Regulation and Function of Mitochondria–Lysosome Membrane Contact Sites in Cellular Homeostasis

Trends in Cell Biology, Год журнала: 2019, Номер 29(6), С. 500 - 513

Опубликована: Март 18, 2019

Язык: Английский

---

Mitochondria–Lysosome Crosstalk: From Physiology to Neurodegeneration

Trends in Molecular Medicine, Год журнала: 2019, Номер 26(1), С. 71 - 88

Опубликована: Ноя. 29, 2019

The functions of mitochondria and lysosomes are coordinated with cellular metabolism signaling.AMPK mTORC1 mediate mitochondria–lysosome crosstalk.Acute chronic mitochondrial stress has opposite effects on lysosomal biogenesis.Lysosomal storage diseases trigger repression biogenesis.Mitochondria–lysosome crosstalk is impaired in neurodegenerative diseases. Cellular function requires coordination between different organelles metabolic cues. Mitochondria essential for as major contributors chemical energy building blocks. It therefore pivotal to coordinate the roles lysosomes. However, these do more than metabolism, given their fundamental signaling platforms cell that regulate many key processes such autophagy, proliferation, death. Mechanisms discussed, both under physiological conditions affect organelles. Life an elaborate system reactions which require organization. This chemistry often compartmentalized by phases or physical barriers. mitochondria, peroxisomes, lysosomes, others present extreme examples compartmentalization containing a specific set within limits membranes. These carry out together contribute survival cell, eventually its growth division. provided presents, however, challenge cell: must be ensure whole tuned. Multicellular organisms have types, but they all common aspects use ATP thioester bonds currency, well ability survive stresses (e.g., ischemia-induced hypoxia, fever-related heat shock). Cells cope triggering appropriate responder, triggers carefully executed plan adaptation survival. One met almost cells availability nutrients energy, lack thereof. Metabolism component responses because it allows redirection fuels generate (catabolism) conversion into blocks (anabolism). Both branches rely heavily not only providers also regulators activity across cell. Therefore, effectively coordinated. purpose this review discuss recent advances understanding communication how contributes function, perturbations involved pathology. Although outcomes conserved higher lower Eukarya, underlying mechanisms differ significantly. We focus mammalian crosstalk. To organelles, several need controlled: when organelle built (biogenesis), where positioned, performs, removed. Reciprocally, inform status needs, needs react accordingly. kinetics any may respond particular seconds minutes nutrient depletion, exercise, activation immune cells) remain long time infection, genetic defects organelle). Organelle biogenesis used reference transcriptional programs expression complete repertoire proteome, leading import assembly those proteins macromolecular complexes organelle. In review, refers programs. described Box 1, important note transcription factors seem able biogenesis.Box 1Mitochondrial Lysosomal BiogenesisThe comprise genes necessary make functional new complex involve ∼600 [98Palmieri M. et al.Characterization CLEAR network reveals integrated control clearance pathways.Hum. Mol. Genet. 