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Mitochondria importance articles
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65 of 176 articles · updated 2026-09-18T14:04Z
- biorxiv2026-09-08score 94mtDNAtherapeuticsmetabolism
A TYMP mRNA-lipid nanoparticle resets blood nucleosides in a mitochondrial DNA depletion syndrome within hours
Mitochondrial neurogastrointestinal encephalomyopathy is a thymidine-phosphorylase failure that poisons mitochondrial nucleotide pools systemically. Intravenous human TYMP mRNA in lipid nanoparticles puts the enzyme in mouse liver, is tolerated, and returns circulating nucleosides to wild-type in hours for up to three weeks at 0.25 mg/kg. Subcutaneous dosing works if you add hyaluronidase.
Source preprint: mRNA-LNP therapy restores systemic nucleoside imbalance in a mitochon-drial DNA depletion syndrome
- biorxiv2026-08-14score 94OXPHOSmetabolismneurobiology
POLG occipital epilepsy is an immunometabolic lesion: OXPHOS collapse meets innate inflammation in visual cortex
In 12 post-mortem POLG-related epilepsy brains, occipital cortex (BA17) loses mitochondrial proteins and gains an innate-immune proteome, including OXPHOS-poor microglia. Control visual cortex is already richer in OXPHOS and interneuron proteins than frontal cortex — a baseline that may explain why status epilepticus detonates occipitally in this mitochondrial disease.
Source preprint: Neuroinflammation and metabolic dysfunction in POLG-related mitochondrial epilepsy
- biorxiv2026-08-13score 92mtDNAOXPHOSmetabolism
Past 70% mtDNA heteroplasmy, cells need pyruvate carboxylase — or exogenous asparagine — to keep translating
Isogenic mtDNA-deletion lines show linear loss of respiration with heteroplasmy, but redox stress, ISR, and translation failure only after discrete thresholds (~50% and ~70%). Those late defects reverse with asparagine or pyruvate carboxylase overexpression. Respiration-deficient cells become asparagine auxotrophs when PC is low — and L-asparaginase shrinks a high-heteroplasmy, low-PC thyroid tumor model.
Source preprint: Respiration-Deficient Cells Require Pyruvate Carboxylase to Suppress Asparagine Auxotrophy
- biorxiv2026-09-03score 91cardiologymetabolismautophagy
Adult cardiomyocyte prohibitin knockout unleashes mTORC1, Warburg-like amino-acid synthesis, and fatal DCM
Delete the PHB1/2 complex in adult mouse cardiomyocytes and mTORC1 runs unrestrained. Glucose carbon swings toward de novo amino acids, mitochondrial calcium handling breaks, autophagy fails, the heart dilates, and the animals die within 12 weeks. mTORC1 inhibition eases remodeling only in females.
Source preprint: Cardiomyocyte prohibitin ablation reprograms cardiac metabolism revealing a pathogenic role for mTORC1 in dilated cardiomyopathy
- biorxiv2026-08-12score 91OXPHOSmetabolismredox biology
Clever-1 sits on AML mitochondria, feeds complex IV with lipoprotein lipid, and is a bexmarilimab-sensitive OXPHOS liability
Clever-1 is not only an immune scavenger receptor. In AML it localizes to mitochondria, associates with ATAD3, delivers lipoprotein-derived lipid, and supports complex IV assembly, cristae, and spare respiratory capacity. Antibody blockade (bexmarilimab) collapses that program, hardest in OXPHOS-high models and under lipid restriction.
Source preprint: Clever-1 blockade disrupts lipid metabolism and mitochondrial fitness in acute myeloid leukemia
- biorxiv2026-09-03score 90mitochondrial transferimmunologyislet
Beta cells hand mitochondria to islet macrophages, and the receivers turn on Arc and make more protein
Mice with beta-cell-only mitochondrial GFP show those organelles arriving in islet macrophages in vivo and in vitro. Diabetogenic stress does not change how often it happens. Macrophages that took the gift synthesize more protein and raise Arc; blocking actin dynamics stops the transfer. Islet homeostasis now includes organelle traffic, not only cytokines.
Source preprint: Mitochondrial transfer mediates metabolic communication between beta cells and islet macrophages
- medrxiv2026-08-25score 90mtDNAgeneticsmetabolism
251,512 biobank genomes already held mitochondrial DNA. This pipeline finally calls it.
A portable Mitoverse mtDNA-Server 2 Fusion workflow, run natively at Mount Sinai (54,151 whole-exome participants) and reimplemented under All of Us Workbench constraints (197,361 whole-genome participants), produced 12.9 million mitochondrial DNA variant observations across 251,512 people without new sequencing. The missing product was never the reads. It was a harmonized, heteroplasmy-aware call set that biobanks would actually ship.
Source preprint: A Scalable Framework for Harmonized mtDNA Analysis Across Diverse Biobanks
- biorxiv2026-08-15score 88OXPHOSredox biologyapoptosis
IVF and vitrification depolarize the blastocyst mitochondrion; the adult mouse heart still shows the bioenergetic scar
Mouse IVF and embryo vitrification are separable mitochondrial injuries. Both lower blastocyst ΔΨm and glutathione; ROS is highest in vitrified IVF embryos. After transfer, adult left-ventricular mitochondria have less OXPHOS capacity, more H2O2 per oxygen, altered OXPHOS subunit abundance, and reduced complex I, III and IV activity. The organelle is a plausible lasting carrier of ART cardiovascular risk.
Source preprint: In vitro fertilisation and vitrification disrupt embryo mitochondrial function and redox balance that persists into adulthood in mice
- biorxiv2026-08-13score 88neurobiologycalcium signalingOXPHOS
LRRK2 astrocytes extrude calcium slowly; PRKN astrocytes run hotter OXPHOS; both fragment mitochondria
Parkinson’s hiPSC astrocytes are not a single mitochondrial phenotype. LRRK2 G2019S cells hold less cytosolic calcium and extrude it more slowly after ATP. PRKN mutant astrocytes run a more oxidative bioenergetic program than LRRK2 mutants. Both genotypes fragment mitochondria, park them at the periphery, alter DRP1 phosphorylation, and lose respiratory-complex protein.
