ER Tubules Mark Sites of Mitochondrial Division

Friedman, Jonathan R.; Lackner, Laura L.; West, Matthew; DiBenedetto, Jared R.; Nunnari, Jodi; Voeltz, Gia K.

doi:10.1126/science.1207385

Cited by 1,705 publications

(1,792 citation statements)

References 29 publications

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“…The plasmids pXY142-mitodsRED (mitoRED) [32], p412-ADH1 mitoTagBFP (mitoBFP::LEU) [12], p416ADH1 mitotagBFP (mitoBFP::URA), Ruby-Tub1::LEU, and pFA6-link-mKate- spHIS5 [17], pKT127 pFA6-link-yEGFP-KAN, pKT209 pFA6-link-yEGFP-CaURA3, and pKT128 pFA6a–link–yEGFP–SpHIS5 [33], p416-ADH1 and p414-MET25 [34] were described previously. pHIS3p:mRuby2-Tub1 + 3'UTR::HPH (Ruby-Tub1::HYG) (Addgene plasmids #50,633) was a gift from W. Lee, UMass Amherst [35].…”

Section: Methodsmentioning

confidence: 99%

The role of mitochondria in anchoring dynein to the cell cortex extends beyond clustering the anchor protein

et al. 2018

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Organelle distribution is regulated over the course of the cell cycle to ensure that each of the cells produced at the completion of division inherits a full complement of organelles. In yeast, the protein Num1 functions in the positioning and inheritance of two essential organelles, mitochondria and the nucleus. Specifically, Num1 anchors mitochondria as well as dynein to the cell cortex, and this anchoring activity is required for proper mitochondrial distribution and dynein-mediated nuclear inheritance. The assembly of Num1 into clusters at the plasma membrane is critical for both of its anchoring functions. We have previously shown that mitochondria drive the assembly of Num1 clusters and that these mitochondria-assembled Num1 clusters serve as cortical attachment sites for dynein. Here we further examine the role for mitochondria in dynein anchoring. Using a GFP-αGFP nanobody targeting system, we synthetically clustered Num1 on eisosomes to bypass the requirement for mitochondria in Num1 cluster formation. Utilizing this system, we found that mitochondria positively impact the ability of synthetically clustered Num1 to anchor dynein and support dynein function even when mitochondria are no longer required for cluster formation. Thus, the role of mitochondria in regulating dynein function extends beyond simply concentrating Num1; mitochondria likely promote an arrangement of Num1 within a cluster that is competent for dynein anchoring. This functional dependency between mitochondrial and nuclear positioning pathways likely serves as a mechanism to order and integrate major cellular organization systems over the course of the cell cycle.

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Section: Methodsmentioning

confidence: 99%

The role of mitochondria in anchoring dynein to the cell cortex extends beyond clustering the anchor protein

et al. 2018

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“…The microtubules are of vital importance in this network and are in contact with the sarcoplasmic/ER and mitochondria (FIG. 2b); loss of contact results in Ca 2+ overload in the organelles, unfolded protein response in the ER, and mitochondrial dysfunction [50][51][52][53] . Contact between organelles and traf ficking through the cells is mediated by acetylated microtubules 52 .…”

Section: Key Pointsmentioning

confidence: 99%

“…Contact between organelles and traf ficking through the cells is mediated by acetylated microtubules 52 . Consequently, both trafficking of pro teins and contractile function are heavily impaired by histone deacetylase 6 (HDAC6) induced depolymeriza tion of the microtubules 52,53 . Therefore, a functional cytoskeletal network underlies balanced communica tion in the proteostasis network and ensures proper contractile function.…”

Section: Key Pointsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

140

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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“…The main protein driving mitochondrial fragmentation is the GTPase Dynamin-Related-Protein-1 (Drp1) [26]. Mechanistically, the endoplasmic reticulum (ER) and actin filaments can generate an initial constriction at OMM [27,28], which subsequently allows for Drp1 recruitment and aggregation into oligomeric ring-like structures at the point of future fission events [29], where it wraps and severs mitochondrial membranes through its GTP hydrolysis [30,31]. Drp1 is post-transcriptionally regulated by phosphorylation, SUMOylation, ubiquitination, S-nitrosylation and O-GlcNAcylation (see [30] for a review).…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial dynamics in cancer and immune-surveillance

Simula

Nazio

Campello

2017

Seminars in Cancer Biology

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A B S T R A C TMitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence.

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ER Tubules Mark Sites of Mitochondrial Division

Cited by 1,705 publications

References 29 publications

The role of mitochondria in anchoring dynein to the cell cortex extends beyond clustering the anchor protein

The role of mitochondria in anchoring dynein to the cell cortex extends beyond clustering the anchor protein

Proteostasis in cardiac health and disease

The mitochondrial dynamics in cancer and immune-surveillance

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