EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation

Zhang, Chenge; Jin, Yinhua; Marchetti, M. A.; Lewis, Mitchell R.; Hammouda, Omar T.; Edgar, Bruce A.

doi:10.1016/j.cub.2022.07.003

Cited by 24 publications

(16 citation statements)

References 70 publications

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“…The fat body and midgut are essential to management of organismal energy balance. Several studies have demonstrated the role of mitochondrial metabolism in the proper differentiation and function of the intestine (Deng et al, 2018;Liu et al, 2016;Wisidagama and Thummel, 2019;Zhang et al, 2022), as well as its requirement in the fat body for long range growth control (Banerjee et al, 2013;Song et al, 2017). In humans the myocardium is the richest source of mitochondria (Page and McCallister, 1973) and in flies proper mitochondrial dynamics are essential for cardiac function (Dorn et al, 2011).…”

Section: Developmental But Not Adulthood CI Depletion Results In Spec...mentioning

confidence: 99%

Developmental mitochondrial Complex I activity determines lifespan

Stefanatos

Robertson

Uribe

et al. 2023

Preprint

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Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that adaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of these maladaptations could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to an 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic and metabolomic responses which overlap significantly in discreet models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits an adaptive response which severely reduces survival, while CI depletion from adulthood is not sufficient to reduce survival and stress resistance.

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Section: Developmental But Not Adulthood CI Depletion Results In Spec...mentioning

confidence: 99%

Developmental mitochondrial Complex I activity determines lifespan

Stefanatos

Robertson

Uribe

et al. 2023

Preprint

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show abstract

“…Epidermal growth factor (EGF) can activate the mitogen-activated protein kinase (MAPK) signaling pathways and increase the p-MEK1/2 levels. 31 , 32 We used EGF to stimulate MEK1 or MEK2 knockdown cells, then treated these cells with azelnidipine. The results revealed that MEK1 or MEK2 knockdown cells increased their sensitivity to azelnidipine after EGF treatment.…”

Section: Resultsmentioning

confidence: 99%

Azelnidipine inhibits esophageal squamous cell carcinoma proliferation in vivo and in vitro by targeting MEK1/2

Zhao

Zhang

et al. 2022

Molecular Therapy - Oncolytics

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“…Subsequently, we functionally tested two of the P/LP LZTR1 variants, p.Arg283Trp and p.Tyr535Ter, as well as a presumably benign LZTR1 variant, p.Lys761Arg, which was identified in a pediatric patient with anaplastic large cell lymphoma. We utilized a Drosophila model that is particularly suited for the functional evaluation of Ras pathway activity on proliferation 5–7 . Thus, we assessed the functionality of hLZTR1 p.Arg283Trp , hLZTR1 p.Tyr535Ter and hLZTR1 p.Lys761Arg in vivo .…”

Section: Figurementioning

confidence: 99%

“…We utilized a Drosophila model that is particularly suited for the functional evaluation of Ras pathway activity on proliferation. [5][6][7] Thus, we assessed the functionality of hLZTR1 p.Arg283Trp , hLZTR1 p.Tyr535Ter and hLZTR1 p.Lys761Arg in vivo. We employed the "ReDDM" (Repressible Dual Differential Marker, Supporting Information S1: Figure S1A) tracing method to determine the role of LZTR1 variants in Ras signaling-dependent intestinal stem cell (ISC) lineage production.…”

mentioning

confidence: 99%

Hyperdiploid acute lymphoblastic leukemia in children with LZTR1 germline variants

Zipper,

Wagener,

Fischer

et al. 2024

HemaSphere

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EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation

Cited by 24 publications

References 70 publications

Developmental mitochondrial Complex I activity determines lifespan

Developmental mitochondrial Complex I activity determines lifespan

Azelnidipine inhibits esophageal squamous cell carcinoma proliferation in vivo and in vitro by targeting MEK1/2

Hyperdiploid acute lymphoblastic leukemia in children with LZTR1 germline variants

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