeted destruction of damaged mitochondria, however, how disrupting this process leads to neuronal death was unclear until recently. An elegant study in mice revealed that the loss of Pink1 or Prkn coupled with an additional mitochondrial stress resulted in the aberrant activation of the innate immune signalling, mediated via the cGAS/STING pathway, causing degeneration of dopaminergic neurons and motor impairment. Genetic knockout of Sting was sufficient to completely prevent neurodegeneration and accompanying motor deficits. To determine whether Sting plays a conserved role in Pink1/parkin related pathology, we tested for genetic interactions between Sting and Pink1/parkin in Drosophila. Surprisingly, we found that loss of Sting, or its downstream effector Relish, was insufficient to suppress the behavioural deficits or mitochondria disruption in the Pink1/parkin mutants. Thus, we conclude that phenotypes associated with loss of Pink1/parkin are not universally due to aberrant activation of the STING pathway.

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Section: Resultsmentioning

confidence: 99%

The STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/parkin or mtDNA mutator models

Lee

Andreazza

Whitworth

2020

Sci Rep

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“…In a final effort to assess whether the Drosophila Pink1/parkin-Sting axis acts in an analogous fashion to mice, we sought to recapitulate the conditions assessed by Sliter et al 10 and test the role of Sting when an additional mitochondrial stress is combined with parkin loss-of-function. To do this, we used our previously established mtDNA mutator model (mito-APOBEC1), which generates high levels of deleterious mtDNA mutations in somatic tissues, disrupting mitochondrial function and causing motor defects and shortened lifespan 20 . Notably, the loss of parkin or Sting did not exacerbate the impact of mito-APOBEC1 alone on locomotor function (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The following strains were obtained from the Bloomington Drosophila Stock Center (RRID:SCR_006457): w 1118 (RRID:BDSC_6326), da-GAL4 (RRID:BDSC_55850), Sting TRiP (RRID:BDSC_31565), Relish TRiP (RRID:BDSC_33661), Relish E20 (RRID:BDSC_9457), UAS-mito-HA-GFP (RRID:BDSC_8443); and the Vienna Drosophila Resource Center (RRID:SCR_013805): Sting GD (P{GD1905}v4031), Relish GD (P{GD1199}v49413), and lacZ RNAi (P{GD936}v51446) used as a control RNAi. Other lines were kindly provided as follows: Sting ΔRG5 from A. Goodman 11 , Pink1 B9 mutants from J. Chung 18 , and the park 25 mutants and UAS-mito-APOBEC1 have been described previously 17,20 . All experiments were conducted using male flies.…”

