bims-minimp 2021-12-12 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2021‒12‒12
ten papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control.
The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites.
Lipid Droplets Protect Aging Mitochondria and Thus Promote Lifespan in Yeast Cells.
Supercomplex organization of the electron transfer system in marine bivalves, a model of extreme longevity.
Molecular species selectivity of lipid transport creates a mitochondrial sink for di-unsaturated phospholipids.
2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA.
The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice.
Untangling senescent and damage-associated microglia in the aging and diseased brain.
MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.
Parvovirus B19 (B19V) induces cellular senescence in human dermal fibroblasts: putative role in SSc-associated fibrosis.

Nat Cell Biol. 2021 Dec 06.

MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control.

Tim König, Hendrik Nolte, Mari J Aaltonen, Takashi Tatsuta, Michiel Krols, Thomas Stroh, Thomas Langer, Heidi M McBride.

Mitochondrial-derived vesicles (MDVs) are implicated in diverse physiological processes-for example, mitochondrial quality control-and are linked to various neurodegenerative diseases. However, their specific cargo composition and complex molecular biogenesis are still unknown. Here we report the proteome and lipidome of steady-state TOMM20+ MDVs. We identified 107 high-confidence MDV cargoes, which include all β-barrel proteins and the TOM import complex. MDV cargoes are delivered as fully assembled complexes to lysosomes, thus representing a selective mitochondrial quality control mechanism for multi-subunit complexes, including the TOM machinery. Moreover, we define key biogenesis steps of phosphatidic acid-enriched MDVs starting with the MIRO1/2-dependent formation of thin membrane protrusions pulled along microtubule filaments, followed by MID49/MID51/MFF-dependent recruitment of the dynamin family GTPase DRP1 and finally DRP1-dependent scission. In summary, we define the function of MDVs in mitochondrial quality control and present a mechanistic model for global GTPase-driven MDV biogenesis.

DOI: https://doi.org/10.1038/s41556-021-00798-4
Nat Metab. 2021 Dec 06.

The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites.

Camilla Bean, Matteo Audano, Tatiana Varanita, Francesca Favaretto, Marta Medaglia, Marco Gerdol, Lena Pernas, Fabio Stasi, Marta Giacomello, Stèphanie Herkenne, Maheswany Muniandy, Sini Heinonen, Emma Cazaly, Miina Ollikainen, Gabriella Milan, Alberto Pallavicini, Kirsi H Pietiläinen, Roberto Vettor, Nico Mitro, Luca Scorrano.

White to brown/beige adipocytes conversion is a possible therapeutic strategy to tackle the current obesity epidemics. While mitochondria are key for energy dissipation in brown fat, it is unknown if they can drive adipocyte browning. Here, we show that the mitochondrial cristae biogenesis protein optic atrophy 1 (Opa1) facilitates cell-autonomous adipocyte browning. In two cohorts of patients with obesity, including weight discordant monozygotic twin pairs, adipose tissue OPA1 levels are reduced. In the mouse, Opa1 overexpression favours white adipose tissue expandability as well as browning, ultimately improving glucose tolerance and insulin sensitivity. Transcriptomics and metabolomics analyses identify the Jumanji family chromatin remodelling protein Kdm3a and urea cycle metabolites, including fumarate, as effectors of Opa1-dependent browning. Mechanistically, the higher cyclic adenosine monophosphate (cAMP) levels in Opa1 pre-adipocytes activate cAMP-responsive element binding protein (CREB), which transcribes urea cycle enzymes. Flux analyses in pre-adipocytes indicate that Opa1-dependent fumarate accumulation depends on the urea cycle. Conversely, adipocyte-specific Opa1 deletion curtails urea cycle and beige differentiation of pre-adipocytes, and is rescued by fumarate supplementation. Thus, the urea cycle links the mitochondrial dynamics protein Opa1 to white adipocyte browning.

DOI: https://doi.org/10.1038/s42255-021-00497-2
Front Cell Dev Biol. 2021 ;9 774985

Lipid Droplets Protect Aging Mitochondria and Thus Promote Lifespan in Yeast Cells.

