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| Open AccessCdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila
Mitochondrial fission, performed by Drp1, is carefully regulated, particularly in neurons. Here, the authors examine Drosophila Cdk8/CDK19 function in mitochondrial fission and uncover a role phosphorylating Drp1 in the cytoplasm and show overexpression suppresses a Parkinson’s disease model.
- Jenny Zhe Liao
- , Hyung-lok Chung
- & Esther M. Verheyen
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Article
| Open AccessCross-link assisted spatial proteomics to map sub-organelle proteomes and membrane protein topologies
The spatial mapping of proteins can give important functional insights. Here, Zhu et al. develop a cross-linking mass spectrometry-based spatial proteomics method that does not require protein engineering, affords sub-organelle resolution, and elucidates both protein locations and membrane topologies.
- Ying Zhu
- , Kerem Can Akkaya
- & Fan Liu
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Article
| Open AccessNaked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles
The naked mole-rat exhibits extreme longevity, resistance to hypoxia and absence of cardiovascular disease. Here, Faulkes et al. identify mechanisms behind these traits by comparing cardiac metabolomes and transcriptomes of naked more-rats to other African mole-rat genera and evolutionary divergent mammals.
- Chris G. Faulkes
- , Thomas R. Eykyn
- & Dunja Aksentijevic
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Article
| Open AccessDefective mitochondria remodelling in B cells leads to an aged immune response
B cell activation in the germinal centre (GC) is accompanied by metabolic adaptation, but the functions of mitochondria remodelling during this process is unclear. Here the authors find that B cell-specific deficiency of Tfam, a transcription factor modulating mitochondria remodelling, impacts GC responses and induces aged immune features in B cells.
- Marta Iborra-Pernichi
- , Jonathan Ruiz García
- & Nuria Martínez-Martín
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Article
| Open AccessOsteocyte mitochondria regulate angiogenesis of transcortical vessels
Osteocytes are the key cellular components of cortical bone. Here they show that osteocytes transfer mitochondria to the endothelial cells of transcortical vessels (TCVs), which promotes angiogenesis and increases function of the TCV network.
- Peng Liao
- , Long Chen
- & Junjie Gao
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Article
| Open AccessThe AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions
Mitochondria emerged as essential actors of neural circuits development. Here, the authors uncovered that the AMPK-related kinase NUAK1 controls axonal mitochondrial metabolism through the regulation of the mitochondrial microprotein BRAWNIN.
- Marine Lanfranchi
- , Sozerko Yandiev
- & Julien Courchet
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Article
| Open AccessActivity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo
The mechanisms regulating mitochondrial architecture in neurons remain unclear. The authors report that in dendrites, mitochondria structure is specified by the CAMKK2-AMPK pathway through compartment-specific and activity-dependent levels of fission.
- Daniel M. Virga
- , Stevie Hamilton
- & Tommy L. Lewis Jr
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Article
| Open AccessNDUFS4 regulates cristae remodeling in diabetic kidney disease
Mitochondrial Ndufs4, a subunit of complex I, is a regulator of the electron transport chain. Here, the authors show that forced expression of Ndufs4 in podocytes improves the assembly of respiratory supercomplexes, maintains cristae integrity, and mitigates the progression of diabetic kidney disease
- Koki Mise
- , Jianyin Long
- & Farhad R. Danesh
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Article
| Open AccessOrthoID: profiling dynamic proteomes through time and space using mutually orthogonal chemical tools
Proteomics at the organelle contact site remains challenging due to the spatial and temporal dynamics of proteins. Here, the authors developed OrthoID, a mutually orthogonal dual enzymatic proteomics approach to explore the proteome at the contact site of the endoplasmic reticulum and mitochondria.
- Ara Lee
- , Gihyun Sung
- & Kimoon Kim
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Article
| Open AccessA spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling
Kang et al. reveal structural and functional differences in mitochondria across the hepatic lobule. Mitochondrial distinct phosphoproteome influences their functions highlighting how nutrient availability helps to shape mitochondria zonation.
- Sun Woo Sophie Kang
- , Rory P. Cunningham
- & Natalie Porat-Shliom
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Article
| Open AccessReducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans
Synthesis of ribosomal RNA (rRNA) by Pol I sustains cell growth but is highly energy demanding. Here the authors show that curbing of Pol I activity lowers systemic energy utilization and delays metabolic aging by reducing triglyceride lipolysis and mitochondrial oxygen consumption.
- Samim Sharifi
- , Prerana Chaudhari
- & Maria Ermolaeva
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Article
| Open AccessStalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis
Ribosome associated quality control (RQC) is a new area of biological investigation with emerging connection to a broad range of diseases. Here authors show that mitochondrial stress can upregulate a new RQC pathway important for tissue homeostasis.
