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Mitochondria importance articles
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49 of 176 articles · updated 2026-09-18T14:04Z
- 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
- biorxiv2026-09-07score 93OXPHOSstructural biologyassembly
Cryo-EM shows Complex III does not assemble the two protomers in parallel, and CIII2CIV is born during that assembly
The textbook stepwise, symmetric assembly of dimeric mitochondrial Complex III is wrong in the cryo-EM intermediates. Subunit incorporation can uncouple from folding (cytochrome c1), and after dimerization the two protomers do not mature in lockstep (intermembrane-space domain). Non-vertebrate supercomplex CIII2CIV forms on that same assembly path, which favors cooperative supercomplex birth over late docking of finished complexes.
Source preprint: Cryo-EM reveals the central steps of mitochondrial complex III assembly and the cooperative assembly of supercomplex CIII2CIV
- biorxiv2026-08-26score 93calcium signalingtherapeuticsapoptosis
NLRX1 is the CypD-independent handle on the mitochondrial permeability transition pore
Two chemically unrelated, brain-penetrant inhibitors of the mitochondrial permeability transition pore (mPTP) bind the mitochondrial NOD-like receptor NLRX1, and binding potency tracks pore blockade. Loss of NLRX1 raises the calcium threshold for pore opening in CRISPR-edited human cells and Nlrx1-knockout mouse tissue, independently of cyclophilin D (CypD); the oral lead GSK900 is active in an mPTP-sensitive neurological injury model.
Source preprint: NLRX1 is an essential, druggable regulator of mitochondrial permeability transition
- 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
- biorxiv2026-09-17score 91OXPHOScardiologyAMPK
AMPK restores respiration in TMEM70 Complex V-deficient human cardiomyocytes without fixing ATP synthase
TMEM70 is the most common nuclear cause of mitochondrial ATP synthase (Complex V) deficiency, and the heart is where it hurts. In CRISPR-edited human induced pluripotent stem-cell cardiomyocytes, the organelle looks fine in the stem-cell state and then loses membrane potential, respiratory capacity, and structural discipline once the cells become heart muscle. Chronic AMP-activated protein kinase (AMPK) activation puts respiration and fatty-acid metabolism back and quiets pathological remodeling, even though Complex V itself stays broken.
Source preprint: AMPK reinforces mitochondrial metabolism and suppresses pathological remodeling in Complex V-deficient cardiomyocytes
- 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
- biorxiv2026-09-01score 90Parkinson diseaseimportOXPHOS
VDAC1 sends DJ-1 into the matrix under stress; only matrix DJ-1 saves neuronal respiration
Endogenous DJ-1 binds VDAC1. Without VDAC1, stress-driven DJ-1 fails to reach the mitochondrial matrix. VDAC1-null neurons fragment, lose OXPHOS and ATP, mishandle ROS, and die more to MPP+. Matrix-targeted DJ-1, not outer-membrane DJ-1, restores basal, ATP-linked, and maximal respiration, shape, and survival. ATP-synthase inhibition itself recruits mitochondrial DJ-1.
Source preprint: VDAC1 regulates stress-associated matrix localization of DJ-1 to support mitochondrial homeostasis and neuronal survival
- biorxiv2026-09-07score 89cancerOXPHOSfusion
Triple-negative cells that survive radiation rebuild mitochondria through the short OPA1 isoform
After ionizing radiation, residual triple-negative breast-cancer cells swell their mitochondrial mass, cristae, oxidative phosphorylation, and metabolites, then largely revert when they regrow. The short OPA1 isoform rises in the residual state; OPA1 knockout erases the rewiring, and genetic or drug OPA1 blockade improves the radiation response.
Source preprint: Mitochondrial rewiring supports survival of triple negative breast cancer cells after ionizing radiation
- biorxiv2026-08-20score 89cancerOXPHOSredox biology
HES1-low senescent CTCs keep OXPHOS and SOD1 — and those are the cells that regrow metastases
Senescence in circulating tumor cells is not one state. HES1-low senescent CTCs keep mitochondrial fitness, oxidative phosphorylation, and SOD1-dependent ROS detox, and they regrow tumors more efficiently than HES1-high cells. HES1 binds the Sod1 promoter and represses it; dual SOD1 inhibition plus ABT737 hits both residual pools in vivo.
Source preprint: The HES1-SOD1 Antagonism Shapes Senescence Heterogeneity and Impacts Metastatic Relapse of Circulating Tumor Cells
- biorxiv2026-09-17score 88OXPHOSagingAMPK
Complex I and Complex IV longevity in C. elegans use opposite retrograde paths, and metformin can tell them apart
Mild electron-transport-chain lesions extend Caenorhabditis elegans life, and the usual story treats mitohormesis as one program. Knock down Complex I (nuo-6) and lifespan needs the mitochondrial unfolded protein response factor ATFS-1 and ignores the AMP-activated protein kinase (AMPK) ortholog AAK-2. Knock down Complex IV (cco-1) and the dependencies flip. Metformin, a Complex I inhibitor and AMPK activator, then suppresses one longevity genotype and leans toward helping the other.
