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Efficient 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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Mitochondria 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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Brain 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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Structural 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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Myonectin 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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Targeting 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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Nuclear 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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Three-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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Hypoxia-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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Immunoproteasome-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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Mitochondrial 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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Mitochondrial 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
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Intrinsic TGF-β signaling attenuates proximal tubule mitochondrial injury and inflammation in chronic kidney disease
Chronic kidney disease (CKD) is a disease that irreversibly leads to loss of renal function. Here, the authors demonstrate the beneficial effect of intrinsic TGF-b signaling on mitochondrial function and inflammation in the proximal tubule epithelium in response to kidney injury.
- Merve Kayhan
- , Judith Vouillamoz
- & Stellor Nlandu Khodo
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M1BP is an essential transcriptional activator of oxidative metabolism during Drosophila development
The transcriptional regulation of mitochondrial oxidative phosphorylation gene expression is poorly understood. Using the developing Drosophila flight muscle, the authors identify the transcription factor M1BP as a new major regulator of this process.
- Gabriela Poliacikova
- , Marine Barthez
- & Andrew J. Saurin
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Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
Reversible mitochondrial stress leading to improved mitochondrial function (mitohormesis) has been reported as an anti-aging mechanism. Here the authors report that harmol (a beta-carboline compound) induces mitohormesis in peripheral organs, alleviates aging-related phenotypes in mice, and extends lifespan in invertebrate models.
- Luis Filipe Costa-Machado
- , Esther Garcia-Dominguez
- & Pablo J. Fernandez-Marcos
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Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria
Mitochondria modulate both normal and premature aging, yet if primary oxidative phosphorylation deficiency can cause progeria has been unclear. Here, the authors show that mice with severe isolated respiratory complex III deficiency display cellular senescence and juvenile-onset segmental progeria.
- Janne Purhonen
- , Rishi Banerjee
- & Jukka Kallijärvi
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Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria
Mitochondrial SKD3 is an essential protein disaggregase. Here, authors solve the X-ray structures of SKD3Ank domain suggesting that the disease-associated mutation Y272C leads to a disulfide bond formation that impairs SKD3 function under oxidizing conditions.
- Sukyeong Lee
- , Sang Bum Lee
- & Francis T. F. Tsai
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NAD+ repletion with niacin counteracts cancer cachexia
The loss of nicotinamide adenine dinucleotide is reported to be associated with muscle mitochondrial dysfunction in murine cancer models. Here the authors show that niacin supplementation improves mitochondrial metabolism and reduces muscle wasting in mouse models of cachexia.
- Marc Beltrà
- , Noora Pöllänen
- & Fabio Penna
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Mitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemia stress
Despite common use as a diabetes mellitus supplement, chromium(III)’s pharmacological effects remain unknown. We identified the Cr(III)-proteome in cells with a metalloproteomic approach and uncovered ATP synthase as a vital target to relieve hyperglycaemia stress.
- Haibo Wang
- , Ligang Hu
- & Hongzhe Sun
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A defect in mitochondrial protein translation influences mitonuclear communication in the heart
The heart requires high levels of mitochondria to sustain function, and mitochondrial stressors can be transmitted to the nucleus and reprogram metabolism. Here, the authors show that a mitochondrial ribosomal protein is important for heart development in mice by increasing nuclear Klf15 expression.
- Feng Gao
- , Tian Liang
- & Jinghai Chen
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TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport
The mechanisms of microtubule-based mitochondrial transport remain poorly understood. Here, the authors show that the mitochondrial TRAK adaptors activate the dynein-dynactin complex, enhance the motility of kinesin, and can scaffold both motors to control bidirectional transport.
- John T. Canty
- , Andrew Hensley
- & Ahmet Yildiz
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A FRET-based respirasome assembly screen identifies spleen tyrosine kinase as a target to improve muscle mitochondrial respiration and exercise performance in mice
Mitochondrial supercomplex assembly may efficiently supply energy, yet its role remains controversial. Here, the authors show that SYK inhibitors increase supercomplex assembly and mitochondrial respiration in cells and can enhance exercise performance in mice.
- Ami Kobayashi
- , Kotaro Azuma
- & Satoshi Inoue
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Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation
Some forms of mitochondrial dysfunction can cause sterile inflammation, but the way in which it might affect muscle fitness is not well understood. Here, the authors show that altered mitochondrial dynamics can cause the production of mitochondrial DNA-driven inflammatory signals mediated by endosome-mitochondria contacts, leading to muscle inflammation, atrophy, reduced physical performance and enhanced exercise-induced inflammatory responses.
- Andrea Irazoki
- , Isabel Gordaliza-Alaguero
- & Antonio Zorzano
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The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction
Impaired liver metabolic function is related to mortality in severely malnourished children. Here the authors report a role for the tryptophan-NAD + pathway in reduced hepatic mitochondrial function and liver steatosis in a mouse model of severe malnutrition.
