Faculty Opinions recommendation of The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis.

Mitochondrial fission is mediated by the dynamin-related protein Drp1 in metazoans. Drp1 is recruited from the cytosol to mitochondria by the mitochondrial outer membrane protein Mff. A second mitochondrial outer membrane protein, named Fis1, was previously proposed as recruitment factor, but Fis1−/− cells have mild or no mitochondrial fission defects. Here we show that Fis1 is nevertheless part of the mitochondrial fission complex in metazoan cells. During the fission cycle, Drp1 first binds to Mff on the surface of mitochondria, followed by entry into a complex that includes Fis1 and endoplasmic reticulum (ER) proteins at the ER–mitochondrial interface. Mutations in Fis1 do not normally affect fission, but they can disrupt downstream degradation events when specific mitochondrial toxins are used to induce fission. The disruptions caused by mutations in Fis1 lead to an accumulation of large LC3 aggregates. We conclude that Fis1 can act in sequence with Mff at the ER–mitochondrial interface to couple stress-induced mitochondrial fission with downstream degradation processes.

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DRP1 regulates endoplasmic reticulum sheets to control mitochondrial DNA replication and segregation

10.1101/2021.12.09.472002 ◽

2021 ◽

Author(s):

Hema Saranya Ilamathi ◽

Sara Benhammouda ◽

Justine Desrochers-Goyette ◽

Matthew A Lines ◽

Marc Germain

Keyword(s):

Endoplasmic Reticulum ◽

Mitochondrial Dna ◽

Protein Complexes ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Mitochondrial Diseases ◽

Contact Sites ◽

Transport Chain ◽

Essential Components ◽

Mtdna Replication

Mitochondria are multi-faceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) codes for several essential components of the electron transport chain, and mtDNA maintenance defects lead to mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is regulated by mitochondrial dynamics. Specifically, mitochondrial fusion is essential for mtDNA maintenance. In contrast, while loss of mitochondrial fission causes the aggregation of nucleoids (mtDNA-protein complexes), its role in nucleoid distribution remains unclear. Here, we show that the mitochondrial fission protein DRP1 regulates nucleoid segregation by altering ER sheets, the ER structure associated with protein synthesis. Specifically, DRP1 loss or mutation leads to altered ER sheets that physically interact with mitobulbs, mitochondrial structures containing aggregated nucleoids. Importantly, nucleoid distribution and mtDNA replication were rescued by expressing the ER sheet protein CLIMP63. Thus, our work identifies a novel mechanism by which DRP1 regulates mtDNA replication and distribution.

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Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol

The Journal of Cell Biology ◽

10.1083/jcb.200212059 ◽

2003 ◽

Vol 160 (7) ◽

pp. 1115-1127 ◽

Cited By ~ 377

Author(s):

David G. Breckenridge ◽

Marina Stojanovic ◽

Richard C. Marcellus ◽

Gordon C. Shore

Keyword(s):

Endoplasmic Reticulum ◽

Cytochrome C ◽

Mitochondrial Fission ◽

Integral Membrane Protein ◽

Caspase 8 ◽

Cytochrome C Release ◽

Caspase Cleavage ◽

Endoplasmic Reticulum Calcium ◽

Induced Apoptosis ◽

Stress Pathway

Stimulation of cell surface death receptors activates caspase-8, which targets a limited number of substrates including BAP31, an integral membrane protein of the endoplasmic reticulum (ER). Recently, we reported that a caspase-resistant BAP31 mutant inhibited several features of Fas-induced apoptosis, including the release of cytochrome c (cyt.c) from mitochondria (Nguyen, M., D.G. Breckenridge, A. Ducret, and G.C. Shore. 2000. Mol. Cell. Biol. 20:6731–6740), implicating ER-mitochondria crosstalk in this pathway. Here, we report that the p20 caspase cleavage fragment of BAP31 can direct pro-apoptotic signals between the ER and mitochondria. Adenoviral expression of p20 caused an early release of Ca2+ from the ER, concomitant uptake of Ca2+ into mitochondria, and mitochondrial recruitment of Drp1, a dynamin-related protein that mediates scission of the outer mitochondrial membrane, resulting in dramatic fragmentation and fission of the mitochondrial network. Inhibition of Drp1 or ER-mitochondrial Ca2+ signaling prevented p20-induced fission of mitochondria. p20 strongly sensitized mitochondria to caspase-8–induced cyt.c release, whereas prolonged expression of p20 on its own ultimately induced caspase activation and apoptosis through the mitochondrial apoptosome stress pathway. Therefore, caspase-8 cleavage of BAP31 at the ER stimulates Ca2+-dependent mitochondrial fission, enhancing the release of cyt.c in response to this initiator caspase.