Source preprint: Mitochondrial Metabolism and Calcium Handling in Parkinson's Disease hiPSC-derived Astrocytes
- biorxiv2026-08-12score 87metabolismOXPHOSmitochondrial dynamics
DGAT1 lipid droplets shield nurse-cell mitochondria — without them, fatty acids flood in and oogenesis arrests
Drosophila nurse-cell mitochondria oxidize fatty acids in a stage-dependent way, peaking at mid-oogenesis, and they draw that fuel from ATGL-released lipid-droplet triglyceride. Blocking droplet formation with DGAT1 mutants dumps fatty acids into mitochondria, collapses function, and arrests the follicle. Restricting fatty-acid influx into the follicle or into mitochondria rescues. Lipid droplets are a mitochondrial buffer, not just an embryonic larder.
Source preprint: Monitoring fatty acid trafficking during Drosophila melanogaster oogenesis reveals a role for the triglyceride synthase DGAT1 in protecting mitochondrial integrity
- biorxiv2026-08-11score 87cancertherapeuticsOXPHOS
ClpP agonist TR-107 collapses ACC respiration at nanomolar doses and synergizes with IGF-1R blockade
TR-107, a selective agonist of the mitochondrial protease ClpP, kills adrenocortical carcinoma cells and patient-derived organoids at nanomolar concentrations by wrecking oxidative phosphorylation. Oxygen consumption falls, ROS rise, ferroptosis-rheostat proteins come up, and the compound is not an ABCB1 substrate. Combined with IGF-1R inhibitors, the kill is synergistic.
Source preprint: TR-107, a novel mitochondrial ClpP agonist, induces robust antitumor activity against preclinical models of adrenocortical carcinoma
- biorxiv2026-09-03score 86mitochondrial dynamicsredox biologymetabolism
Losing ELM1B freezes moss mitochondrial fission, oxidizes the matrix, and weakens stress tolerance
In the moss Physcomitrium patens, mito-paraquat oxidizes glutathione in mitochondria, cytosol, and chloroplasts, elongates mitochondria within hours, and raises a heterogeneous matrix EOS-red signal that the authors propose as a protein-damage mark. Genetic loss of PpELM1B (ELONGATED MITOCHONDRIA 1B) locks that elongated state, shifts matrix glutathione more oxidized, increases EOS red, slows growth and respiration, and makes plants more sensitive to oxidative stress, even though matrix mixing still occurs at the same slow, days-long rate as in wild type.
Source preprint: Loss of ELM1B impairs mitochondrial fission, matrix redox state and stress tolerance in Physcomitrium patens
- biorxiv2026-08-17score 86OXPHOSredox biologymetabolism
APX2014 rewires mitochondrial cysteine, phospho, and acetyl marks in minutes — the proteome has not moved yet
A 30–120 minute pulse of the Ref-1/APE1 redox inhibitor APX2014 remakes PTMs, not protein abundance, in PDAC cells. Cysteine oxidation leads; phosphorylation and lysine acetylation follow; the earliest enriched processes are mitochondrial translation, electron transport, TCA metabolism, and mitochondrial redox homeostasis, matching a functional drop in TCA-substrate use.
Source preprint: Integrated Post-Translational Modification (PTM) Proteomics Reveals Early Redox and Mitochondrial Remodeling Following Ref-1 Inhibition in Pancreatic Cancer
- biorxiv2026-09-09score 85redox biologyneurobiologymetabolism
Female hypothalamic microglia resist early obesity with a redox-and-mitochondria program until mTORC1 breaks it
In females, not males, hypothalamic microglia answer a high-fat diet with more antioxidant capacity and a remodeled mitochondrial network, which delays early weight gain. Microglial mTORC1 later wrecks those mitochondria and ends the grace period. Sex-specific obesity risk has an organelle switch in a brain-resident immune cell.
Source preprint: A Female-Specific Microglial Redox Program Gates Susceptibility to Obesity
- biorxiv2026-08-17score 85metabolismtherapeuticscancer
Sertraline plus carfilzomib starves SSP-active T-cell tumors of cholesterol flux and mitochondrial respiration
In T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphoma (PTCL) cells that run the serine/glycine synthesis pathway (SSP), the antidepressant sertraline and the proteasome inhibitor carfilzomib are synergistic because they pull cholesterol in opposite directions and together collapse mitochondrial respiration. The pair works in an aggressive MYCN PTCL mouse model and remakes the immune microenvironment, while largely sparing SSP-inactive tumor cells and healthy blood cells.
Source preprint: Sertraline and Carfilzomib Synergize to Target T-cell Malignancies with Serine/Glycine synthesis activity via Cholesterol Dysregulation, Cellular Stress and Immune Modulation
- biorxiv2026-09-09score 84fissionfusionstem cells
Light-dark cycles tune Drp1 on ovarian stem-cell mitochondria so a protein-rich diet can make eggs
Drosophila ovarian germline stem cells only convert a protein-rich meal into eggs if the light-dark clock has parked the fission protein Drp1 on mitochondria in the right pattern. Cryptochrome sets the rhythm, Opa1 can reverse it, threonine is the amino-acid cue, and follicle stem cells want a different Drp1 tune. The same priming undoes a diabetes-like brake on egg development.
Source preprint: Interaction of light-dark and dietary cues prime Drosophila ovarian stem cell properties by precisely tuning Drp1 recruitment and organization on mitochondria
- medrxiv2026-09-02score 84mitophagytherapeuticsaging
Pemafibrate restores TFEB-driven mitophagy and flattens FEV1 decline versus older fibrates
Chronic obstructive pulmonary disease (COPD) airway epithelium is short on transcription factor EB (TFEB). Pemafibrate, a selective peroxisome proliferator-activated receptor alpha agonist already used for lipids, restores autophagy and mitophagy flux plus lysosomal acidification in smoke-exposed human bronchial epithelial cells, limits emphysema and lung stiffness in chronically smoked mice, and in a retrospective clinic cohort associates with slower forced expiratory volume in 1 second (FEV1) decline than bezafibrate or fenofibrate.