- Ji Geng
- , Shuangxi Li
- & Bingwei Lu
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Article
| Open AccessALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy
Allophagy eliminates paternal mitochondria in C. elegans embryos. This study reveals that an autophagy adaptor, ALLO-1, recognizes cargos and initiates autophagosome formation by gathering with the ULK complex in an IKKE-1 kinase-dependent manner.
- Taeko Sasaki
- , Yasuharu Kushida
- & Miyuki Sato
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Article
| Open AccessA system for inducible mitochondria-specific protein degradation in vivo
Conditional degradation of proteins is instrumental to advance our knowledge of cell biology but has been lacking for organelles like mitochondria. Here, the authors develop a proteolysis system based on the mycoplasma Lon protease that functions selectively within mitochondria in yeast and human cells.
- Swastika Sanyal
- , Anna Kouznetsova
- & Camilla Björkegren
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Article
| Open AccessStructural basis for regulated assembly of the mitochondrial fission GTPase Drp1
Structural and functional studies highlight the molecular regulation of assembling the mitochondrial division machinery. The core unit is closed, and specific interactions open this unit to facilitate assembly at the right place and time in cells.
- Kristy Rochon
- , Brianna L. Bauer
- & Jason A. Mears
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Article
| Open AccessRescue of mitochondrial import failure by intercellular organellar transfer
Mitochondrial biogenesis and maintenance relies on protein import from the cytosol. Here, authors show that import failure impacts organelle structure and dynamics. They also identify a rescue mechanism involving intercellular mitochondrial transfer.
- Hope I. Needs
- , Emily Glover
- & Ian Collinson
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Article
| Open AccessA universal metabolite repair enzyme removes a strong inhibitor of the TCA cycle
Succinate dehydrogenase converts malate to enoloxaloacetate, a metabolically inactive and inhibitory side product of the TCA cycle. Here, Zmuda et al. describe a conserved metabolite damage repair enzyme that can remove enol-oxaloacetate and is critical for efficient aerobic respiration.
- Anthony J. Zmuda
- , Xiaojun Kang
- & Thomas D. Niehaus
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Article
| Open AccessMitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging
Dysregulated autophagy and mitochondrial function are two well-described hallmarks of aging. Here, the authors describe an unexpected age-associated upregulation of mitophagy in response to neuroinflammation triggered by leaked mtDNA.
- Juan Ignacio Jiménez-Loygorri
- , Beatriz Villarejo-Zori
- & Patricia Boya
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Article
| Open AccessTwo mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality
Chiang et al. map a genetic interaction in animal mitochondrial DNA by recombination. This reveals how polymorphisms in two complex IV subunits jointly affect cardiolipin binding to impact complex stability, organismal fitness and disease expression.
- Ason C. Y. Chiang
- , Jan Ježek
- & Hansong Ma
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Article
| Open AccessNAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations
How age-accumulated mtDNA mutations in the small intestine modulate intestinal homeostasis is unclear. Here, the authors show that increased mtDNA mutation burden triggers an ATF5 dependent UPRmt by NAD+ depletion, and thus regulates intestinal aging through impaired Wnt/β-catenin signaling.
- Liang Yang
- , Zifeng Ruan
- & Xingguo Liu
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Article
| Open AccessMuscle abnormalities worsen after post-exertional malaise in long COVID
In this longitudinal, case-controlled, cohort design study, authors show that post-exertional malaise is associated with severe exercise-induced myopathy, local and systemic metabolic disturbances and infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID.
- Brent Appelman
- , Braeden T. Charlton
- & Rob C. I. Wüst
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Article
| Open AccessMic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease
The molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, authors uncover a role for the EMC2- SLC25A46-Mic19 axis in mitochondrial lipid metabolism and liver disease
- Jun Dong
- , Li Chen
- & He He
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Article
| Open AccessMtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis
Excessive lipid accumulation in hepatocytes causes fatty liver disease and liver failure. Here the authors show that ablation of Mitochondrial Fission Process 1 in hepatocytes in mice protects fatty liver disease and dysfunction caused by high fat diet.
- Cecilia Patitucci
- , Juan Diego Hernández-Camacho
- & Timothy Wai
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Article
| Open AccessPhospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase
Mitochondria depend on phospholipids supplied by the endoplasmic reticulum. Here, using biochemical assays and molecular dynamics simulations, authors identify VDAC as a scramblase-type lipid transporter that catalyze lipid entry.