2011; 20: 3852-3866Crossref PubMed Scopus (325) Google Scholar] ∼1000–1500 [99Pagliarini D.J. al.A protein compendium elucidates I disease biology.Cell. 2008; 134: 112-123Abstract Full Text PDF (1194) Scholar]. Specific cis-elements promoters enhancers drive expression.Multiple promote biogenesis, nuclear respiratory factor 1 (NRF1), peroxisome proliferator-activated receptor α (PPAR-α), PPAR-β/δ, PPAR-γ, estrogen-related (ERRα), ERRγ, Myc, 2 (known GA-binding factor, composed β subunits, GABPA GABPB; NRF2 should avoided unrelated erythroid 2-like 2, NFE2L2, coordinates antioxidant responses) examples. Many other been implicated some genes, less clear whether can entire program SP1, MEF2, CREB, FoxO, YY-1, E2F1, among others. promoting work association coactivators PGC-1α PGC-1β. A comprehensive discussion outside scope article summarized elsewhere [100Quiros P.M. al.Mitonuclear homeostasis stress.Nat. Rev. Cell Biol. 2016; 17: 213-226Crossref (192) Notably, although known activate two were recently found repress biogenesis. KLF2 ETV1 silence nucleus-encoded overexpression results impairment chain [42Yambire K.F. al.Mitochondrial transcriptionally repressed lipid diseases.eLife. 2019; 8: e39598Crossref (1) Scholar].The (nucleus-encoded encode proteins) ensured microphthalmia TFEB, MITF, TFE3, TFEC [101Sardiello gene regulating function.Science. 2009; 325: 473-477Crossref (943) coactivator ACSS2 cooperates TFEB [102Li X. al.Nucleus-translocated promotes autophagy.Mol. Cell. 2017; 66: 684-697Abstract (47) Other induce PPARα, E2F1 [103Fullgrabe J. al.Transcriptional regulation autophagy at glance.J. Sci. 129: 3059-3066Crossref (35) Several autophagy-related same regulatory circuits genes. As case there negative lysosomal/autophagy farnesoid X (FXR) bromodomain BRD4 Scholar].Interestingly, influence E2F1. remains unclear simultaneously, evidence TFE3 lines vivo [104Pastore N. al.TFE3 regulates whole-body cooperation TFEB.EMBO Med. 9: 605-621Crossref (16) Scholar], possibly involving induction PGC1α, coordinator (and peroxisomal) [105Wu Z. al.Mechanisms controlling respiration through thermogenic PGC-1.Cell. 1999; 98: 115-124Abstract (2571) represent mechanism peroxisomes). expression. Multiple Interestingly, positioning overlooked issue. There populations positions relative plasma membrane nucleus [1Korolchuk V.I. al.Lysosomal responses.Nat. 13: 453-460Crossref (393) are, normal conditions, spread around relatively uniform manner, rapidly relocate perinuclear region onset [2De Paepe B. al.Fluorescence imaging cultured skin fibroblasts: useful method detection oxidative phosphorylation defects.Pediatr. Res. 2012; 72: 232-240Crossref (8) Scholar,3Al-Mehdi A.B. al.Perinuclear clustering creates oxidant-rich domain required hypoxia-induced transcription.Sci. Signal. 5: ra47Crossref (156) Importantly, distribution considered importance interactions contact sites) fission) Ca2+ homeostasis, cholesterol trafficking, phospholipid synthesis [4Scorrano L. al.Coming define sites.Nat. Commun. 10: 1287Crossref (17) role sites discussed later article. constantly rest using multiple strategies. referred 'retrograde' originate nucleus, opposed 'anterograde' machinery modulates [5Raimundo signaling.in: Hockenberry D.M. Death. Humana Press, 2015: 169-184Google For example, retain calcium (Ca2+), iron, cholesterol, sphingomyelin, each sensed [6Perera R.M. Zoncu R. lysosome hub.Annu. Dev. 32: 223-253Crossref relay increasing/decreasing uptake, slowing down import, releasing metabolites, reactive oxygen species (ROS), vesicles, exporting peptides (such ClpP- HAF-1-dependent peptide export C. elegans proteotoxic MOTS-c mammals) DNA (mtDNA) [7Pellegrino M.W. al.Signaling unfolded response.Biochim. Biophys. Acta. 2013; 1833: 410-416Crossref (176) Scholar,8West A.P. primes antiviral innate response.Nature. 