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Receptor-mediated Drp1 oligomerization on endoplasmic reticulum

10.1101/190538 ◽

2017 ◽

Author(s):

Wei-Ke Ji ◽

Rajarshi Chakrabarti ◽

Xintao Fan ◽

Lori Schoenfeld ◽

Stefan Strack ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Mammalian Cells ◽

Actin Polymerization ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Outer Mitochondrial Membrane ◽

Mitochondrial Division ◽

Knock Out ◽

Multiple Factors ◽

Latrunculin A

AbstractDrpl is a dynamin GTPase important for mitochondrial and peroxisomal division. Drp1 oligomerization and mitochondrial recruitment are regulated by multiple factors, including interaction with mitochondrial receptors such as Mff, MiD49, MiD51 and Fis. In addition, both endoplasmic reticulum (ER) and actin filaments play positive roles in mitochondrial division, but mechanisms for their roles are poorly defined. Here, we find that a population of Drp1 oligomers is ER-associated in mammalian cells, and is distinct from mitochondrial or peroxisomal Drp1 populations. Sub-populations of Mff and Fis1, which are tail-anchored proteins, also localize to ER. Drp1 oligomers assemble on ER, from which they can transfer to mitochondria. Suppression of Mff or inhibition of actin polymerization through the formin INF2 significantly reduces all Drp1 oligomer populations (mitochondrial, peroxisomal, ER-bound) and mitochondrial division, while Mff targeting to ER has a stimulatory effect on division. Our results suggest that ER can function as a platform for Drp1 oligomerization, and that ER-associated Drp1 contributes to mitochondrial division.SummaryAssembly of the dynamin GTPase Drp1 into constriction-competent oligomers is a key event in mitochondrial division. Here, Ji et al show that Drp1 oligomerization can occur on endoplasmic reticulum through an ER-bound population of the tail-anchored protein Mff.Abbreviations used in this paper: Drp1, dynamin-related protein 1; Fis1, mitochondrial fission 1 protein; INF2, inverted formin 2; KD, siRNA-mediated knock down; KI, CRISPR-mediated knock in; KO, CRISPR-mediated knock out; LatA, Latrunculin A; MDV, mitochondrially-derived vesicle; Mff, mitochondrial fission factor; MiD49 and MiD51, mitochondrial dynamics protein of 49 and 51 kDa; OMM, outer mitochondrial membrane; TA, tail-anchored.

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ER–mitochondria contacts: Actin dynamics at the ER control mitochondrial fission via calcium release

The Journal of Cell Biology ◽

10.1083/jcb.201711075 ◽

2017 ◽

Vol 217 (1) ◽

pp. 15-17 ◽

Cited By ~ 13

Author(s):

Janos Steffen ◽

Carla M. Koehler

Keyword(s):

Endoplasmic Reticulum ◽

Actin Filaments ◽

Actin Polymerization ◽

Calcium Uptake ◽

Calcium Release ◽

Mitochondrial Fission ◽

Actin Dynamics ◽

Mitochondrial Division ◽

Cell Biol ◽

Important Player

The formin-like protein INF2 is an important player in the polymerization of actin filaments. In this issue, Chakrabarti et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201709111) demonstrate that INF2 mediates actin polymerization at the endoplasmic reticulum (ER), resulting in increased ER–mitochondria contacts, calcium uptake by mitochondria, and mitochondrial division.

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