ERK regulates mitochondrial membrane potential in fission deficient Drosophila follicle cells during differentiation

Abstract

Mitochondrial morphology regulatory proteins interact with signaling pathways involved in differentiation. In Drosophila oogenesis, EGFR signaling regulates mitochondrial fragmentation in posterior follicle cells (PFCs). EGFR driven oocyte patterning and Notch signaling mediated differentiation are abrogated when PFCs are deficient for the mitochondrial fission protein Drp1. It is not known whether fused mitochondrial morphology in drp1 mutant PFCs exerts its effects on these signaling pathways through a change in mitochondrial electron transport chain (ETC) activity. In this study we show that aggregated mitochondria in drp1 mutant PFCs have increased mitochondrial membrane potential. We perform experiments to assess the signaling pathway regulating mitochondrial membrane potential and how this impacts follicle cell differentiation. We find that drp1 mutant PFCs show increase in phosphorylated ERK (dpERK) formed downstream of EGFR signaling. ERK regulates high mitochondrial membrane potential in drp1 mutant PFCs. PFCs depleted of ERK and drp1 are able to undergo Notch mediated differentiation. Notably mitochondrial membrane potential decrease via ETC inhibition activates Notch signaling at an earlier stage in wild type and suppresses the Notch signaling defect in drp1 mutant PFCs. Thus, this study shows that the EGFR pathway maintains mitochondrial morphology and mitochondrial membrane potential in follicle cells for its functioning and decrease in mitochondrial membrane potential is needed for Notch mediated differentiation.

Signaling Diversity Enabled by Rap1-Regulated Plasma Membrane ERK with Distinct Temporal Dynamics

“…ERK substrates have been identified in many subcellular compartments including at the Golgi Apparatus (20–22), at the mitochondrial membrane (23,24), and near the plasma membrane (5,6). However, studies investigating the spatial regulation of ERK have primarily focused on understanding its activation and role in shuttling between the nucleus and cytoplasm, leaving the regulation and function of ERK in other subcellular compartments relatively unexplored.…”

TNFα promotes glioblastoma A172 cell mitochondrial apoptosis via augmenting mitochondrial fission and repression of MAPK–ERK–YAP signaling pathways

“…First, more robust data concerning the inhibitory effects of MAPK–ERK pathways on mitochondrial fission have been provided by several in vitro and in vivo studies. 53 More importantly, the MAPK–ERK pathway, as the classical antiapoptotic pathway, has been demonstrated to send beneficial signals to cells under various states of stress. 54 As a new downstream effector of MAPK–ERK pathways, YAP was originally identified as a proto-oncogene.…”

Mitochondrial fusion regulates proliferation and differentiation in the type II neuroblast lineage inDrosophila

“…It is interesting to speculate the reasons for observing tissue specific differences in the requirement of mitochondrial fusion for Notch signaling in differentiation. We had previously found that EGFR signaling regulates fragmented morphology for appropriate Notch signaling in Drosophila follicle cells [18,19]. It is likely that fragmented mitochondrial morphology leads to an interaction between EGFR and Notch signaling pathways in follicle cells and possibly other cell types such as cardiomyocytes and TNBCs where Notch signaling increase occurs only on loss of mitochondrial membrane potential or fragmentation.…”

“…The copyright holder for this preprint this version posted January 8, 2021. ; https://doi.org/10.1101/2021.01.08.425832 doi: bioRxiv preprint 25 E: Quantification of Pros positive GMCs (yellow arrows point to nuclear Pros) per type II NB lineage (E) of mCherry RNAi (18 type II NB lineages,5 brains), opa1 RNAi (18,5), marf RNAi (19,5), Drp1 SD (26,9). Scale bar-10μm C, D, E: Graphs show mean + sd.…”

“…How might loss of mitochondrial fusion and activity affect differentiation in the type II NB lineage?Mitochondrial morphology changes may have an effect on the fate of the cell by In triple negative breast cancer (TNBC) Notch signaling enhances mitochondrial fission via drp1[56]. In Drosophila ovarian posterior follicle cells, mitochondrial fusion induces an increase in mitochondrial membrane potential and loss of Notch signaling[18,19]. Loss of opa1 in cardiomyocytes leads to decrease in differentiation due in enhanced Notch processivity[20].…”