Melanie Kovacs, Florian Geltinger, Thomas Verwanger, Richard Weiss, Klaus Richter, Mark Rinnerthaler.

  Besides their role as a storage for neutral lipids and sterols, there is increasing evidence that lipid droplets (LDs) are involved in cellular detoxification. LDs are in close contact to a broad variety of organelles where protein- and lipid exchange is mediated. Mitochondria as a main driver of the aging process produce reactive oxygen species (ROS), which damage several cellular components. LDs as highly dynamic organelles mediate a potent detoxification mechanism by taking up toxic lipids and proteins. A stimulation of LDs induced by the simultaneously overexpression of Lro1p and Dga1p (both encoding acyltransferases) prolongs the chronological as well as the replicative lifespan of yeast cells. The increased number of LDs reduces mitochondrial fragmentation as well as mitochondrial ROS production, both phenotypes that are signs of aging. Strains with an altered LD content or morphology as in the sei1∆ or lro1∆ mutant lead to a reduced replicative lifespan. In a yeast strain defective for the LON protease Pim1p, which showed an enhanced ROS production, increased doubling time and an altered mitochondrial morphology, a LRO1 overexpression resulted in a partially reversion of this "premature aging" phenotype.

Keywords:  ROS-; aging; detoxification; lipid droplet (LD); mitochondrial damage; protein homeostais; reactive oxygen species

DOI:  https://doi.org/10.3389/fcell.2021.774985
J Gerontol A Biol Sci Med Sci. 2021 Dec 06. pii: glab363. [Epub ahead of print]

Supercomplex organization of the electron transfer system in marine bivalves, a model of extreme longevity.

Enrique Rodríguez, Amanda Radke, Tory M Hagen, Pierre U Blier.

  The mitochondrial oxidative stress theory of aging (MOSTA) suggests that the organelle's decay contributes to the aging phenotype via exacerbated oxidative stress, loss of organ coordination and energetics, cellular integrity and activity of the mitochondrial electron transfer system (ETS). Recent advances in understanding the structure of the ETS show that the enzymatic complexes responsible for oxidative phosphorylation are arranged in supramolecular structures called supercomplexes that lose organization during aging. Their exact role and universality among organisms are still under debate. Here, we take advantage of marine bivalves as an aging model to compare the structure of the ETS among species ranging from 28 to 507 years in maximal lifespan. Our results show that regardless of lifespan, the bivalve ETS is arrayed as a set of supercomplexes. However, bivalve species display varying degrees ETS supramolecular organization with the highest supercomplex structures found in A. islandica, the longest-lived of the bivalve species under study. We discuss this comparative model in light of differences in the nature and stoichiometry of these complexes, and highlight the potential link between the complexity of these superstructures and longer lifespans.

Keywords:  Electron transfer system; Invertebrate; Mitochondria; Supercomplex

DOI:  https://doi.org/10.1093/gerona/glab363
EMBO J. 2021 Dec 07. e106837

Molecular species selectivity of lipid transport creates a mitochondrial sink for di-unsaturated phospholipids.

Mike F Renne, Xue Bao, Margriet Wj Hokken, Adolf S Bierhuizen, Martin Hermansson, Richard R Sprenger, Tom A Ewing, Xiao Ma, Ruud C Cox, Jos F Brouwers, Cedric H De Smet, Christer S Ejsing, Anton Ipm de Kroon.

  Mitochondria depend on the import of phospholipid precursors for the biosynthesis of phosphatidylethanolamine (PE) and cardiolipin, yet the mechanism of their transport remains elusive. A dynamic lipidomics approach revealed that mitochondria preferentially import di-unsaturated phosphatidylserine (PS) for subsequent conversion to PE by the mitochondrial PS decarboxylase Psd1p. Several protein complexes tethering mitochondria to the endomembrane system have been implicated in lipid transport in yeast, including the endoplasmic reticulum (ER)-mitochondrial encounter structure (ERMES), ER-membrane complex (EMC), and the vacuole and mitochondria patch (vCLAMP). By limiting the availability of unsaturated phospholipids, we created conditions to investigate the mechanism of lipid transfer and the contributions of the tethering complexes in vivo. Under these conditions, inactivation of ERMES components or of the vCLAMP component Vps39p exacerbated accumulation of saturated lipid acyl chains, indicating that ERMES and Vps39p contribute to the mitochondrial sink for unsaturated acyl chains by mediating transfer of di-unsaturated phospholipids. These results support the concept that intermembrane lipid flow is rate-limited by molecular species-dependent lipid efflux from the donor membrane and driven by the lipid species' concentration gradient between donor and acceptor membrane.