2015; 520: 553-557Crossref (89) paradigm, retrograde depends properties signal: trigger, intensity, frequency, duration. duration signal aspect acute remarkably different, least [9Raimundo Mitochondrial pathology: signals from factory.Trends 2014; 282-292Abstract (66) determinants termination. occasions cessation normoxia after hypoxic conditions) sufficient remove signal, termination achieved removal perturbed damaged maintenance healthy organellar function. strategies place recognize eliminate typically selective (mitophagy) (lysophagy). manner defective recognized differs 'red flag' seems depolarization, diverse ubiquitination outer membrane, recruitment mitophagy receptors, delivery mitochondria-containing autophagosomes degradation [10Youle R.J. Narendra D.P. mitophagy.Nat. 12: 9-14Crossref (1490) main event demise rupture, exposure parts glycocalyx galectin family proteins, then ruptured [11Jia al.Galectins mTOR response endomembrane damage.Mol. 2018; 70: 120-135Abstract (28) detailed lysophagy comprehensively reviews. interdependence underscored obtained malfunction. mouse embryonic fibroblasts lacking AIFM1 (apoptosis-inducible factor), OPA1, fusion, PINK1, quality mitophagy, show [12Demers-Lamarche al.Loss impairs lysosomes.J. Chem. 291: 10263-10276Crossref (57) evidenced enlargement (LAMP1-positive) become nonacidic lose hydrolytic detrimental effect dysfunction constant types vitro clonal lines) effector T cells, Huntington's heart) [13Baixauli F. controls during inflammatory responses.Cell Metab. 22: 485-498Abstract Scholar, 14Fernandez-Mosquera deficiency inhibits hydrolysis.Autophagy. 15: 1572-1591Crossref (3) 15Joshi A.U. al.Drp1/Fis1-mediated fragmentation leads cardiac models disease.J. Cardiol. 127: 125-133Abstract (0) 16Padman B.S. al.The protonophore CCCP interferes autophagic cargo yeast cells.Autophagy. 1862-1875Crossref does related decreased 13Baixauli mentioned above, increase similar paradigm observed function: (transcription EB) activated Scholar,17Fernandez-Mosquera al.Acute differentially biogenesis.Sci. Rep. 7: 45076Crossref 18Ivankovic D. following PINK1/parkin-mediated mitophagy.J. Neurochem. 136: 388-402Crossref 19Nezich C.L. al.MiT/TFE downstream Parkin Atg5.J. 210: 435-450Crossref occurs stress, [17Fernandez-Mosquera was pharmacologic inhibition high first hours inhibition, returned basal levels, actively inhibited persisted over 24 h (TFAM) protein, maintenance, transcription, replication mtDNA, upregulated Nevertheless, determined TFEB-dependent, what is, Tfam−/− still dysfunctional Furthermore, even classic biogenesis-stimulating amino acid starvation [14Fernandez-Mosquera Considering general picture emerges gears whereas shut inhibited. interpreted that, ultimately result elimination stimulating autophagosome formation, ensuring capacity increased occur indefinitely, would run constitute threat life most types. Thus, period 'clean-up' mode on, prefers inhibiting formation – better live unable efficiently phosphorylation, no irreversibly impair phospholipids, heme, Fe–S clusters. underlie uncovered. triggered factors, particularly exactly ones likely dependent type AMPK (AMP-dependent kinase) activation, [20Young N.P. al.AMPK governs lineage specification Tfeb-dependent lysosomes.Genes 30: 535-552Crossref (37) sensor charge [21Garcia Shaw AMPK: Sensing restoration balance.Mol. 789-800Abstract grand regulator activates catabolic pathways while anabolism. counterbalance mTORC1, kinase anabolic pathways. interplay brief int