- Guanlan Hu
- , Catriona Ling
- & Robert H. J. Bandsma
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Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation
Cellular metabolism is important in pluripotency and cell fate regulation. Here, authors observe chromatin remodeling followed by TCA enzyme translocation from the mitochondria to the nucleus, demonstrating pluripotency regulation by mitochondria to nucleus retrograde signaling.
- Wei Li
- , Qi Long
- & Xingguo Liu
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mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity
Lung branching requires differentiation of progenitor cells to be coordinated with morphogenetic events. Zhang et al. find that loss of mTORC1 signaling in the distal SOX9+ lung progenitors reduces mitochondrial capacity and ATP production, thus disrupting the formation of the conducting airways without affecting the development of the gas exchange unit.
- Kuan Zhang
- , Erica Yao
- & Pao-Tien Chuang
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Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells
Chronic hyperglycemia impairs insulin secretion from pancreatic beta cells in diabetes. Here, the authors reveal that a glucose metabolite is responsible and show lowering glucose metabolism during hyperglycemia prevents loss of beta-cell function.
- Elizabeth Haythorne
- , Matthew Lloyd
- & Frances M. Ashcroft
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Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA
Mitochondrial quality control mechanisms prevent damage accumulation, including in mitochondrial DNA (mtDNA). Here, Sen et al. show that altered mtDNA elicits local rearrangements in mitochondrial membrane potential and cristae structure, with mtDNA eliminated through VPS35 endosomes.
- Ayesha Sen
- , Sebastian Kallabis
- & David Pla-Martín
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Identification of evolutionarily conserved regulators of muscle mitochondrial network organization
Mitochondrial networks are carefully positioned to facilitate energy distribution within muscle cells. Here they show that energetic demands and conserved transcription factors regulate mitochondrial network organization and contractile phenotypes independently in Drosophila.
- Prasanna Katti
- , Peter T. Ajayi
- & Brian Glancy
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Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure
Mitochondria power the beating heart. Here, Donnarumma et al. show that loss of the inner mitochondrial membrane protein MTFP1 in cardiomyocytes reduces bioenergetic efficiency and cell death resistance leading to heart failure in mice.
- Erminia Donnarumma
- , Michael Kohlhaas
- & Timothy Wai
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Human mtRF1 terminates COX1 translation and its ablation induces mitochondrial ribosome-associated quality control
How translation termination is achieved for the non-conventional mtDNA-encoded COX1 and ND6 was so far unknown. Here, Nadler et al. address this question by assessing the functions and specificity of the mitochondrial release factors mtRF1 and mtRF1a.
- Franziska Nadler
- , Elena Lavdovskaia
- & Ricarda Richter-Dennerlein
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Mitochondrial network configuration influences sarcomere and myosin filament structure in striated muscles
How different physical configurations between sarcomeres and mitochondria alter energetic support for contractile function of skeletal muscle is not clear. Here the authors use advanced 3D imaging and analysis techniques to show how space is made for mitochondria within the tightly packed sarcomere networks of striated muscle cells.
- Prasanna Katti
- , Alexander S. Hall
- & Brian Glancy
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ANGEL2 phosphatase activity is required for non-canonical mitochondrial RNA processing
A subset of mitochondrial transcripts is not flanked by tRNAs and thus does not conform to the canonical mode of processing. Here, Clemente et al. demonstrate that phosphatase activity of ANGEL2 is required for correct processing of these transcripts.
- Paula Clemente
- , Javier Calvo-Garrido
- & Anna Wredenberg
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Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy
Mitophagy activation is mediated by mitochondrial depolarization. Here, the authors show that mitochondrial protein misfolding can activate mitophagy in a depolarization-independent manner mediated by a protein import reduction.
- Jonas Benjamin Michaelis
- , Melinda Elaine Brunstein
- & Christian Münch
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Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA
Mitochondrial tRNAs are indispensable and yet underwent an extreme mutational erosion. The authors report the structures of a mitochondrial aaRS-tRNA complex and show how the most degenerated of all human mtRNAs is recognized by its cognate synthetase to maintain mitochondrial gene expression.
- Bernhard Kuhle
- , Marscha Hirschi
- & Paul Schimmel
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Highly conserved shifts in ubiquitin-proteasome system (UPS) activity drive mitochondrial remodeling during quiescence
Dynamic regulation of cellular proteostasis is linked to the metabolic state of quiescent cells in vivo. Here, the authors show, in multiple organisms, that shifts in the ubiquitin-proteome system are coupled to mitochondrial metabolic changes and subsequent respiratory quiescence.
- Sibiao Yue
- , Lei Wang
- & Matthew H. Sieber
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Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing
The regulatory mechanisms contributing to male reproductive ageing are unknown. Here, the authors show that Nestin-dependent mito-ER contacts (MERCs) regulate stem Leydig cell (SLC) senescence and provide insights into SLCs-targeting therapies.
- Senyu Yao
- , Xiaoyue Wei
- & Jiancheng Wang
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Modulating mitofusins to control mitochondrial function and signaling
Mitofusins regulate mitochondrial fusion. Here the authors identify small molecules that activate or inhibit mitofusins’ activity and modulate mitochondrial fusion and functionality. Inhibition of mitochondrial fusion promotes minority MOMP, caspase-3/7 activation, and DNA damage.