Source preprint: Senotherapeutic role of pemafibrate through autophagy/mitophagy regulation in chronic obstructive pulmonary disease
- biorxiv2026-08-19score 84metabolismOXPHOScancer
GALC knockout loads melanoma mitochondria with ceramide and sphingomyelin and throttles respiration without wrecking structure
Knocking out the lysosomal sphingolipid enzyme β-galactosylceramidase (GALC) in A2058 human melanoma cells remakes the mitochondrial sphingolipid profile and produces bioenergetic insufficiency without major mitochondrial structural change. The authors attribute the energy failure to ceramide- and sphingomyelin-driven impairment of respiratory-chain function. GALC is a lipid-to-OXPHOS lever in this line, consistent with prior work that treated GALC as pro-oncogenic.
Source preprint: Impact of the sphingolipid metabolizing enzyme β-galactosylceramidase on mitochondrial sphingolipid profile and energetic metabolism in human melanoma cells
- biorxiv2026-09-07score 83metabolismcytoskeletoninsulin
Losing PTPRF rewires actin, raises mitochondrial respiration in hepatocytes, and frees insulin granules in beta cells
The receptor phosphatase PTPRF is a nutrient-stress checkpoint: spliced XBP1 turns it down, actin filaments reorganize, hepatocytes shift toward oxidative mitochondrial metabolism and less steatosis, and obese beta cells release more insulin. Cytoskeleton and mitochondria are on the same adaptive circuit, not parallel chapters.
Source preprint: PTPRF is a stress-responsive cytoskeletal checkpoint that coordinates metabolic adaptation in hepatocytes and β cells
- biorxiv2026-08-20score 82OXPHOSthermogenesisbioenergetics
Human UCP1 uncouples like mouse UCP1 but prefers ATP over GDP, tracing in part to F88S
Human and mouse uncoupling protein 1 (UCP1), expressed with adeno-associated virus in mouse liver and assayed in isolated liver mitochondria, both cause marked innate uncoupling without added fatty acids. Mouse UCP1 keeps classical GDP inhibition and oleate reactivation. Human UCP1 is only weakly GDP-inhibited, is strongly fatty-acid responsive, and is potently inhibited by ATP (apparent IC50 about 0.4 mM versus about 1.4 mM for GDP). Molecular dynamics point to a persistent GDP–F88 contact in mouse UCP1 that is missing at S88 in human UCP1.
Source preprint: Differential Nucleotide Inhibition Profile of Mouse and Human UCP1 Expressed in Liver Mitochondria Is Associated with an F88S Mutation
- biorxiv2026-08-13score 82metabolismcardiologylipid
2-Hydroxyglutarate parks fatty acids in triglycerides and away from mitochondria and lipotoxic membranes
Both D- and L-2-hydroxyglutarate push fatty acids into triglyceride droplets and away from phospholipid synthesis, mitochondrial oxidation, and lipotoxic intermediates in primary human cardiac and vascular cells. L2HG is more potent despite lower accumulation: it raises DGAT-dependent TG synthesis, slows TG turnover, and constrains the ethanolamine Kennedy branch, depleting phosphatidylethanolamine. FAO, long-chain acylcarnitines, and lipid peroxidation fall, independent of pseudohypoxic transcription. In mice L2HG causes hypertriglyceridemia, remakes cardiac TG acyl chains, and limits ischemia-induced cardiac acylcarnitine buildup, matching a human 2HG–triglyceride association. 2HG decides how fat is allocated, not only whether it is burned.
Source preprint: 2-Hydroxyglutarate Redirects Fatty Acid Partitioning to Mitigate Lipotoxic Stress and Preserve Metabolic Fuel
- biorxiv2026-09-03score 81computationalmetabolismOXPHOS
Underpredicted mitochondrial ADP/ATP carrier kcat values, not leaderboard scores, break yeast growth models
Six machine-learning predictors of enzyme turnover number (kcat) are only moderately accurate on a BRENDA-derived set and collapse to R-squared of 0.20 or lower on EnzyExtract, where training-set overlap is thinner. When those predicted kcat values parameterize enzyme-constrained genome-scale models of Saccharomyces cerevisiae, benchmark rank does not predict growth accuracy. The failure localizes to high-leverage mitochondrial ADP/ATP carrier turnover numbers: underpredict them and the model chokes adenine nucleotide exchange and invents a cytosolic ATP shortage.
Source preprint: Beyond benchmark accuracy: machine-learning turnover-number predictors require system-level validation
- biorxiv2026-08-21score 81computationalgeneticsmtDNA
Plant mitochondria keep a compact AOX–NAC stress module; human disease genes pile onto an expanded ISR–mtDNA network
An Arabidopsis-versus-human in silico comparison finds the same mitochondrial stress logic in both kingdoms, but not the same architecture. Plants organize alternative respiration and retrograde signaling as a compact AOX–NAC module. Humans expand integrated-stress-response and mtDNA-maintenance neighborhoods — and those expanded modules are the ones enriched for mitochondrial disease genes.
Source preprint: From Plants to Patients: Mitochondrial Stress Signaling as a Systems Framework for Human Disease Vulnerability
- biorxiv2026-08-17score 81metabolismredox biologyTCA cycle
Chlamydomonas NADK2 parks in mitochondria in the dark; without it the TCA cycle and heterotrophy fail
In Chlamydomonas reinhardtii, NADK2 is dual-targeted: mostly chloroplast in the light or on mixotrophy, increasingly mitochondrial in the dark on acetate. nadk2 mutants cannot make enough mitochondrial NADP(H), so the TCA cycle stalls and heterotrophic growth collapses. In the light, chloroplast NADK1 covers energy needs and acetate is rerouted through the glyoxylate shunt, bypassing TCA and cutting mitochondrial ROS. NAD kinase localization is plastic, and bypass metabolism is how the mutant survives daylight.
Source preprint: Dual-targeted NADK2 Links Mitochondrial Redox Homeostasis to Carbon Partitioning and Heterotrophic Growth in Chlamydomonas reinhardtii
- biorxiv2026-09-05score 80metabolismnephrologyproteomics
Diabetic proximal tubule turns mitochondrial programs up; glomeruli just lose oxidative capacity
Deep visual proteomics of streptozotocin diabetic kidney splits two organelles’ fates. Proximal tubule loses proteostasis and structure and compensates with mitochondrial and lipid metabolism. Glomeruli lose oxidative metabolic capacity and do not compensate. Fourteen of the top twenty tubule candidates, including mitochondrial LARS2, move the same way in human CKD tubulointerstitium.