Section: Methodsmentioning

confidence: 99%

The STING pathway does not contribute to Pink1/parkin phenotypes in Drosophila

Lee

Andreazza

Whitworth

2019

Preprint

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Mutations in PINK1 and Parkin/PRKN cause the degeneration of dopaminergic neurons in familial forms of Parkinson's disease but the precise pathogenic mechanisms are unknown. The PINK1/Parkin pathway has been described to play a central role in mitochondrial homeostasis by signaling the targeted destruction of damaged mitochondria, however, how disrupting this process leads to neuronal death until recently was unclear. An elegant study in mice revealed that the loss of Pink1 or Prkn coupled with an additional mitochondrial stress resulted in the aberrant activation of the innate immune signaling, mediated via the cGAS/STING pathway, causing degeneration of dopaminergic neurons and motor impairment. Genetic knockout of Sting was sufficient to completely prevent neurodegeneration and accompanying motor deficits. To determine whether Sting plays a conserved role in Pink1/parkin related pathology, we tested for genetic interactions between Sting and Pink1/parkin in Drosophila. Surprisingly, we found that loss of Sting, or its downstream effector Relish, was insufficient to suppress the behavioral deficits or mitochondria disruption in the Pink1/parkin mutants. Thus, we conclude that phenotypes associated with loss of Pink1/parkin are not universally due to aberrant activation of the STING pathway. IntroductionLoss of function mutations in PINK1 and PRKN cause familial parkinsonism, an incurable neurodegenerative disorder predominantly associated with the progressive loss of dopaminergic neurons in substantia nigra leading to loss of motor control. PRKN encodes a cytosolic ubiquitin E3 ligase, Parkin, and PINK1 encodes a mitochondrially targeted kinase. Extensive evidence shows that they cooperate in signaling the targeted autophagic destruction of damaged mitochondria (mitophagy) as part of a homeostatic mitochondrial quality control process 1,2 .Mitochondria are essential organelles that perform many critical metabolic functions but are also a major source of damaging reactive oxygen species (ROS) and harbor pro-apoptotic factors.Hence, multiple homeostatic processes, such as mitophagy, operate to maintain mitochondrial integrity and prevent potentially catastrophic consequences. Such homeostatic mechanisms are particularly important for post-mitotic, energetically demanding tissues such as nerves and muscles.The molecular details of PINK1/Parkin-induced mitophagy are well characterized in cultured cells, however, relatively little is known about mitophagy under physiological conditions in vivo 3-5 .Nevertheless, several studies provide evidence consistent with PINK1 and Parkin acting to remove mitochondrial damage in vivo. One study used a mass spectrometry-based analysis of mitochondrial protein turnover in Drosophila 6 , which revealed that fly PINK1 and Parkin selectively affect the degradation of certain mitochondrial proteins under physiological conditions. Another found that loss of Prkn in mice, which alone has very little phenotype 7,8 , exacerbated the phenotypic effects of a mitochondrial DNA mutator strai...

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“…Its high-level expression in SSA/Ps extends down into the serrated crypts but stops short of the crypt base. It remains to be seen whether apolipoprotein B editing and/or APOBEC1mediated DNA mutagenesis (i.e., C > T transitions stemming from unrepaired cytosine deaminations) are increased in these neoplastic crypts [72] [73]. It is interesting to note that C > T transitions at CpG dinucleotides are over-represented in the DNA mutation signature of CRCs displaying MMR-de ciency [74] [75], which, as discussed above, is caused by CIMP-mediated silencing of MLH1 expression.…”

Section: Discussionmentioning

confidence: 99%

An “Expressionistic” Look at Serrated Precancerous Colorectal Lesions

Marra¹

2020

Preprint

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Background: Approximately 60% of colorectal cancer (CRC) precursor lesions are the genuinely-dysplastic conventional adenomas (cADNs). The others include hyperplastic polyps (HPs), sessile serrated adenoma/polyps (SSA/Ps), and traditional serrated adenomas (TSAs), subtypes of a class of lesions collectively referred to as “serrated.” Endoscopic and histologic differentiation between cADNs and serrated lesions, and between serrated lesion subtypes can be difficult. Methods: We used in situ hybridization to verify the expression patterns in CRC precursors of 21 RNA molecules that appear to be promising differentiation markers on the basis of previous RNA sequencing studies.Results: SSA/Ps could be clearly differentiated from cADNs by the expression patterns of 9 of the 12 RNAs tested for this purpose (VSIG1, ANXA10, ACHE, SEMG1, AQP5, LINC00520, ZIC5/2, FOXD1, NKD1). Expression patterns of all 9 in HPs were similar to those in SSA/Ps. Nine putatively HP-specific RNAs were also investigated, but none could be confirmed as such: most (e.g., HOXD13 and HOXB13), proved instead to be markers of the normal mucosa in the distal colon and rectum, where most HPs arise. TSAs displayed mixed staining patterns reflecting the presence of serrated and dysplastic glands in the same lesion. Conclusions: Using a robust in situ hybridization protocol, we identified promising tissue-staining markers that, if validated in larger series of lesions, could facilitate more precise histologic classification of CRC precursors and, consequently, more tailored clinical follow-up of their carriers. Our findings should also fuel functional studies on the pathogenic significance of specific gene expression alterations in the initiation and evolution of CRC precursor subtypes.

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Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila

Cited by 27 publications

References 49 publications

The STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/parkin or mtDNA mutator models

The STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/parkin or mtDNA mutator models

The STING pathway does not contribute to Pink1/parkin phenotypes in Drosophila

An “Expressionistic” Look at Serrated Precancerous Colorectal Lesions

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