- Emmanouil Zacharioudakis
- , Bogos Agianian
- & Evripidis Gavathiotis
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Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression
Cancer cells downregulate surface expression of major histocompatibility complex I (MHC-I) for immune evasion. Here, the authors show that rapid mitochondrial fission activates the ER-stress response leading to reduced MHC-I complex formation and cell surface expression in solid cancer cells; moreover inhibition of mitochondrial fission increases the immune-mediated anticancer response in murine models.
- Xinyuan Lei
- , Hsinyu Lin
- & Jinsong Li
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Sex differences in heart mitochondria regulate diastolic dysfunction
In this paper, the authors show that sex differences in mitochondrial DNA levels and function in the heart contribute to sex biases in functions relevant to heart failure, identifying Acsl6 as a mitochondrial sex-biased regulator of diastolic function.
- Yang Cao
- , Laurent Vergnes
- & Aldons J. Lusis
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DDX1 vesicles control calcium-dependent mitochondrial activity in mouse embryos
The DEAD box protein DDX1 is known to form large aggregates in the cytoplasm of early mouse embryos. Here the authors identify DDX1-containing vesicles and show that loss of Ddx1 affects their integrity, compromising mitochondria function and causing embryonic lethality.
- Yixiong Wang
- , Lubna Yasmin
- & Roseline Godbout
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Structural basis for mitoguardin-2 mediated lipid transport at ER-mitochondrial membrane contact sites
The ER-mitochondria contact sites are crucial for exchanging phospholipids. Here, Kim et al. present crystal structures of mitoguardin-2 (MIGA2) which reveal that MIGA2 directly binds phospholipids and transfers them between the ER and mitochondria.
- Hyunwoo Kim
- , Seowhang Lee
- & Changwook Lee
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Coordination of metal center biogenesis in human cytochrome c oxidase
Mitochondrial cytochrome c oxidase is a heme aa3-copper oxygen reductase. Here, authors report that metal center-specific metallochaperones form dynamic assemblies to control heme a biosynthesis and coordinate copper transfer to the copper sites.
- Eva Nývltová
- , Jonathan V. Dietz
- & Antoni Barrientos
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Substrate binding in the mitochondrial ADP/ATP carrier is a step-wise process guiding the structural changes in the transport cycle
The mitochondrial ADP/ATP carrier transports adenine nucleotides. Here, authors identify the residues involved in substrate binding. One set forms the central substrate binding site and two asparagine/arginine pairs help to guide the substrates during the transport cycle.
- Vasiliki Mavridou
- , Martin S. King
- & Edmund R. S. Kunji
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FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion
Fragmented mitochondria are a frequent hallmark of cancer, but the cause and consequence are less clear. The authors demonstrate that elevated FUNDC2 causes mitochondrial fragmentation through inhibition of MFN1 in hepatocellular carcinoma and that knockdown of FUNDC2 inhibits liver tumorigenesis in mice.
- Shuaifeng Li
- , Shixun Han
- & Bin Zhao
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Activation of Nkx2.5 transcriptional program is required for adult myocardial repair
Cardiac developmental genes have been associated with regenerative potential. Here the authors identify a Nkx2.5-dependent gene regulatory network operating through ect2, psmb3, and psmd7 to orchestrate cell cycle re-entry, proteolysis, and mitochondrial metabolism during myocardial repair.
- Carmen de Sena-Tomás
- , Angelika G. Aleman
- & Kimara L. Targoff
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Influence of NAFLD and bariatric surgery on hepatic and adipose tissue mitochondrial biogenesis and respiration
Impaired mitochondrial function in liver tissue may contribute to the pathogenesis and disease progression of nonalcoholic fatty liver disease (NAFLD). Here the authors report that patients with obesity have lower mitochondrial capacity in adipose tissues but higher capacity in the liver, without overall associations to NAFLD severity, and that bariatric surgery increases hepatic mitochondrial respiration and mitochondrial biogenesis.
- Julie S. Pedersen
- , Marte O. Rygg
- & Flemming Dela
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Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment
Mitochondrial complex I deficiency is frequent in congenital, neurologic and cardiovascular disease. Here the authors demonstrate that Complex I stimulates the turnover of a mitochondrial calcium channel, which becomes stabilized during Complex I deficiency, preserving energetic homeostasis.
- Enrique Balderas
- , David R. Eberhardt
- & Dipayan Chaudhuri
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Identification of a modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast
Actin cables affect lifespan by supporting movement and inheritance of fitter mitochondria to daughter cells in yeast. Here the authors show that branched-chain amino acid (BCAA) levels affect actin cable stability and a role for YKL075C/AAN1 in control of BCAA metabolism and actin cable stability and function.
- Cierra N. Sing
- , Enrique J. Garcia
- & Liza A. Pon
BAP1 promotes osteoclast function by metabolic reprogramming