Source preprint: Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans
- biorxiv2026-09-08score 88OXPHOSimmunologyinfection
As tuberculosis becomes chronic, myeloid cells lose electron-transport-chain transcripts and then lose control of the bacillus
Single-cell RNA-seq of mouse tuberculosis shows a coordinated collapse of mitochondrial electron-transport-chain genes across myeloid subsets as disease chronicles. Knocking down macrophage Complex I (Ndufs4) drops MHC-II, scrambles inflammatory transcription, and lets Mycobacterium tuberculosis replicate. Household contacts who convert an interferon-gamma release assay carry almost the same respiratory-remodeling program.
Source preprint: Loss of Mitochondrial Respiratory Capacity Reshapes Myeloid Cell Function during Mycobacterium tuberculosis infection
- biorxiv2026-09-06score 88bioenergeticscardiolipinOXPHOS
Cardiolipin’s minus-two charge digs a 14.3 kT well that keeps protons on the inner membrane
A constrained two-dimensional continuum model, trained on DOPG fluorescence kinetics and real buffer-consumption rates, splits the interfacial proton trap into a 5.7 kT water barrier plus a 4.3 kT monovalent-lipid electrostatics term. Cardiolipin’s −2e charge then predicts a 14.3 kT well that holds protons 1–2 nm from the membrane, kills vertical leak, and accelerates lateral delivery to ATP synthase.
Source preprint: Nanoscale spatial confinement of proton flux by cardiolipin drives high-speed lateral proton transport in mitochondria
- 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
- biorxiv2026-09-09score 86OXPHOSredox biologyiron
Rotenone Complex I block raises mitochondrial iron through ROS, then iron feeds the ROS back
In differentiated dopaminergic neurons, rotenone inhibition of mitochondrial Complex I is enough to mis-place iron: mitochondria and the whole cell gain iron while the cytosol loses labile iron. Reactive oxygen species (ROS) sit in the middle of that shift, and iron then amplifies the same ROS, a loop with a direct line to Parkinson disease and other iron-loading mitochondrial disorders.
Source preprint: Reactive Oxygen Species Generation Drives Iron Accumulation by Rotenone-Mediated Inhibition of Mitochondrial Complex I in Dopaminergic Neurons
- 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
- biorxiv2026-08-17score 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
- biorxiv2026-09-03score 84OXPHOSinfectionstructural biology
Toxoplasma crosslinking finds a divergent ATP-synthase alpha subunit the parasite cannot live without
A proteome-wide XL-MS map of Toxoplasma (29,624 crosslinked pairs, 2,859 interactions) plus structure models turns up new essential-complex members, including an apicomplexan-specific ATP-synthase alpha in a structurally distinct subcomplex required for fitness. Core mitochondrial machinery diversified, and that is a drug-shaped hole.
Source preprint: Proteome-wide crosslinking mass spectrometry reveals novel components of essential complexes in Toxoplasma
- 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
- biorxiv2026-08-19score 83OXPHOSneurobiologyimmunology
In Ndufs4 Leigh mice, hypoxia sits upstream of immune attack; stopping it detonates disease
In the Ndufs4 knockout mouse model of Leigh syndrome, brainstem immune profiling and timed therapy cessations split two preclinical interventions. Pexidartinib and rapamycin leave benefits that persist after the drugs stop. Stopping chronic mild hypoxia (11% oxygen) triggers rapid disease onset and faster progression. Pre-onset animals lack an inflammatory signature; wiping out leukocytes erases the molecular disease signature, and macrophages/monocytes appear to drive pathology. Hypoxia looks upstream of immune activation, which is a translational warning: hypoxia is not a durable disease-modifying holiday the way immune targeting can be.
Source preprint: Hypoxia versus immune depletion - immune profiling and treatment cessation provide mechanistic insights and considerations for translation in Leigh syndrome
- 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
- biorxiv2026-09-03score 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
- biorxiv2026-09-05score 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
- biorxiv2026-08-19score 80bioenergeticscardiolipinOXPHOS
Cardiolipin raises surface proton activity fourfold and supports traveling H+ fronts on membranes
Cardiolipin, the dianionic inner-mitochondrial-membrane lipid, concentrates protons at the membrane surface. On giant planar phosphatidylcholine membranes, 20% cardiolipin enrichment raises surface H+ activity about fourfold, measured with fluorescein-DHPE. Both PC and cardiolipin membranes show non-Gaussian H+ profiles from a point source and support reversible acidification fronts that travel at constant speed between high- and low-pH states. A reaction-diffusion model attributes the fronts to autocatalytic (de)protonation of the surface. In mitochondria, the authors argue, such fronts would make cardiolipin-rich inner-membrane domains a higher-H+ low-pH state, potentially feeding the respiratory chain on one leaflet and ATP synthase on the other.
