Pink1 and Parkin regulate<i>Drosophila</i>intestinal stem cell proliferation during stress and aging

Koehler, Christopher L.; Perkins, Guy; Ellisman, Mark H.; Jones, D. Leanne

doi:10.1083/jcb.201610036

Cited by 44 publications

(38 citation statements)

References 65 publications

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“…It will be interesting to test this hypothesis in the context of cellular metabolism, as recent studies indicate that changes in energy metabolism are critical to ensure or sustain appropriate proliferative responses. ISC proliferation is influenced by mitochondrial pyruvate intake, mitochondrial fission and fusion, and lipid metabolism (48)(49)(50). A central coordinator of nutrient sensing, translation, and autophagy, the TOR signaling pathway, is also required for efficient entry of ISCs into the active state (42).…”

Section: Regulation Of Intestinal Stem Cell Proliferationmentioning

confidence: 99%

“…indicates that ISC dysfunction can develop independently of the described bacterial dysbiosis and inflammatory response. Recent studies have described a loss of proteostatic capacity in older ISCs due to a loss of Nrf2 activity (102), a decline of mitochondrial function in stem and progenitor cells (49), increased endoplasmic reticulum stress (93), activation of retrotransposon expression and ensuing DNA damage (103), changes in autophagy (104) and heterochromatin (105), and increased polymerase III transcriptional activity (106). All of these mechanisms seem to contribute to dysplasia in the aging intestine, yet it remains unclear how these processes interact at the level of the stem cell and with the wider inflammatory condition developing in the epithelium (90)(91)(92)(93)(94)(95).…”

Section: Age-related Dysfunction In a Variety Of Intrinsic Signaling mentioning

confidence: 99%

“…All of these mechanisms seem to contribute to dysplasia in the aging intestine, yet it remains unclear how these processes interact at the level of the stem cell and with the wider inflammatory condition developing in the epithelium (90)(91)(92)(93)(94)(95). Strikingly, ISCs of old flies also display frequent somatic mutations, resulting in neoplasias (94), and the fly intestine may thus also serve as a model for the age-related increase in cancer formation in vertebrates (49,(90)(91)(92)(93)(94)(95)104). These stem cell-intrinsic mechanisms of age-related decline also serve as targets for interventions, as improved homeostasis, and in some cases even life span extension, was observed when perturbations were targeted toward ISCs in the studies described above (93,(103)(104)(105)(106).…”

Section: Age-related Dysfunction In a Variety Of Intrinsic Signaling mentioning

confidence: 99%

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Intestinal Stem Cell Aging: Origins and Interventions

Jasper¹

2020

Annu. Rev. Physiol.

127

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Regenerative processes that maintain the function of the gastrointestinal (GI) epithelium are critical for health and survival of multicellular organisms. In insects and vertebrates, intestinal stem cells (ISCs) regenerate the GI epithelium. ISC function is regulated by intrinsic, local, and systemic stimuli to adjust regeneration to tissue demands. These control mechanisms decline with age, resulting in significant perturbation of intestinal homeostasis. Processes that lead to this decline have been explored intensively in Drosophila melanogaster in recent years and are now starting to be characterized in mammalian models. This review presents a model for age-related regenerative decline in the fly intestine and discusses recent findings that start to establish molecular mechanisms of age-related decline of mammalian ISC function. 203 Annu. Rev. Physiol. 2020.82:203-226. Downloaded from www.annualreviews.org Access provided by 44.224.250.200 on 07/08/20. For personal use only.

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Section: Regulation Of Intestinal Stem Cell Proliferationmentioning

confidence: 99%

Section: Age-related Dysfunction In a Variety Of Intrinsic Signaling mentioning

confidence: 99%

Section: Age-related Dysfunction In a Variety Of Intrinsic Signaling mentioning

confidence: 99%

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Intestinal Stem Cell Aging: Origins and Interventions

Jasper¹

2020

Annu. Rev. Physiol.