Keywords:  lipid transport; membrane contact sites; membrane lipid homeostasis; membrane lipid unsaturation; mitochondria

DOI:  https://doi.org/10.15252/embj.2020106837
Nat Commun. 2021 Dec 06. 12(1): 6997

2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA.

Boris Pantic, Daniel Ives, Mara Mennuni, Diego Perez-Rodriguez, Uxoa Fernandez-Pelayo, Amaia Lopez de Arbina, Mikel Muñoz-Oreja, Marina Villar-Fernandez, Thanh-Mai Julie Dang, Lodovica Vergani, Iain G Johnston, Robert D S Pitceathly, Robert McFarland, Michael G Hanna, Robert W Taylor, Ian J Holt, Antonella Spinazzola.

Pathological variants of human mitochondrial DNA (mtDNA) typically co-exist with wild-type molecules, but the factors driving the selection of each are not understood. Because mitochondrial fitness does not favour the propagation of functional mtDNAs in disease states, we sought to create conditions where it would be advantageous. Glucose and glutamine consumption are increased in mtDNA dysfunction, and so we targeted the use of both in cells carrying the pathogenic m.3243A>G variant with 2-Deoxy-D-glucose (2DG), or the related 5-thioglucose. Here, we show that both compounds selected wild-type over mutant mtDNA, restoring mtDNA expression and respiration. Mechanistically, 2DG selectively inhibits the replication of mutant mtDNA; and glutamine is the key target metabolite, as its withdrawal, too, suppresses mtDNA synthesis in mutant cells. Additionally, by restricting glucose utilization, 2DG supports functional mtDNAs, as glucose-fuelled respiration is critical for mtDNA replication in control cells, when glucose and glutamine are scarce. Hence, we demonstrate that mitochondrial fitness dictates metabolite preference for mtDNA replication; consequently, interventions that restrict metabolite availability can suppress pathological mtDNAs, by coupling mitochondrial fitness and replication.

DOI: https://doi.org/10.1038/s41467-021-26829-0
Nat Metab. 2021 Dec 06.

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice.

Qixia Xu, Qiang Fu, Zi Li, Hanxin Liu, Ying Wang, Xu Lin, Ruikun He, Xuguang Zhang, Zhenyu Ju, Judith Campisi, James L Kirkland, Yu Sun.

Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies.

DOI: https://doi.org/10.1038/s42255-021-00491-8
FEBS J. 2021 Dec 06.

Untangling senescent and damage-associated microglia in the aging and diseased brain.

Pei Y Ng, Taylor L McNeely, Darren J Baker.

  Microglial homeostasis has emerged as a critical mediator of health and disease in the central nervous system. In their neuroprotective role as the predominant immune cells of the brain, microglia surveil the microenvironment for debris and pathogens, while also promoting neurogenesis and performing maintenance on synapses. Chronological aging, disease onset, or traumatic injury promotes irreparable damage or deregulated signaling to reinforce neurotoxic phenotypes in microglia. These insults may include cellular senescence, a stable growth arrest often accompanied by the production of a distinctive pro-inflammatory secretory phenotype, which may contribute to age- or disease-driven decline in neuronal health and cognition and is a potential novel therapeutic target. Despite this increased scrutiny, unanswered questions remain about what distinguishes senescent microglia and non-senescent microglia reacting to insults occurring in aging, disease, and injury, and how central the development of senescence is in their pivot from guardian to assailant. To intelligently design future studies to untangle senescent microglia from other primed and reactionary states, specific criteria must be developed that define this population and allow for comparisons between different model systems. Comparing microglial activity seen in homeostasis, aging, disease, and injury allows for a more coherent understanding of when and how senescent and other harmful microglial subpopulations should be targeted.