Source preprint: Cardiolipin increases the peak of reversible traveling H+ fronts at the membrane surface
- 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 80protein importquality controlOXPHOS
Mitochondrial import stress dumps hydrophobic OXPHOS proteins at the ER for MARCHF6-led quality control
When mitochondrial import fails, hydrophobic oxidative phosphorylation (OXPHOS) proteins reroute to the endoplasmic reticulum (ER). Proximity proteomics, a split-fluorescence reporter, and genome-wide CRISPR show they then split into stable ER residents versus clients of ER-associated degradation (ERAD), with the ubiquitin ligase MARCHF6 as a central, partly redundant ligase. The ER is therefore a holding-and-disposal organelle for mistargeted mitochondrial proteins.
Source preprint: Selective quality control of mistargeted mitochondrial proteins at the endoplasmic reticulum
- 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
- biorxiv2026-08-26score 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
- biorxiv2026-08-14score 79islet biologydiabetesOXPHOS
MAFB knockdown in adult human α-cells collapses glucagon, identity, and respiration
In primary human pseudoislets, short hairpin RNA knockdown of the large MAF transcription factor MAFB impairs glucagon synthesis and secretion while barely touching insulin. Restricting the knockdown to CD26-positive α-cells shows a cell-autonomous failure of stimulus-secretion coupling, loss of canonical α-cell and neuroendocrine genes, ectopic mesenchymal and extracellular-matrix programs, and downregulation of electron-transport-chain genes in the largest α-cell subcluster that registers as weaker islet-wide mitochondrial respiration.
Source preprint: MAFB is essential for the maintenance of adult human α-cell identity and glucagon secretion
- biorxiv2026-08-10score 79OXPHOSredox biologysignaling
ADP keeps cytochrome oxidase’s nitrite-to-NO activity alive even in high oxygen, in an isoform-specific way
Detergent-solubilized yeast and mouse-brain cytochrome c oxidase (Cco) can reduce 1 mM nitrite to nitric oxide when driven by ascorbate/TMPD/cytochrome c. ADP and ATP gate that Cco/NO activity differently. ADP extends measurable NO formation across the whole oxygen range tested, up to 175 µM O2. ATP slightly inhibits Va-containing Cco and strongly stimulates Vb-containing Cco under anoxia. Cellular ADP/ATP and subsequently assayed Cco/NO both rise transiently after a hypoxic shift. The paper claims metabolic and isoform gating of catalytic capacity, not the enzyme’s share of cellular NO at physiological nitrite in coupled mitochondria.
Source preprint: Mitochondrial Signaling: Nitric Oxide Synthesis by Cytochrome c Oxidase and Its Oxygen Sensitivity Are Modulated by Adenine Nucleotides
- 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
- biorxiv2026-08-08score 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
- biorxiv2026-09-16score 77immunometabolismOXPHOStherapeutics
AS-3 turns RAPTOR-mTORC1 on in CD8 T cells, lifting mitochondrial metabolism and adoptive therapy
Adoptive cell therapy fails when expanded CD8 T cells lose metabolic fitness. AS-3, found by phenotypic screening and medicinal chemistry, is a small-molecule RAPTOR-dependent activator of mechanistic target of rapamycin complex 1 (mTORC1). It raises effector cytokines without killing the cells, pushes glycolysis and mitochondrial oxidative phosphorylation, keeps signaling alive under rapamycin, and improves two independent adoptive-therapy models with more persistence and less exhaustion.
Source preprint: Discovery of a Small-Molecule mTORC1 Pathway Activator that Enhances Adoptive T-Cell Therapy via Immuno-metabolic Reprogramming of CD8+ T Cells
- 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
- biorxiv2026-08-15score 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
- biorxiv2026-09-01score 75methodsnephrologytoxicology
Proxiloid kidney tubules catch adefovir mitochondrial toxicity that rodent tests missed
Human iPSC proxiloids become lumenized, polarized proximal-tubule organoids in 14 days with transport and oxidative metabolic competence. They see aminoglycoside injury better than matched 2D cultures and flag adefovir mitochondrial toxicity that rodents missed. A scalable NAM for PT drugs that hit mitochondria.