127

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“…Dopaminergic overexpression of parkin or PINK1 prevents the loss of DA neurons and rescues climbing defects in the PARIS transgenic flies ( Fig. 3a-d, Additional file 9, Targeted knockdown of either parkin or PINK1 using specific shRNA lines [48][49][50] in the DA neurons leads to loss of DA neurons and climbing defects and further exacerbates these dopaminergic phenotypes in the PARIS overexpressing flies ( Fig. 3a-d Figure S2 and Additional file 13, Figure S3 Immunoblot analysis reveals that dopaminergic knockdown of parkin or PINK1 leads to marked accumulation of PARIS whereas PARIS levels are significantly decreased in flies overexpressing parkin or PINK1 (Fig.…”

Section: Parkin Pink1 and Pgc-1α Rescue Dopaminergic Neuron Loss Caumentioning

confidence: 99%

PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency

Pirooznia

Yuan

Khan

et al. 2020

Mol Neurodegeneration

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Background: Mutations in PINK1 and parkin cause autosomal recessive Parkinson's disease (PD). Evidence placing PINK1 and parkin in common pathways regulating multiple aspects of mitochondrial quality control is burgeoning. However, compelling evidence to causatively link specific PINK1/parkin dependent mitochondrial pathways to dopamine neuron degeneration in PD is lacking. Although PINK1 and parkin are known to regulate mitophagy, emerging data suggest that defects in mitophagy are unlikely to be of pathological relevance. Mitochondrial functions of PINK1 and parkin are also tied to their proteasomal regulation of specific substrates. In this study, we examined how PINK1/parkin mediated regulation of the pathogenic substrate PARIS impacts dopaminergic mitochondrial network homeostasis and neuronal survival in Drosophila. Methods: The UAS-Gal4 system was employed for cell-type specific expression of the various transgenes. Effects on dopamine neuronal survival and function were assessed by anti-TH immunostaining and negative geotaxis assays. Mitochondrial effects were probed by quantitative analysis of mito-GFP labeled dopaminergic mitochondria, assessment of mitochondrial abundance in dopamine neurons isolated by Fluorescence Activated Cell Sorting (FACS) and qRT-PCR analysis of dopaminergic factors that promote mitochondrial biogenesis. Statistical analyses employed two-tailed Student's T-test, one-way or two-way ANOVA as required and data considered significant when P < 0.05. Results: We show that defects in mitochondrial biogenesis drive adult onset progressive loss of dopamine neurons and motor deficits in Drosophila models of PINK1 or parkin insufficiency. Such defects result from PARIS dependent repression of dopaminergic PGC-1α and its downstream transcription factors NRF1 and TFAM that cooperatively promote mitochondrial biogenesis. Dopaminergic accumulation of human or Drosophila PARIS recapitulates these neurodegenerative phenotypes that are effectively reversed by PINK1, parkin or PGC-1α overexpression in vivo. To our knowledge, PARIS is the only co-substrate of PINK1 and parkin to specifically accumulate in the DA neurons and cause neurodegeneration and locomotor defects stemming from disrupted dopamine signaling.

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“…Like the mammalian intestinal epithelium, the Drosophila midgut epithelium is continually renewed by controlled intestinal stem cell (ISC) proliferation and differentiation of their progeny (Micchelli and Perrimon, 2006;Ohlstein and Spradling, 2006). ISC proliferation is finely tuned by diet, aging, and the microbiota ecosystem (Choi et al, 2011;Koehler et al, 2017;O'Brien et al, 2011), using many of the same biochemical pathways that control intestinal epithelial renewal in mammals (Pasco et al, 2015). In addition to self-renewal, ISC division produces two types of postmitotic progeny: enteroendocrine cells (EECs) and enteroblasts (EBs).…”

Section: Introductionmentioning

confidence: 99%

IRBIT Directs Differentiation of Intestinal Stem Cell Progeny to Maintain Tissue Homeostasis

et al. 2020

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The maintenance of the intestinal epithelium is ensured by the controlled proliferation of intestinal stem cells (ISCs) and differentiation of their progeny into various cell types, including enterocytes (ECs) that both mediate nutrient absorption and provide a barrier against pathogens. The signals that regulate transition of proliferative ISCs into differentiated ECs are not fully understood. IRBIT is an evolutionarily conserved protein that regulates ribonucleotide reductase (RNR), an enzyme critical for the generation of DNA precursors. Here, we show that IRBIT expression in ISC progeny within the Drosophila midgut epithelium cells regulates their differentiation via suppression of RNR activity. Disruption of this IRBIT-RNR regulatory circuit causes a premature loss of intestinal tissue integrity. Furthermore, age-related dysplasia can be reversed by suppression of RNR activity in ISC progeny. Collectively, our findings demonstrate a role of the IRBIT-RNR pathway in gut homeostasis.

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Pink1 and Parkin regulateDrosophilaintestinal stem cell proliferation during stress and aging

Cited by 44 publications

References 65 publications

Intestinal Stem Cell Aging: Origins and Interventions

Intestinal Stem Cell Aging: Origins and Interventions

PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency

IRBIT Directs Differentiation of Intestinal Stem Cell Progeny to Maintain Tissue Homeostasis

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