Source preprint: Deep visual proteomics reveals distinct proximal tubular and glomerular injury programs in experimental diabetic kidney disease
- biorxiv2026-08-17score 80OXPHOSmetabolismcardiology
Losing FAHD1 stalls Complex II, derails the myosin switch, and hypertrophies maturing cardiomyocytes
The mitochondrial oxaloacetate decarboxylase FAHD1 is not a biochemical footnote. Germline Fahd1 knockout mice lose Complex II respiration and pyruvate, slide toward glycolysis and anabolic biosynthesis, fail the fetal-to-adult myosin switch, and develop left-ventricular systolic dysfunction with cardiomyocyte hypertrophy. That makes FAHD1 a gatekeeper of postnatal cardiac mitochondrial maturation.
Source preprint: A novel role for Oxaloacetate Decarboxylase FAHD1 in cardiomyocyte maturation
- biorxiv2026-08-17score 80immunologyOXPHOSmetabolism
HIF-1α makes intestinal RORγt+ Tregs mitochondrially sloppy and inflammatory
Hypoxia-inducible factor 1-alpha (HIF-1α) is a context-dependent checkpoint in intestinal RORγt-positive regulatory T cells. Deleting Hif1a in RORγt-expressing cells protects mice in acute dextran sulfate sodium (DSS) colitis, T-cell-transfer colitis, and azoxymethane/DSS colitis-associated cancer. Protection can travel with the Treg genotype alone. Those Tregs make more IL-10, less IL-17A and IFN-γ, suppress better, carry fewer dysfunctional and mitochondrial-ROS-high mitochondria, favor fusion-associated transcription, and show higher basal and maximal oxygen consumption and reserve capacity.
Source preprint: HIF-1α integrates metabolic and immunoregulatory programs in RORγt⁺ regulatory T cells during intestinal inflammation
- biorxiv2026-08-13score 80cardiologytherapeuticsOXPHOS
Pan-KDM inhibitor JIB-04 reverses MYH7-like HCM and restores mitochondrial respiration in iPSC-CMs
The pan-histone-lysine-demethylase inhibitor JIB-04 prevents and reverses hypertrophic cardiomyopathy in Myh6 R403Q/+ mice (the murine stand-in for human MYH7 R403Q). It cuts hypertrophy and fibrosis, preserves function, and fully prevents sudden death in cyclosporin A–accelerated disease; it also works after disease is established, after drug withdrawal, and in aged spontaneous HCM. In MYH7 R403Q iPSC-cardiomyocytes it normalizes disease genes, restores connexin-43 membrane localization, and improves mitochondrial respiration. PHF2 (KDM7C) is a candidate target in mouse and human HCM hearts.
Source preprint: Histone lysine demethylase inhibition is a disease-modifying therapy for hypertrophic cardiomyopathy
- biorxiv2026-08-11score 80protein importphospholipidsmetabolism
Djp1 delivers Psd1 and separately keeps mitochondrial phospholipid metabolism alive
The Hsp40 cochaperone Djp1, already known for ER-SURF handover of mitochondrial precursors, is a specific biogenesis factor for phosphatidylserine decarboxylase 1 (Psd1), the inner-membrane enzyme that makes mitochondrial phosphatidylethanolamine. That job depends on Psd1’s targeting signal and is not copied by other Hsp40s or ER-targeting factors. Losing Djp1 and Psd1 together is synthetically sick in a way that reveals extra, Psd1-independent roles for Djp1 in mitochondrial phospholipid metabolism.
Source preprint: Djp1 is a multifunctional Hsp40 cochaperone for mitochondrial phospholipid metabolism
- biorxiv2026-08-11score 80mtDNAtranslationreproduction
Sperm finish maturation by translating first in a leftover droplet, then on midpiece mitochondria
Transcriptionally silent, cytoplasm-stripped mammalian sperm still need about ten days of epididymal protein synthesis to become motile and fertile. Testicular sperm keep a cytoplasmic droplet with ribosomes and intact tRNAs and make protein there. In the epididymis that droplet fragments and synthesis moves to the midpiece, where mitochondrial translation turns on. Blocking cytosolic translation in testicular sperm or mitochondrial translation in epididymal sperm abolishes motility. Both apparatuses are required for maturation.
Source preprint: Life without cytoplasm: sperm sustain protein production utilizing cytoplasmic droplets and mitochondria as translational apparatuses
- biorxiv2026-09-10score 79mitophagyautophagymetabolism
ULK1 and ULK2 hold muscle size down by restraining mTORC1 and protecting mitochondrial protein turnover
The autophagy-initiating kinases ULK1 and ULK2 are a dual brake on skeletal-muscle growth: they keep autophagy running, hold mTORC1 in check, and help degrade mitochondrial and sarcoplasmic proteins. Lifelong loss makes fibers bigger and weaker; a few weeks of loss makes them bigger while force still holds.
Source preprint: ULK1 and ULK2 Restrain Skeletal Myofiber Growth by Balancing Protein Synthesis and Degradation
- biorxiv2026-08-26score 79OXPHOSmetabolismimmunology
After stem-cell transplant, jSSc monocytes quiet NF-κB and turn mitochondrial genes back on
In three children with juvenile systemic sclerosis, longitudinal CITE-seq of blood monocytes before autologous stem cell transplantation and at 6, 12, and 24 months after shows systemic-sclerosis-linked genes (including SERPINE1) falling, NF-κB inflammatory signaling decaying from a high baseline, and mitochondrial-function plus oxidative phosphorylation genes rising. An immune reset in this fibrotic disease is also a bioenergetic reset.
Source preprint: Longitudinal single-cell modeling reveals monocyte reprogramming in juvenile systemic sclerosis following autologous stem cell transplantation
- biorxiv2026-08-14score 79immunologyOXPHOSmetabolism
Mycoplasma gallisepticum raises itaconate in finch PBMCs and blocks the SDH-linked immune burst
In house finches, live Mycoplasma gallisepticum (MG) suppresses the early circulating immune-metabolic burst that heat-killed MG elicits. Heat-killed bacteria raise succinate dehydrogenase (SDH)-dependent respiration in peripheral blood mononuclear cells and cytokine genes in erythrocytes; live MG instead accumulates itaconate in PBMCs and skips those increases. Dimethyl itaconate copies the suppressed blood-cell phenotype. At the conjunctiva, live MG still raises mitochondrial respiration and cytokines. The pathogen looks like it commandeers an itaconate–SDH brake in circulating cells while allowing local inflammation at the infection site.
