An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion

Nguyen, Tricia T; Voeltz, Gia K.

doi:10.7554/elife.84279

Cited by 38 publications

(40 citation statements)

References 85 publications

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“…Since the ER is known to be involved in mitochondrial constriction, 15,16 we tested whether HK1-rings are localized at the ER using the marker BFP-KDEL. Indeed, HK1-rings colocalized with ER tubules (Figure 2C, white arrows; 3D animation in Video S2A).…”

Section: Resultsmentioning

confidence: 99%

Hexokinase 1 forms rings that constrict mitochondria during energy stress

Pilic

Gottschalk

Koshenov

et al. 2023

Preprint

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Despite progress in understanding cellular energy stress responses, the role of metabolic enzymes in these processes remains understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, clusters into ring-like structures around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial constriction sites. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the clustering of HK1. We found several structural features that are critical for the formation of HK1-rings. Our findings highlight that HK1 is a robust energy stress sensor that regulates the shape, position, and connectivity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy stress-related pathologies.

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Section: Resultsmentioning

confidence: 99%

Hexokinase 1 forms rings that constrict mitochondria during energy stress

Pilic

Gottschalk

Koshenov

et al. 2023

Preprint

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“…An extended palette in which green (GA) or red (RA) A monomers can be complemented interchangeably with a B monomer was subsequently developed (Alford, Ding, et al, 2012; Ding et al, 2015). Although ddFPs have primarily been used to study protein-protein interactions, the ddFP system has been adapted to detect MCSs including ER-mitochondria (Alford, Ding, et al, 2012; Naon et al, 2016; Nguyen & Voeltz, 2022), ER-P-body (Lee et al, 2020) or mitochondria-mitochondria (Abrisch et al, 2020) contacts. Because the interaction between ddFP monomers is reversible, ddFPs are more amenable than split FP systems for studying MCS dynamics.…”

Section: Introductionmentioning

confidence: 99%

Contact-FP: a dimerization-dependent fluorescent protein toolkit for visualizing membrane contact site dynamics

Miner,

Smith,

Showalter

et al. 2023

Preprint

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Membrane contact sites (MCSs) are sites of close apposition between two organelles used to exchange ions, lipids, and information. Cells respond to changing environmental or developmental conditions by modulating the number, extent, or duration of MCSs. Because of their small size and dynamic nature, tools to study the dynamics of MCSs in live cells have been limited. Dimerization-dependent fluorescent proteins (ddFPs) targeted to organelle membranes are an ideal tool for studying MCS dynamics because they reversibly interact to fluoresce specifically at the interface between two organelles. Here, we build on previous work using ddFPs as sensors to visualize the morphology and dynamics of MCSs. We engineered a suite of ddFPs called Contact-FP that targets ddFP monomers to lipid droplets (LDs), the endoplasmic reticulum (ER), mitochondria, peroxisomes, lysosomes, plasma membrane, caveolae, and the cytoplasm. We show that these probes correctly localize to their target organelles. Using LDs as a test case, we demonstrate that Contact-FP pairs specifically localize to the interface between two target organelles. Titration of LD-mitochondria ddFPs revealed that these sensors can be used at high concentrations to drive MCSs or can be titrated down to minimally perturb and visualize endogenous MCSs. We show that Contact-FP probes can be used to: (1) visualize LD-mitochondria MCS dynamics, (2) observe changes in LD-mitochondria MCS dynamics upon overexpression of PLIN5, a known LD-mitochondrial tether, and (3) visualize two MCSs that share one organelle simultaneously (e.g., LD-mitochondria and LD-ER MCSs). Contact-FP probes can be optimized to visualize MCSs between any pair of organelles represented in the toolkit.

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“…Interorganelle contacts, primarily between the ER and mitochondria, mark sites of membrane pre-constriction that precedes mitochondrial fission in both yeast and humans (Friedman et al, 2011;Guo et al, 2018;Kleele et al, 2021). In human cells, the ER membrane phospholipid modifying enzyme ABHD16A may contribute to mitochondrial constrictions by acting in trans on the mitochondrial surface (Nguyen and Voeltz, 2022), though the ER may also promote mitochondrial constrictions via INF2-dependent polymerization of actin at the membrane contact site (MCS) (Chakrabarti et al, 2018;Korobova et al, 2013;Manor et al, 2015). In addition to external determinants, fission of the organelle must also be coordinated with factors inside mitochondria.…”

Section: Introductionmentioning

confidence: 99%

An intermembrane space protein facilitates completion of mitochondrial division in yeast

Connor

Matta

Friedman

2023

Preprint

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Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by the dynamin-related protein Dnm1 (Drp1 in humans), a large GTPase that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity alone is sufficient to complete fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1. Loss of Mdi1 leads to hyper-fused mitochondria networks due to defects in mitochondrial fission, but not lack of Dnm1 recruitment to mitochondria. Mdi1 plays a conserved role in fungal species and its homologs contain a putative amphipathic alpha-helix, mutations in which disrupt mitochondrial morphology. One model to explain these findings is that Mdi1 associates with and distorts the mitochondrial inner membrane to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of a protein that resides inside mitochondria.

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An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion

Cited by 38 publications

References 85 publications

Hexokinase 1 forms rings that constrict mitochondria during energy stress

Hexokinase 1 forms rings that constrict mitochondria during energy stress

Contact-FP: a dimerization-dependent fluorescent protein toolkit for visualizing membrane contact site dynamics

An intermembrane space protein facilitates completion of mitochondrial division in yeast

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