Source preprint: Scalable proxiloids enable human-relevant assessment of kidney proximal tubule toxicity
- biorxiv2026-09-08score 73neurobiologygliaaging
Old male brains, stripped of microglia, downregulate mitochondrial ATP-synthesis proteins
When 21-month-old mice lose microglia to CSF1R blockade, both sexes drop microglia-enriched microRNAs, but the proteome diverges hard: 295 changing proteins in males versus 34 in females. Male synaptic-vesicle proteins go up; mitochondrial ATP-synthesis machinery goes down. Microglial absence in the aged brain is a sex-specific bioenergetic event.
Source preprint: Sex-divergent responses to microglial depletion suggest distinct regulatory dependencies in the aged brain
- 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
- biorxiv2026-09-08score 72methodsneurobiologyOXPHOS
A widely used TBI atlas called microglia neurons, then invented a KCNC3 OXPHOS signature
Most cells labeled “glutamatergic neuron” in CEREBRI, the dominant single-cell traumatic-brain-injury atlas, are glia. That contamination manufactured a biphasic ion-channel trajectory and a KCNC3-specific oxidative-phosphorylation signature that vanish when the labels are audited. Mitochondrial stories in public atlases are only as good as the cell-type names.
Source preprint: AnnoAudit: a marker-based protocol for auditing single-cell atlas annotations reveals annotation-driven artifacts in a widely used traumatic brain injury resource
- biorxiv2026-09-03score 72nephrologyOXPHOStherapeutics
DVA proteomics in CKD restores OXPHOS proteins and turns down Rho-GTPase inflammatory cytoskeleton programs
DIA proteomics of a CKD model with DVA, KY, and combo arms finds a cluster of mitochondrial/OXPHOS/metabolic proteins that CKD turns down and DVA turns back up, and a second cluster of immune, oxidative-stress, and cytoskeletal proteins that CKD turns up and DVA turns down. The title's mitochondrial restoration is that first cluster.
Source preprint: Systems-level proteomic reprogramming reveals mitochondrial restoration and inhibition of Rho GTPase-mediated cytoskeletal and inflammatory signaling in CKD
- 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).
- biorxiv2026-08-21score 68diabetesskeletal muscleOXPHOS
In 301 muscle biopsies, type 2 diabetes dysregulates fiber mitochondria and splicing
Weighted gene co-expression analysis of 301 living-donor skeletal-muscle biopsies yields 56 modules that, mapped onto single-nucleus RNA-seq cell-type signatures, show type 2 diabetes associated with muscle-fiber mitochondrial function and messenger-RNA splicing, endothelial vascularization and phospholipase D signaling, and macrophage- and T-cell-associated inflammation. Candidate drivers include ATP5L, ATF2, SIRT1, and THRAP3 in fibers; JAM2 and CLEC14A in endothelium; and F13A1 and IRF8 in immune cells. Fiber and endothelial modules are enriched for type 2 diabetes and related-trait genome-wide association signals in a single-nucleus ATAC-seq overlay.
Source preprint: Integrated Analysis of Skeletal Muscle Transcriptional Networks Characterizes Dysregulation in Pathways and Trait-Associated Regulatory Regions in Type 2 Diabetes
- biorxiv2026-08-14score 64bioenergeticsOXPHOStheory
A theory paper: infrared photons as a Marcus-theory bias on mitochondrial electron transfer
This is a physical-framework essay, not an experiment. The authors note that built environments replaced infrared-rich daylight with narrow visible lighting, and that the solar photon-energy peak near 0.75 eV overlaps mitochondrial electron-transfer reorganization energies. In a Marcus-type picture, infrared photons could bias barrier crossing rather than donate chemical energy, and they penetrate tissue as a diffuse field. They name this “photometabolism” and offer a scaling argument that photon interception in this band tracks basal metabolic rate with body mass. No mitochondrion was illuminated in a controlled assay in the abstract.
Source preprint: Metabolism in the Solar Photon Field A physical framework for photon-assisted modulation of mitochondrial electron-transfer kinetics
- biorxiv2026-08-12score 62computationalOXPHOSimmunology
PerturbLDM predicts unseen drug–dose–line transcriptomes and keeps an interferon FAO-OXPHOS program
PerturbLDM is a Tahoe-100M-pretrained latent-diffusion model that generates single-cell transcriptional responses to perturbations. On 13,942 held-out drug/dose/line combinations it beats leading methods and beats an additive marginal baseline in 95.2% of conditions. It ranks PANACEA compounds by pathway neighbors, builds a fetal-colon state more accurately than Squidiff, and in PBMCs captures six of seven interferon/antiviral programs plus an interferon-associated FAO-OXPHOS program better than scGen. The mitochondrial hook is that FAO-OXPHOS module, not a new metabolic mechanism.
Source preprint: PerturbLDM: conditional latent diffusion for modelling single-cell perturbation responses