Source preprint: Mycoplasma gallisepticum uses itaconate-associated mitochondrial inhibition to suppress host immunometabolism
- biorxiv2026-09-03score 78metabolismhepatologyredox biology
Losing ER NADPH enzyme H6PD fills the liver with triglycerides and slows mitochondrial beta-oxidation
Hexose-6-phosphate dehydrogenase makes NADPH inside the ER. Knock it out in mice and the liver piles unsaturated long-chain triglycerides; Nile red agrees; proteomics turn fatty-acid pathways up. An AML12 CRISPR knockout accumulates lipid, cuts mitochondrial beta-oxidation, and the abstract cuts off mid-assay.
Source preprint: Hexose-6-phosphate dehydrogenase deficiency disrupts hepatic fatty acid homeostasis and induces triglyceride accumulation
- biorxiv2026-08-19score 78therapeuticscardiologyOXPHOS
Liver-approved PPAR-α/δ agonist elafibranor eases TGF-β1 fibrosis and restores respiration in human cardiac models
Elafibranor, a dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist already approved for liver disease, blunts transforming growth factor beta 1 (TGF-β1) fibrosis programs in human cardiac fibroblasts, spheroids, and contracting microtissues while partially restoring mitochondrial respiratory capacity, remodeling NAD and adenine-nucleotide pools, and recovering some calcium-handling and contraction parameters. That is a bioenergetic anti-fibrotic signal in human in-vitro systems, not a clinical cardiomyopathy trial.
Source preprint: The dual PPAR-α/δ agonist elafibranor attenuates TGF-β 1 -induced cardiac fibrosis through redox-metabolic and bioenergetic reprogramming in human cardiac models
- biorxiv2026-08-15score 78metabolismcancerNAD
Oncogenic tyrosine kinases phosphorylate NAMPT at Y188 and turn on NAD+ salvage, including at mitochondria
Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD+ salvage enzyme, is a direct substrate of proto-oncogenic tyrosine kinases (ALK, insulin receptor, IGF1R, PDGFRA). Phosphoproteomics name Y188 as the major site, including on the fusion kinase NPM1::ALK. NAMPT meets NPM1::ALK in cytoplasm, nucleus, and mitochondria. Y188 phosphorylation raises catalytic activity, nicotinamide mononucleotide (NMN)/NAD+ biosynthesis, and downstream metabolism. A Y188F mutant or a dimerization break weakens enzyme, proliferation, and clonogenicity. NAMPT inhibition hits ALK-inhibitor-sensitive and -resistant lymphoma and pairs with ALK blockade.
Source preprint: Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer
- medrxiv2026-08-14score 78neurobiologymetabolismepigenetics
Early KAT6A truncations empty the gene; late ones invert neuronal metabolism and mitochondria
Arboleda-Tham syndrome is not one molecular disease. In patient iPSCs, early-truncating KAT6A variants (exons 1–15) are loss-of-function via nonsense-mediated decay; late-truncating variants (exons 16–17) escape NMD and act as gain-of-function. Those opposite mechanisms invert the direction of change in neuronal gene regulation, metabolism, and mitochondrial physiology, and they split facial gestalt and DNA-methylation episignatures. Therapy splits with them: inhibit KAT6A for late truncations; rescue dosage for early ones.
Source preprint: Dominant truncating variants in KAT6A cause two neurodevelopmental disorders with opposite gene regulatory and metabolic changes.
- biorxiv2026-08-08score 78neurobiologyOXPHOSmetabolism
Visual cortex sits on mitochondria-poor tissue; semantic cortex sits on mitochondria-rich tissue
7T fMRI during natural-scene viewing, split by image-to-brain encoding into variance unique to visual versus semantic features, was compared with postmortem mitochondrial atlases under spatial-autocorrelation-preserving inference. Visual-specific cortical variance aligns negatively with mitochondrial density and respiratory capacity. Semantic-specific variance aligns positively with mitochondrial density. Transcriptomic enrichments run in opposite mitochondrial and cellular programs along those two representational axes. How cortex represents the world tracks how the tissue is provisioned with mitochondria.
Source preprint: Distinct mitochondrial phenotypes align with visual and semantic representations across human cortex
- biorxiv2026-09-04score 77metabolismimmunologyOXPHOS
Tirzepatide keeps hematopoietic progenitors cycling and OXPHOS-competent while cutting inflammatory monocytes
Matched weight loss in obese mice splits by method. Caloric restriction empties blood lineages and shuts HSPC nutrient-sensing, proliferation, and oxidative phosphorylation. Tirzepatide keeps blood counts, preserves more progenitor cycling and OXPHOS, and specifically cuts Ly6C-high CCR2-positive monocytes. Those monocytes bounce back when the drug stops.
Source preprint: Tirzepatide preserves hematopoietic stem and progenitor cycling while remodeling inflammatory monocytes in obese mice
- biorxiv2026-08-21score 77agingtherapeuticsredox biology
TLR2 plus peroxide senescence in human disc cells opens a metabolic-activity window for senolytic screens
Cherif and colleagues build a standardized senescence recipe for primary human intervertebral disc cells — TLR2 ligand plus tert-butyl hydroperoxide — and show that Alamar Blue can find a senolytic therapeutic window. Outer annulus fibrosus cells senesce hardest. o-Vanillin, RG-7112, and ABT-199 drop metabolic activity in mixed senescent cultures without killing non-senescent cells, and those drops track β-galactosidase and p16.
Source preprint: A Standardized In Vitro Platform for Senolytic Drug Discovery in Human Musculoskeletal Cells
- biorxiv2026-08-15score 77metabolismOXPHOSproteostasis
Z-AAT polymers clog hepatic lipid handling and leave mitochondria numerous but respiratory-poor
Z-variant alpha-1 antitrypsin (Z-AAT) polymers accumulate in Z-HepG2 cells and patient-derived ZZ hepatic organoids, cut secretion, and bring lipid storage, mitochondrial structural abnormalities, more mitochondria with less respiratory capacity, reduced oxidative phosphorylation, a partial glucose lean, and increased peroxisomal mass. Controls mount an adaptive mitochondrial transcriptional response to lipid supplementation; Z-HepG2 cells barely do. Proteotoxic AATD liver disease is also a failure of organelle metabolic flexibility.
