PXD031699

PXD031699 is an original dataset announced via ProteomeXchange.

Title	Parallel kinase pathways stimulate actin polymerization at depolarized mitochondria
Description	Mitochondrial damage (MtD) represents a dramatic change in cellular homeostasis, necessitating metabolic changes and stimulating mitophagy. One rapid response to MtD is rapid peri-mitochondrial actin polymerization, termed ADA (acute damage-induced actin). The activation mechanism for ADA is unknown. Here, we use mitochondrial depolarization or the complex I inhibitor metformin to induce ADA. We show that two parallel signaling pathways are required for ADA. In one pathway, increased cytosolic calcium activates in turn PKC-β, Rac, WAVE regulatory complex, and Arp2/3 complex. In the other pathway, a drop in cellular ATP activates in turn AMPK (through LKB1), Cdc42, and FMNL formins. We also identify putative guanine nucleotide exchange factors for Rac and Cdc42, Trio and Fgd1 respectively, whose phosphorylation states increase upon mitochondrial depolarization and whose suppression inhibits ADA. The depolarization-induced calcium increase is dependent on the mitochondrial sodium-calcium exchanger NCLX, suggesting initial mitochondrial calcium efflux. We also show that ADA inhibition results in enhanced mitochondrial shape changes upon mitochondrial depolarization, suggesting that ADA inhibits these shape changes. These depolarization-induced shape changes are not fragmentation but a circularization of the inner mitochondrial membrane, dependent on the inner mitochondrial membrane protease Oma1. ADA inhibition increases proteolytic processing of an Oma1 substrate, the dynamin GTPase Opa1. These results show that ADA requires the combined action of Arp2/3 complex and formin proteins to polymerize a network of actin filaments around mitochondria, and that the ADA network inhibits the rapid mitochondrial shape changes that occur upon mitochondrial depolarization.
HostingRepository	PRIDE
AnnounceDate	2022-03-15
AnnouncementXML	Submission_2022-03-18_07:11:12.919.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD031699
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Tak Shun Fung
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-16 01:53:52	ID requested
1	2022-03-15 04:25:58	announced
⏵ 2	2022-03-18 07:11:13	announced	2022-03-18: Updated publication reference for PubMed record(s): 35290799.

Fung TS, Chakrabarti R, Kollasser J, Rottner K, Stradal TEB, Kage F, Higgs HN, Parallel kinase pathways stimulate actin polymerization at depolarized mitochondria. Curr Biol, 32(7):1577-1592.e8(2022) [pubmed]

submitter keyword: Phosphoproteomics, mitochondria, Rac GEF, Cdc42 GEF, actin, MEFs

Henry N Higgs
contact affiliation	Dartmouth College
contact email	henry.n.higgs@dartmouth.edu
lab head
Tak Shun Fung
contact affiliation	Dartmouth College
contact email	Tak.Shun.Fung.GR@Dartmouth.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031699
     1. Label: PRIDE project
     2. Name: Parallel kinase pathways stimulate actin polymerization at depolarized mitochondria