Язык: Английский

---

Emerging roles of ATG proteins and membrane lipids in autophagosome formation

Cell Discovery, Год журнала: 2020, Номер 6(1)

Опубликована: Май 25, 2020

Autophagosome biogenesis is a dynamic membrane event, which executed by the sequential function of autophagy-related (ATG) proteins. Upon autophagy induction, cup-shaped structure appears in cytoplasm, then elongates sequestering cytoplasmic materials, and finally forms closed double autophagosome. However, how this complex vesicle formation event strictly controlled achieved still enigmatic. Recently, there accumulating evidence showing that some ATG proteins have ability to directly interact with membranes, transfer lipids between membranes regulate lipid metabolism. A novel role for various autophagosome also emerging. Here, we highlight past recent key findings on related consider control organize collaborating lipids.

Язык: Английский

---

Direct lysosome-based autophagy of lipid droplets in hepatocytes

Proceedings of the National Academy of Sciences, Год журнала: 2020, Номер 117(51), С. 32443 - 32452

Опубликована: Дек. 7, 2020

Hepatocytes metabolize energy-rich cytoplasmic lipid droplets (LDs) in the lysosome-directed process of autophagy. An organelle-selective form this (macrolipophagy) results engulfment LDs within double-membrane delimited structures (autophagosomes) before lysosomal fusion. Whether is an exclusive autophagic mechanism used by hepatocytes to catabolize unclear. It also unknown whether lysosomes alone might be sufficient mediate LD turnover absence autophagosomal intermediate. We performed live-cell microscopy monitor dynamic interactions between and real-time. additionally a fluorescent variant LD-specific protein (PLIN2) that exhibits altered fluorescence response with lysosome. find mammalian undergo during which proteins lipids can transferred from directly into lysosomes. Electron (EM) primary or hepatocyte-derived cell lines supports existence these interactions. reveals dramatic whereby contents "extruded" lumen under nutrient-limited conditions. Significantly, are not affected perturbations crucial components canonical macroautophagy machinery occur lipoautophagosomes. These findings implicate cells for direct transfer lysosome breakdown. This further emphasizes critical role hepatic catabolism provides insights mechanisms underlying homeostasis liver.

Язык: Английский

---

MIGA2 Links Mitochondria, the ER, and Lipid Droplets and Promotes De Novo Lipogenesis in Adipocytes

Molecular Cell, Год журнала: 2019, Номер 76(5), С. 811 - 825.e14

Опубликована: Окт. 15, 2019

Язык: Английский

---

A High-Density Human Mitochondrial Proximity Interaction Network

Cell Metabolism, Год журнала: 2020, Номер 32(3), С. 479 - 497.e9

Опубликована: Сен. 1, 2020

Язык: Английский

---

Cryo-EM reconstruction of a VPS13 fragment reveals a long groove to channel lipids between membranes

The Journal of Cell Biology, Год журнала: 2020, Номер 219(5)

Опубликована: Март 17, 2020

A single particle cryo-EM reconstruction of an ∼160-kD N-terminal fragment the lipid transport protein VPS13 reveals ∼160-Å long channel lined with hydrophobic residues suitable for solubilizing multiple fatty acid moieties. The structure suggests that and related proteins, like autophagy ATG2, can act as bridges between organelle membranes to allow bulk flow organelles.

Язык: Английский

---

Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation

Journal of Biological Chemistry, Год журнала: 2019, Номер 294(50), С. 18952 - 18966

Опубликована: Окт. 2, 2019

Intercellular propagation of protein aggregation is emerging as a key mechanism in the progression several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia (FTD). However, we lack systematic understanding cellular pathways controlling prion-like aggregation. To uncover such pathways, here performed CRISPR interference (CRISPRi) screens human cell-based model tau monitored by FRET. Our uncovered that knockdown components endosomal sorting complexes required for transport (ESCRT) machinery, charged multivesicular body 6 (CHMP6), or CHMP2A combination with CHMP2B (whose gene linked to familial FTD), promote We found knocking down genes encoding these proteins also causes damage endolysosomal membranes, consistent role ESCRT pathway membrane repair. Leakiness compartment significantly enhanced aggregation, likely making seeds more available pools cytoplasmic tau. Together, findings suggest escape critical step diseases. Leaky endosomes push over seed limitJournal Biological ChemistryVol. 294Issue 50PreviewThe inter- intracellular aggregated like central behind various The steps which aggregates propagates currently unclear. Chen et al. now combine genetic screen identify complex machinery mediators aggregates. Full-Text PDF Open Access

Язык: Английский

---

Hepatic lipid droplet homeostasis and fatty liver disease

Seminars in Cell and Developmental Biology, Год журнала: 2020, Номер 108, С. 72 - 81

Опубликована: Май 20, 2020

Язык: Английский

---

VPS13D bridges the ER to mitochondria and peroxisomes via Miro

The Journal of Cell Biology, Год журнала: 2021, Номер 220(5)

Опубликована: Апрель 23, 2021

Mitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their supply ER, where most lipids synthesized. In yeast, outer mitochondrial membrane GTPase Gem1 is an accessory factor of ERMES, ER–mitochondria tethering complex that contains domains and functions, partially redundantly with Vps13, in transfer between two organelles. metazoa, VPS13, but not present, orthologue Miro was linked to dynamics transport. Here we show Miro, including its peroxisome-enriched splice variant, recruits protein VPS13D, turn binds ER a VAP-dependent way thus could provide conduit mitochondria. These findings reveal so far missing link function(s) Gem1/Miro yeast higher eukaryotes, Parkin substrate, potential implications Parkinson’s disease pathogenesis.

Язык: Английский

---