Source preprint: Z-AAT impairs organelle homeostasis and reduces adaptive response to lipids in alpha-1 antitrypsin deficiency models
- biorxiv2026-09-08score 76translationcancermetabolism
eIF4A inhibitors starve BRAF-resistant melanoma of translation and of mitochondrial metabolic output
Kinase-inhibitor-resistant BRAF-mutant melanoma still depends on eIF4A-driven mRNA translation. Blocking that helicase (CR-1-31-B) cuts survival proteins, flattens a high-output mitochondrial/metabolic state, restricts glutamine carbon past uptake, and deepens BRAF-inhibitor control in xenografts.
Source preprint: eIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma
- biorxiv2026-08-20score 76proteostasisredox biologymetabolism
Peroxide cataracts in zebrafish switch on the unfolded and mitochondrial unfolded protein responses
Hydrogen peroxide injected into the aqueous humor of adult zebrafish produces cortical cataracts and a cortex proteome that activates the unfolded and mitochondrial unfolded protein responses, alongside energy-metabolism, calcium, degradation, and remodeling shifts. Crossing reduced NRF2 defense with a crystallin/proteostasis mutant (cryaba) is meant to mimic aged human lenses. The mitochondrial claim is not that the lens is a new OXPHOS organ, but that mitoUPR joins UPR as a candidate therapeutic axis in oxidative cataract.
Source preprint: Upregulation of the Unfolded and Mitochondrial Unfolded Protein Responses in Oxidative Stress-Induced Cataract
- biorxiv2026-08-17score 75neurobiologymtDNAmetabolism
Fractionated 20 Gy X-rays senesce F11 sensory neurons and raise mtDNA copy number without a ROS or OCR hit
Four daily 5 Gy X-ray fractions (20 Gy total) leave F11 dorsal-root-ganglion neuron-like cells senescent, with higher mitochondrial DNA copy number and a shifted NAD+/NADH pathway, but without a change in oxygen consumption rate or an oxidative-stress signal 24 hours after the last dose. Gene-expression changes land on mechanoreceptor-fiber programs that can be pro-nociceptive. Radiotherapy-linked chronic pain, in this cell line, is not a simple mitochondrial ROS story.
Source preprint: Fractionated ionising radiation affects cellular functions, and gene expression associated to subpopulation of F11 dorsal root ganglia neurons without inducing oxidative stress
- biorxiv2026-09-09score 74metabolismcancermtDNA
IDH1-mutant gliomas split into quiet mitochondrial one-carbon states and a high-OCM subset that dies sooner
IDH1-mutant gliomas are not one metabolically meek tumor. A 64-gene one-carbon-metabolism score on 709 TCGA/CGGA cases, plus U87 R132H cells, splits a suppressed, mitochondrially compensated state from an aggressive subset that hyperactivates proliferative one-carbon genes and has worse survival (CGGA hazard ratio 1.61).
Source preprint: One-Carbon Metabolic Reprogramming Stratifies Prognosis and Defines Distinct Biological States in IDH1-Mutant Gliomas
- medrxiv2026-08-17score 73cardiologymetabolismcomputational
A 4.5-million-person HF GWAS puts myocardial energy, the mitochondrial proteome, and adipokines on the target list
Multi-ancestry GWAS of 345,687 heart-failure cases among 4,468,166 people, plus HFpEF and HFrEF splits, with plasma proteomics and multi-tissue transcriptomics, yields 383 loci (166 new) and 568 genes (375 new). Eleven new genes are already drug targets, including a case for expanding aldosterone-synthase inhibitors (CYP11B2) and type-II activin-receptor antagonists (ACVR2A) into HF. Nearly 100 genes sit in food intake, energy expenditure, fatty-acid/glucose/BCAA metabolism, and the mitochondrial proteome that sustains myocardial ATP. Metabolism and adipokines are framed as primordial HF targets.
Source preprint: Global genomics in over 4 million individuals prioritizes therapeutic targets for heart failure and its subtypes
- biorxiv2026-08-16score 73cancermetabolismhypoxia
IL-1β drives colorectal glycolysis and suppresses mitochondrial respiration through AKT then HIF-1α
Interleukin-1 beta (IL-1β), a cytokine elevated in colorectal cancer, stimulates glycolysis, inhibits maximal mitochondrial respiration, and raises AKT phosphorylation and hypoxia-inducible factor 1-alpha (HIF1α). Knockouts split the pathway: AKT1/2 sit upstream of HIF1α. IL-1β still phosphorylates AKT without HIF1α, but cannot raise HIF1α protein without AKT1/2. Tumor necrosis factor alpha (TNFα) uses the same AKT–HIF1α route to increase glycolysis. The paper also says IL-1β suppresses oxidation of the fiber-derived nutrient butyrate.
Source preprint: Requirement of hypoxia-inducible factor 1 alpha for interleukin 1 beta induced glycolysis in colorectal cancer cells
- biorxiv2026-09-02score 72metabolismOXPHOSgenetics
The rat jaw opener transcribes mitochondrial energy and fatty-acid modules the closer does not
All three rat feeding muscles (anterior digastric, superficial masseter, sternohyoid) express mostly fast-twitch contractile isoforms, but the jaw-opening anterior digastric downshifts several myosin and tropomyosin families, upshifts slower or oxidative myosins (Myh7, Myh2), and is the muscle whose co-expression modules are enriched for fatty-acid catabolism, mitochondrial energy production, and vascular or extracellular-matrix remodeling.
Source preprint: Transcriptomic profile of a rat jaw opener (anterior digastric) and a jaw closer (superficial masseter).
- biorxiv2026-08-25score 72redox biologymetabolismtherapeutics
Thiol-coated iron oxide nanoparticles chelate copper and put tomato mitochondria back to work
MPA-iron oxide nanoparticles sequentially coated with chitosan, glutathione, and 3-mercaptopropionic acid bind more copper than bare iron oxide, lower intracellular reactive oxygen species, restore mitochondrial membrane potential, and rescue germination plus root and shoot growth in copper-stressed tomato (Solanum lycopersicum) seedlings. The plant mitochondrion is treated as the first organelle copper wrecks, and as a readable endpoint for a dual chelator-antioxidant particle.