- Helene Jahn
- , Ladislav Bartoš
- & Anant K. Menon
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Article
| Open AccessInflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation
The immune suppression required for the resolution of acute inflammation is characterised by molecular and metabolic reprogramming of myeloid cells. Authors here show that the transcription factor ZEB1 is a key mediator of the pathway governing transition from inflammation to immunosuppression via regulating mitochondrial translation in macrophages.
- Marlies Cortés
- , Agnese Brischetto
- & Antonio Postigo
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Article
| Open AccessCryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization
The authors characterized puncta in the ASC complex by correlative light microscopy and cryo-ET in cells and propose an ultrastructure of the ASC filament network.
- Yangci Liu
- , Haoming Zhai
- & Yorgo Modis
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Article
| Open AccessARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.
- Maximilian Hirschenberger
- , Alice Lepelley
- & Konstantin M. J. Sparrer
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Article
| Open AccessDIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress
Proximity between mitochondria and endoplasmic reticulum regulates mitochondria fitness and is adversely affected by tissue ischemia. This work reveals that Diaphanous1-Mitofusin2 interaction regulates this proximity and impairs recovery in ischemia.
- Gautham Yepuri
- , Lisa M. Ramirez
- & Ravichandran Ramasamy
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Article
| Open AccessLipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice
Mitochondrial function is essential for energy metabolism in brown adipocytes. Here, the authors show that LCN2 plays a critical role as a phosphatidic acid binding protein in phospholipid acyl chain remodeling and mitochondrial bioenergetics, influencing signaling pathway activation.
- Hongming Su
- , Hong Guo
- & Xiaoli Chen
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Article
| Open AccessThe mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury
The role of the mitochondrial fusion protein OPA1 in liver function is unknown. Here, authors showed that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 deletion prevents liver injury and contributes to liver resiliency.
- Hakjoo Lee
- , Tae Jin Lee
- & Yisang Yoon
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Article
| Open AccessPPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy
The mitochondrial phosphatase PPTC7 has previously been linked to the maintenance of mitochondrial content, but the mechanisms underlying this phenotype remain unclear. Here, the authors demonstrate that loss of Pptc7 results in metabolic defects and further suggest that PPTC7 is a regulator of receptor-mediated mitophagy.
- Natalie M. Niemi
- , Lia R. Serrano
- & David J. Pagliarini
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Article
| Open AccessFAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes
Mammalians rely on brown adipocytes to generate heat under cold exposure, this thermogenic function requires dynamic remodeling of the mitochondria. Here the authors identify a protein called FAM210A as a key regulator of cold-induced mitochondrial remodeling in brown adipocytes.
- Jiamin Qiu
- , Feng Yue
- & Shihuan Kuang
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Article
| Open AccessPositive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice
Metabolic reprogramming is a hallmark of tumorigenesis. Here, the authors show that nuclear myosin 1 regulates mitochondrial oxidative phosphorylation via the TFAM and PGC1α transcription factors and suggest its depletion contributes to the Warburg effect during tumorigenesis.
- Tomas Venit
- , Oscar Sapkota
- & Piergiorgio Percipalle
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Article
| Open AccessDeleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
Mitochondrial DNA is known to exhibit heterogeneity of variants, even within a single cell. Here, the authors assessed this heteroplasmy of mitochondrial DNA within the UK Biobank cohort and showed that the presence of heteroplasmy and a functional score generated from heteroplasmic SNVs were associated with all-cause mortality and certain cancers.
- Yun Soo Hong
- , Stephanie L. Battle
- & Dan E. Arking
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Article
| Open AccessTMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
Mitochondrial dynamics affect the thermogenic capacity of brown adipose tissue. Here, the authors show that TMEM135 regulates thermogenesis and energy homeostasis by mediating mitochondrial fission in brown adipocytes.
- Donghua Hu
- , Min Tan
- & Irfan J. Lodhi
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Article
| Open AccessAll-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ
How ROS diffuse and are cleared between mitochondrial compartments governs oxidative stress and cell signaling. Here, authors map the kinetics of ROS dynamics using optogenetics and discover acute ROS transiently elongates mitochondria.
- Shon A. Koren
- , Nada Ahmed Selim
- & Andrew P. Wojtovich
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Article
| Open AccessBAP1 promotes osteoclast function by metabolic reprogramming
Here, the authors demonstrate that BRCA1-associated protein 1 (Bap1) regulates osteoclast’s capacity to degrade bone. Reprogramming of epigenetic-metabolic axis upon Bap1 loss inhibits bone degradation, preserving bone mass, making it a potential therapeutic target for osteoporosis.
