Endoplasmic reticulum–associated degradation regulates mitochondrial dynamics in brown adipocytes

Zhou, Zhangsen; Torres, Mauricio; Sha, Haibo; Halbrook, Christopher J.; Bergh, Françoise Van den; Reinert, Rachel B.; Yamada, Tatsuya; Wang, Siwen; Luo, Yingying; Hunter, Allen H.; Wang, Chunqing; Sanderson, Thomas H.; Liu, Meilian; Taylor, Alasdair; Sesaki, Hiromi; Lyssiotis, Costas A.; Wu, Jun; Kersten, Sander; Beard, Daniel A.; Qi, Ling

doi:10.1126/science.aay2494

Cited by 133 publications

(121 citation statements)

References 64 publications

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“…ER‐associated proteins, such as Mff, Fis1, MiD49, and MiD51 function as receptors to mediate the process 13,54 . A recent finding further demonstrates that ER‐associated protein degradation (ERAD) regulates directly the dynamics of mitochondria 55 . Here, we report that DRP1 translocates onto ER and facilitate dissociation of newly formed LDs from ER.…”

Section: Discussionmentioning

confidence: 54%

Novel role of dynamin‐related‐protein 1 in dynamics of ER‐lipid droplets in adipose tissue

Yang

Mao

et al. 2020

FASEB j.

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Dynamin‐Related‐Protein 1 (DRP1) critically regulates mitochondrial and peroxisomal fission in multicellular organisms. However, the impact of DRP1 on other organelles, especially its direct influence on ER functions remains largely unclear. Here, we report that DRP1 translocates to endoplasmic reticulum (ER) in response to β‐adrenergic stimulation. To further investigate the function of DRP1 on ER‐lipid droplet (LD) dynamics and the metabolic subsequences, we generated an adipose tissue‐specific DRP1 knockout model (Adipo‐Drp1flx/flx). We found that the LDs in adipose tissues of Adipo‐Drp1flx/flx mice exhibited more unilocular morphology with larger sizes, and formed less multilocular structures upon cold exposure. Mechanistically, we discovered that abnormal LD morphology occurs because newly generated micro‐LDs fail to dissociate from the ER due to DRP1 ablation. Conversely, the ER retention of LDs can be rescued by the overexpressed DRP1 in the adipocytes. The alteration of LD dynamics, combined with abnormal mitochondrial and autophagy functions in adipose tissue, ultimately lead to abnormalities in lipid metabolism in Adipo‐Drp1flx/flx mice.

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Section: Discussionmentioning

confidence: 54%

Novel role of dynamin‐related‐protein 1 in dynamics of ER‐lipid droplets in adipose tissue

Yang

Mao

et al. 2020

FASEB j.

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“…Another known Drp1 receptor, Fis1, has been shown in C. elegans to enter into a complex containing Drp1, Mff, and ER proteins at the ER-mitochondrial interface during stimulation of mitophagy (112). Strikingly, it is recently reported that endoplasmic reticulum-associated degradation (ERAD), an ER quality control mechanism, regulates mitochondrial dynamics (130). Additionally, in human cells, a subset of ER-mitochondria contacts spatially couple mtDNA replication with downstream mitochondrial division (131).…”

Section: Roles Of the Endoplasmic Reticulum In Mitochondrial Dynamicsmentioning

confidence: 99%

Regulation of Mammalian Mitochondrial Dynamics: Opportunities and Challenges

et al. 2020

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Mitochondria are highly dynamic organelles and important for a variety of cellular functions. They constantly undergo fission and fusion events, referred to as mitochondrial dynamics, which affects the shape, size, and number of mitochondria in the cell, as well as mitochondrial subcellular transport, mitochondrial quality control (mitophagy), and programmed cell death (apoptosis). Dysfunctional mitochondrial dynamics is associated with various human diseases. Mitochondrial dynamics is mediated by a set of mitochondria-shaping proteins in both yeast and mammals. In this review, we describe recent insights into the potential molecular mechanisms underlying mitochondrial fusion and fission, particularly highlighting the coordinating roles of different mitochondria-shaping proteins in the processes, as well as the roles of the endoplasmic reticulum (ER), the actin cytoskeleton and membrane phospholipids in the regulation of mitochondrial dynamics. We particularly focus on emerging roles for the mammalian mitochondrial proteins Fis1, Mff, and MIEFs (MIEF1 and MIEF2) in regulating the recruitment of the cytosolic Drp1 to the surface of mitochondria and how these proteins, especially Fis1, mediate crosstalk between the mitochondrial fission and fusion machineries. In summary, this review provides novel insights into the molecular mechanisms of mammalian mitochondrial dynamics and the involvement of these mechanisms in apoptosis and autophagy.

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“…A recent study has implicated components of the ER-associated degradation (ERAD) quality control pathway in regulating mitochondrial dynamics via ER-mitochondria contacts [ 50 ]. In brown adipocytes, loss of the ER-resident ERAD protein Sel1L prevents the mitochondrial fission usually stimulated by cold stress, resulting in enlarged ‘megamitochondria’ with impaired metabolic functions.…”

Section: Mitochondrion-organelle Interactions and Their Physiologicalmentioning

confidence: 99%

“…* MCS components listed are those mentioned in the text; this is not a complete list of all MCS components identified so far. Organelles (MCS) MCS components* Physiological role References Mitochondria – endoplasmic reticulum SigmaR1 (MITO), SEL1L (ER) Regulation of mitochondrial fission [ 50 ] Spire1C (MITO) – INF2 (ER) tether [ [45] , [46] , [47] ] IP 3 R (ER) – GRP75 – VDAC (MITO) tether Transfer of Ca 2+ between ER and MITO; Ca 2+ signalling via MITO-ER contacts [ 56 , 57 ] PDZD8 (MITO/LYS?) – Unknown protein (ER) tether Dendritic Ca 2+ homeostasis in mammalian neurons?…”

Section: Introductionmentioning

confidence: 99%

Maintaining social contacts: The physiological relevance of organelle interactions

Silva

DiGiovanni

Kumar

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Membrane-bound organelles in eukaryotic cells form an interactive network to coordinate and facilitate cellular functions. The formation of close contacts, termed “membrane contact sites” (MCSs), represents an intriguing strategy for organelle interaction and coordinated interplay. Emerging research is rapidly revealing new details of MCSs. They represent ubiquitous and diverse structures, which are important for many aspects of cell physiology and homeostasis. Here, we provide a comprehensive overview of the physiological relevance of organelle contacts. We focus on mitochondria, peroxisomes, the Golgi complex and the plasma membrane, and discuss the most recent findings on their interactions with other subcellular organelles and their multiple functions, including membrane contacts with the ER, lipid droplets and the endosomal/lysosomal compartment.

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Endoplasmic reticulum–associated degradation regulates mitochondrial dynamics in brown adipocytes

Cited by 133 publications

References 64 publications

Novel role of dynamin‐related‐protein 1 in dynamics of ER‐lipid droplets in adipose tissue

Novel role of dynamin‐related‐protein 1 in dynamics of ER‐lipid droplets in adipose tissue

Regulation of Mammalian Mitochondrial Dynamics: Opportunities and Challenges

Maintaining social contacts: The physiological relevance of organelle interactions

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