Source preprint: Efficient Mitigation of Copper Induced Cellular Dysfunction Using Chitosan Based Iron Oxide Nanoparticles
- biorxiv2026-08-13score 72neurobiologyagingmetabolism
CASIN restores aged α-synuclein brain networks along EGFR–PI3K–MAPK routes that feed mitochondria
In an inducible alpha-synuclein oligomer mouse, motor rescue by the CDC42 inhibitor CASIN is age-dependent, and single-nucleus RNA-seq now maps the transcriptional undo. CASIN robustly reverts Parkinson-related programs at 24 months; aging programs are loudest at 16 months. Networks converge on MAPK and PI3K/AKT, and the authors nominate an EGFR–PI3K–MAPK axis as the route by which CDC42 blockade may restore mitochondrial and synaptic function in aging and Parkinson disease.
Source preprint: Targeting CDC42 with CASIN Reprograms Cell Type Specific Transcriptomes and MAPK Driven Transcription Factor Networks in the Aging Brain
- biorxiv2026-09-07score 71stem cellsmetabolismmethods
Culture-acquired BCOR truncations lock human iPS cells into a mitochondrial-metabolism-high adaptive state
The most recurrent culture mutations in human induced pluripotent stem cells are BCOR exon-7 truncating indels, a spectrum unlike BCOR in cancer. Losing BCOR rewires chromatin, RNA, and protein toward developmental, pluripotency, and mitochondrial-metabolism programs. CRISPR correction only partly walks it back, so the adaptive state persists after the allele is gone.
Source preprint: BCOR mutations establish a persistent culture-adaptive state in human induced pluripotent stem cells
- biorxiv2026-09-03score 71cardiologymetabolismlipid
Sex and NOS dose split older mice into HFpEF-like females and HFrEF-like males under fat plus L-NAME
Older mice on high-fat diet plus NOS inhibition do not make one heart-failure model. Low-dose L-NAME females get diastolic failure with preserved systole. High-dose males get hypertension and systolic failure. Lipidomes share sphingolipid and phospholipid remodels with sex-specific phosphatidylinositol and lysophosphatidylcholine species. Transcriptomes share matrix, calcium-handling, and metabolic paths.
Source preprint: Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice.
- biorxiv2026-08-17score 71metabolismredox biologysignaling
Alpha cells bank pentose-phosphate redox at higher glucose so glucagon still fires when sugar falls
Live-cell redox imaging in alpha cells inside intact islets shows that glucose flux through the pentose phosphate pathway raises cytosolic redox potential. That prior redox charge, not a simple low-glucose mitochondrial story, helps keep protein kinase A (PKA) on and glucagon available during hypoglycemia. Antioxidants and a 5 mM glucose pre-incubation manipulate the charge; whole-body redox state changes the mouse counterregulatory response. The authors explicitly ask whether non-mitochondrial glucose metabolism potentiates glucagon at low glucose.
Source preprint: Glucose derived redox equivalents preserve PKA activity and glucagon secretion during hypoglycaemia
- biorxiv2026-08-14score 70immunologymetabolismredox biology
Severe endometriosis lesion vesicles enter endothelial mitochondria and push angiogenesis
Small extracellular vesicles from endometriosis patients change with stage and source. Lesion-derived vesicles lose epithelial surface markers, gain immune signatures, and, when they come from severe disease, show enhanced uptake and mitochondrial localization in human uterine microvascular endothelial cells and promote angiogenesis. Plasma vesicles shift adhesion- and platelet-associated profiles. Multi-omics add coordinated immune, matrix, epithelial, vascular, oxidative-stress, and metabolic programs. The mitochondrial claim is trafficking-plus-function in endothelial cells, not a respiratory-chain map of the lesion.
Source preprint: Endometriosis patient-derived small extracellular vesicles carry unique immune, proteomic and lipidomic signatures associated with mild and severe endometriosis
- biorxiv2026-08-11score 70metabolismautophagylipid droplets
Vlf1, found because LD-less mitochondria look wrong, is a vacuolar brake on yeast lipophagy
Yeast that cannot make neutral lipids, and therefore lack lipid droplets, change many proteins in isolated mitochondrial fractions. Among downregulated proteins is Ylr001c, renamed Vlf1 (Vacuolar Lipophagy Factor 1). Vlf1 is glycosylated and vacuolar, not whatever earlier localizations said. It binds the autophagic lipase Atg15, tunes rapamycin sensitivity, and is the first named vacuolar lipophagy regulator in S. cerevisiae: no Vlf1, more autophagy/lipophagy; extra Vlf1, less. Mitochondria were the discovery compartment, not the home.
Source preprint: Characterization of Vlf1 as a regulator of lipophagy
- biorxiv2026-08-19score 69developmentmetabolismproteostasis
Oocyte DHX36 keeps mitochondria, membranes, and microvilli intact so follicle signals can be delivered
Oocyte-specific deletion of the G-quadruplex helicase DHX36 wrecks antral follicle development and hormone-induced ovulation. Granulosa cells fail to proliferate and cumulus fails to expand because SMAD2/3 and SMAD1/5/8 do not activate, even though major oocyte-secreted factors are still expressed. The delivery hardware is broken: microvilli and transzonal projections. Proteomics, lipidomics, and ultrastructure show disordered phospholipid metabolism, autophagy, and organelle homeostasis, including abnormal mitochondria, lysosomes, and ER. Promoters of the downregulated genes are G4-rich.
Source preprint: DHX36 regulates antral follicle development and ovulation as a non-OSF maternal factor by maintaining oocyte homeostasis and supporting OSF delivery
- biorxiv2026-08-21score 68metabolismredox biologybioprocess
Late CHO fed-batch cells burn fat in mitochondria and peroxisomes, then flirt with ferroptosis
Across ambr250 CHO fed-batch conditions, cultures follow a conserved path: proliferate, transition, then a high-stress end state of mitochondrial and peroxisomal fatty-acid β-oxidation, lipid remodeling, oxidative burden, and ferroptosis-associated pathways. Richer feeds delay that switch via redox/glutathione defense but do not raise antibody titre in proportion. Survival spends the resources that would have been titer. Fatty-acid oxidation and ferroptosis are the late-stage constraints to engineer against.