- Nidhi Rohatgi
- , Wei Zou
- & Steven L. Teitelbaum
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Article
| Open AccessEfficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis
Using healthy mitochondria to restore impaired mitochondrial homeostasis is a promising therapy for pulmonary fibrosis. Here the authors use joint-engineered mesenchymal stem cells for efficient mitochondrial delivery to injured lung cells, showing a successful mitigation of the disease.
- Ting Huang
- , Ruyi Lin
- & Jianqing Gao
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Article
| Open AccessMitochondria are secreted in extracellular vesicles when lysosomal function is impaired
Mitochondrial quality control is critical for cellular homeostasis and survival. Here, the authors identify that defective mitochondria can be eliminated via secretion in large extracellular vesicles when internal lysosomal degradation is compromised.
- Wenjing Liang
- , Shakti Sagar
- & Åsa B. Gustafsson
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Article
| Open AccessBrain mitochondrial diversity and network organization predict anxiety-like behavior in male mice
Brain mitochondria play crucial roles that influence cognition, yet their diversity is often overlooked. This study in mice identifies distinct mitochondrial phenotypes distributed as large-scale networks, accounting for a large portion of animal-to-animal behavioural variation.
- Ayelet M. Rosenberg
- , Manish Saggar
- & Martin Picard
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Article
| Open AccessStructural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition
Aminoacyl-tRNA synthetases catalyze the ligation of amino acids to their cognate tRNAs. Here the authors report the cryo-EM structure of a human mitochondrial seryl-tRNA synthetase•mtRNASer complex showing how strong mutation pressure on mtRNA genes drove a rewiring of intermolecular recognition rules.
- Bernhard Kuhle
- , Marscha Hirschi
- & Paul Schimmel
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Article
| Open AccessMyonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway
Here the authors show that myonectin functions as a protective factor against age-associated, disuse-induced or steroid-induced muscle atrophy, suggesting that myonectin represents a therapeutic target for preventing skeletal muscle dysfunction.
- Yuta Ozaki
- , Koji Ohashi
- & Noriyuki Ouchi
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Article
| Open AccessTargeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction
Dynamin-related protein 1 (Drp1) mediates physiological and pathological mitochondrial fission, and the latter can be selectively blocked by a peptide inhibitor. Here, the authors identify a small molecule that mimics the benefits of this peptide inhibitor in cells and a mouse model of endotoxemia.
- Luis Rios
- , Suman Pokhrel
- & Daria Mochly-Rosen
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Article
| Open AccessNuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism
Chemotherapy can cause severe damage to cardiomyocytes in some patients but it is unclear how cardiomyocytes protect themselves against such stress. Here the authors show that cardiomyocytes initiate an endogenous protective response when exposed to chemotherapeutic agents by translocating mitochondrial enzymes to the nucleus.
- Shubhi Srivastava
- , Priyanka Gajwani
- & Jalees Rehman
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Article
| Open AccessThree-dimensional images reveal the impact of the endosymbiont Midichloria mitochondrii on the host mitochondria
The mitochondrial symbiont, Candidatus Midichloria mitochondrii, exists in the hard tick Ixodus ricinus, the main vector for Lyme disease. Here, the authors use FIB-SEM to characterise mitochondrial morphology and bacterial interactions in the context of oocyte maturation and endosymbiosis.
- Zerrin Uzum
- , Dmitry Ershov
- & Fabrizia Stavru
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Article
| Open AccessHypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion
Several organelle membranes make contact in the cell, with many contacts being spatially segregated sites dedicated to specific functions. Here, Hao et al. show that hypoxia increases mitochondria-lysosome contacts, leading to engulfment and degradation of the mitochondria.
- Tianshu Hao
- , Jianglong Yu
- & Zhiyin Song
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Article
| Open AccessImmunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction
Mitochondrial dysfunction results in the accumulation of mitochondrial proteins in the cytosol. Here, the authors show that the immunoproteasome subunit PSMB9 promotes protein degradation to maintain cellular protein homeostasis.
- Minji Kim
- , Remigiusz A. Serwa
- & Agnieszka Chacinska
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Article
| Open AccessMitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice
Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Here, Park et al. identify LETMD1 as a mitochondrial matrix protein enriched in brown adipose tissue (BAT) and reveal a crucial role for it in maintaining brown adipocyte mitochondrial OXPHOS and thermogenesis upon cold stimulus.
- Anna Park
- , Kwang-eun Kim
- & Jae Myoung Suh
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Article
| Open AccessMitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response
Mitochondrial function has been linked to immunity but the role of the Krebs’s cycle in regards the immune response is not well characterised. Here the authors show that Krebs’s cycle enzyme ACO2 suppresses immunity via modulation of oxaloacetate and the mitochondrial unfolded protein response.
- Eunah Kim
- , Andrea Annibal
- & Seung-Jae V. Lee