Keywords:  TBI; aging; microglia; neurodegenerative disease; senescence

DOI:  https://doi.org/10.1111/febs.16315
J Cell Sci. 2021 Dec 06. pii: jcs.257808. [Epub ahead of print]

MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.

Rajdeep Das, Izaz Monir Kamal, Subhrangshu Das, Saikat Chakrabarti, Oishee Chakrabarti.

  Mutations in Mitofusin2 (MFN2), associated with the pathology of the debilitating neuropathy, Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. One such abundant MFN2 mutant, R364W results in the generation of elongated, interconnected mitochondria. However, the mechanism leading to this mitochondrial aberration remains poorly understood. Here we show that mitochondrial hyperfusion in the presence of R364W-MFN2 is due to increased degradation of DRP1. The Ubiquitin E3 ligase MITOL is known to ubiquitylate both MFN2 and DRP1. Interaction with and its subsequent ubiquitylation by MITOL is stronger in presence of WT-MFN2 than R364W-MFN2. This differential interaction of MITOL with MFN2 in the presence of R364W-MFN2 renders the ligase more available for DRP1 ubiquitylation. Multimonoubiquitylation and proteasomal degradation of DRP1 in R364W-MFN2 cells in the presence of MITOL eventually leads to mitochondrial hyperfusion. Here we provide a mechanistic insight into mitochondrial hyperfusion, while also reporting that MFN2 can indirectly modulate DRP1 - an effect not shown before.

Keywords:  CMT2A-linked MFN2 mutant; DRP1; MITOL; Mitochondrial hyperfusion; Ubiquitylation

DOI:  https://doi.org/10.1242/jcs.257808
Rheumatology (Oxford). 2021 Dec 09. pii: keab904. [Epub ahead of print]

Parvovirus B19 (B19V) induces cellular senescence in human dermal fibroblasts: putative role in SSc-associated fibrosis.

Rosaria Arvia, Krystyna Zakrzewska, Lisa Giovannelli, Sara Ristori, Elena Frediani, Mario Del Rosso, Alessandra Mocali, Maria A Stincarelli, Anna Laurenzana, Gabriella Fibbi, Francesca Margheri.

  OBJECTIVE: Emerging evidence demonstrates that excessive accumulation of senescent cells is associated with some chronic diseases and suggests a pathogenic role of cellular senescence in fibrotic processes, such as that occurring in aging or in systemic sclerosis (SSc). Recently, we demonstrated that parvovirus B19 (B19V) activates normal human dermal fibroblasts and induces expression of different profibrotic/proinflammatory genes. This observation prompted us to investigate whether it is also able to induce fibroblast senescence as a potential pathogenetic mechanism in B19V-induced fibrosis.METHODS: Primary cultures of fibroblasts were infected with B19V and analyzed for the acquisition of senescence markers, such as morphological modifications, senescence-associated beta-galactosidase (SA-β-gal) activity, DNA damage response (DDR) and expression of senescence-associated secretory phenotype (SASP)-related factors.
RESULTS: We demonstrated that B19V-infected fibroblasts develop typical senescence features such as enlarged and flat-shaped morphology and SA-β-gal activity similar to that observed in SSc skin fibroblasts. They also developed a SASP-like phenotype characterized by mRNA expression and release of some proinflammatory cytokines, along with activation of transcription factor NFkB. Moreover, we observed B19V-induced DNA damage with the comet assay: a subpopulation of fibroblasts from B19V-infected cultures showed a significant higher level of DNA strand breaks and oxidative damage compared with mock-infected cells. Increased level and nuclear localization of ɣH2AX, a hallmark of DNA damage response, were also found.
CONCLUSIONS: B19V-induced senescence and production of SASP-like factors in normal dermal fibroblasts could represent a new pathogenic mechanism of non-productive B19V infection, which may have a role in the fibrotic process.

Keywords:  cellular senescence; fibrosis; normal human dermal fibroblasts; parvovirus B19; systemic sclerosis

DOI:  https://doi.org/10.1093/rheumatology/keab904