Source preprint: Fatty Acid β-oxidation and Ferroptosis Define a Survival-Productivity Trade Off in CHO fed-Batch Bioreactors
- biorxiv2026-08-17score 68agingproteostasismetabolism
PCC1 rewrites senescent stromal ribosomes and membranes; mitochondrial-membrane genes stay high
Reanalysis of RNA-seq from bleomycin-senescent PSC27 human stromal cells treated with 50 µM procyanidin C1 (PCC1) finds 8,420 differentially expressed genes. Ribosomal genes move first, then lysosomal ones. Lipid-transport programs that fell in senescence rise after PCC1. Lysosomal-membrane, mitochondrial-membrane, cholesterol, and ion-transport programs rose in senescence and rise again after PCC1. A SASP-effector score falls; a broad Reactome SASP set does not. This is a senomorphic transcriptome, not a mitochondrial biochemistry paper.
Source preprint: PCC1 treatment reshapes ribosomal, lysosomal and membrane-lipid transcriptional programs in therapy-induced senescent human stromal cells
- medrxiv2026-09-04score 67metabolismhepatologydiet
An 8-week very-low-calorie diet drops liver fat as ketones and TCA intermediates rise
In a pilot of women with obesity and metabolic dysfunction-associated steatotic liver disease, an 8-week very-low-calorie diet cut weight about 11% and hepatic controlled-attenuation-parameter fat without changing stiffness. Ketones go up, amino acids go down, and CAP change tracks amino acids up and ketones plus tricarboxylic-acid-cycle intermediates down. A few circulating microRNAs move with CAP and HOMA-IR.
Source preprint: Very low-calorie diet reduces hepatic steatosis and remodels circulating metabolite-microRNAs networks in metabolic dysfunction-associated steatotic liver disease: A pilot study
- medrxiv2026-08-10score 67metabolismneurobiologyclinical
Neuropsychiatric long COVID serum is a lipid-and-acylcarnitine map that tracks mood, fatigue, and cortex
Patients with neuropsychiatric long COVID differ from healthy controls in serum triacylglycerides and acylcarnitines. Those metabolite shifts associate with depressive and fatigue burden and with cortical-thickness differences in multiple regions. The authors read the pattern as lipid-metabolism dysregulation and a possible deficit in mitochondrial energy production. This is a peripheral metabolome association study, not a muscle or brain respirometry.
Source preprint: Peripheral metabolic signatures in patients with neuropsychiatric long COVID syndrome
- biorxiv2026-09-03score 66immunologycancermetabolism
Stool valerate marks CAR-T dysbiosis; the fatty acid itself opens chromatin differently than butyrate
Low stool valerate at CAR-T eligibility tracks a fiber-fermenter-poor, SCFA-poor microbiome. PIM antibiotics leave CD4-skewed, AP-1-high products that predict worse survival. Ex vivo valerate, unlike butyrate or propionate, engages KLF/SP/EGR, opens KLF4, and induces AP-1 and MHC II, while propionate prefers low-mitochondrial-content states. The organelle note is that propionate commitment, not valerate's main act.
Source preprint: Microbial valerate is associated with CAR T dysbiosis and its supplementation enhances CAR T function in B-cell lymphoma
- biorxiv2026-08-13score 66cancerproteomicsmethods
Automated FFPE melanoma proteomes: regressing tumors run hotter mitochondria and quieter complement
A Tecan Fluent 780 automated deparaffinization workflow beats manual processing on 54 primary cutaneous melanomas (6,146 vs 4,941 proteins, less technical noise) while keeping global profiles comparable (8,305 proteins shared, 96.1%). In tumors with histological regression (21 vs 33), 97 proteins are up and 226 down. Enrichment says higher mitochondrial and translational activity and lower innate-immune/complement pathways in regressing lesions. Survival does not differ in this early-stage cohort. Digital pathology says morphology survives automation.
Source preprint: From Routine Pathology to Precision Oncology: Automated FFPE Tissue Processing for Large-Scale Molecular Studies
- biorxiv2026-08-21score 61agingmetabolismtoxicology
Low-dose microcystin-LR hits senescent killifish in two sexes: shared pck1 loss, divergent mitochondria-adjacent programs
Eight-month-old GRZ Nothobranchius furzeri exposed to 0.5 µg/L microcystin-LR show strongly sex-split transcriptomes (313 DEGs male, 263 female, only 27 shared). Shared space includes strong pck1 downregulation and genes of mitochondrial function, metabolism, ECM, and genome maintenance. Males remodel sarcomere/contractile programs; females remodel vitellogenin/zona pellucida and metabolic reproduction. Aging plus a bloom toxin is not one pathway.
Source preprint: Low-Dose Microcystin-LR Elicits Sex-Dimorphic Transcriptomic Responses in Senescent Nothobranchius furzeri: Implications for Cyanotoxin Vulnerability in Aging Vertebrates
- biorxiv2026-08-17score 58metabolismimmunologydevelopment
On a rich diet, fly microbiome timing barely rewires adults; a handful of mitochondrial genes stay marked
Drosophila colonized as newly hatched larvae versus newly eclosed adults, all on a rich diet, show only modest adult transcriptional shifts versus axenic flies (~25–200 DEGs, mostly immune up). Only about 10 genes stay differentially expressed if bacteria are given to adult-axenic flies too late to erase the larval-timing mark. That persistent set includes mitochondrial genes, Adh, and a putative secreted neuropeptide. Development on rich food is mostly robust to when microbes arrive; a thin metabolic/mitochondrial residue may not be.
Source preprint: Role of Early-Life Microbiome Colonization in Physiological Development of Drosophila melanogaster
- biorxiv2026-09-08score 54immunologymetabolismosteoarthritis
Osteoarthritic synovial fibroblasts wreck cartilage after TLR ligation, with barely a dent in mitochondrial respiration
Human osteoarthritis synovial fibroblasts are wired for Toll-like receptors. Hit TLR1/2, 4, 5, or 2/6 and they pour out IL-6, IL-8, G-CSF, MMP3, and MMP10 and then teach autologous chondrocyte spheroids to become inflammatory, catabolic, and small. Mitochondrial respiration, which they measured, barely moves. The organelle is a negative control here, not the driver.
Source preprint: TLR-mediated activation of synovial fibroblasts from osteoarthritis patients promotes chondrocyte dysfunction