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Mitochondria importance articles
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29 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
- biorxiv2026-08-26score 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
- biorxiv2026-09-01score 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
- biorxiv2026-08-13score 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
- biorxiv2026-09-08score 87neurobiologyfusionglia
Low testosterone opens the nucleus-accumbens blood-brain barrier by remodeling astrocyte mitochondria
In outbred male rats, low testosterone is not just a mood correlate. It raises anxiety by loosening the nucleus accumbens blood-brain barrier, and the physical failure is astrocytic: fewer endfeet, disordered endfoot mitochondria, fewer mitochondria-endoplasmic-reticulum contacts, less mitofusin 2. Restore testosterone, or put Mfn2 back in accumbens astrocytes, and anxiety falls.
Source preprint: Low testosterone promotes anxiety through astrocytic mitochondrial remodelling at the nucleus accumbens blood-brain barrier
- 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
- biorxiv2026-08-26score 86mitochondrial dynamicsneurobiologygenetics
TRAK2 unlocks kinesin-1 at coiled-coil 4 by breaking a hidden CC1-CC4 latch
The mitochondrial adaptor TRAK2 binds the kinesin-1 heavy chain KIF5C at the CC4 cargo platform in a defined 2:2 complex that is required to recruit KIF5C to mitochondria. A previously unrecognized intramolecular latch between KIF5C coiled-coil 1 and coiled-coil 4 holds the motor off; TRAK2 and the light chain KLC1 release that latch by different routes, so holoenzyme composition decides whether mitochondria can hire the motor.
Source preprint: Kinesin-1 holoenzyme assembly coordinates cargo-adaptor recognition with heavy-chain autoinhibition
- 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
- biorxiv2026-08-10score 84mitophagyautophagystructural biology
Rubicon clamps PI3KC3-C2 via a UVRAG-shaped BECN1 BARA pose; breaking that interface restores mitophagy
Cryo-electron microscopy of the class III phosphatidylinositol 3-kinase complex II (PI3KC3-C2) bound to Rubicon’s PI3K-binding domain shows why Rubicon inhibits the UVRAG-containing C2 complex and not the ATG14-containing C1 complex. Rubicon binds only the BECN1 BARA domain, a subunit shared by C1 and C2. Selectivity comes from a UVRAG-induced BARA conformation, not from a direct UVRAG contact or ATG14 antagonism. Mutations that break the interface raise mitophagy in human epithelial cells to Rubicon-knockout levels and restore lysosomal flux in Rubicon-overexpressing hippocampal neurons. PI3KC3-C2 suppression fully accounts for Rubicon’s autophagy and endolysosome brake.
Source preprint: Structural basis for the selective inhibition of the PI3KC3-C2 complex by Rubicon in endolysosome maturation and mitophagy
- 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
- medrxiv2026-09-08score 82mtDNAophthalmologybiomarkers
Lower blood mitochondrial DNA copy number tracks faster visual-field loss in open-angle glaucoma
In 200 people with primary open-angle glaucoma followed for about 11 years, fewer mitochondrial DNA copies in blood leukocytes associate with a steeper slide in visual-field mean deviation. The link is strongest when peak intraocular pressure is not the obvious villain, which makes systemic mtDNA copy number a candidate reserve marker, not a pressure surrogate.
Source preprint: Mitochondrial DNA Copy Number Is Associated With Visual Field Progression in Primary Open-Angle Glaucoma
- biorxiv2026-09-04score 79neurobiologydevelopmentautonomic
Early-life adversity ages female vagal neurons along a mitochondrial-dysfunction path
Unpredictable maternal care permanently bends mouse vagal development. Heart-rate-variability trajectories split by sex: females mature too early then decline; males start blunt and recover. Female vagal neurons look mitochondrially broken, male neurons look mitochondrially adaptive, in different stretches of nucleus ambiguus.
Source preprint: Early Life Adversity Produces Enduring Molecular and Functional Disruption of Developing Vagal Circuits
- biorxiv2026-09-05score 78neurobiologybioenergeticsALS
Endogenous TDP-43 A315T in human cortical neurons wrecks respiration before it loses nuclear splicing
A human cortical-neuron line with endogenous ALS-linked TDP-43 A315T and a Dendra2 tag shows neurite loss, bad firing, and impaired mitochondrial respiration while nuclear cryptic-exon control still holds. Cytoplasmic aggregates need autophagy, stress granules rise, and the RNA chaperone Clip34 shrinks both aggregation and granule entry. Early toxic gain-of-function, not basal nuclear loss, is the first act.
Source preprint: A Human Neuronal Cell Model of Endogenous TDP-43 A315T Reveals Altered Protein Dynamics and Disease-Relevant Cellular Dysfunction
- 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
- biorxiv2026-08-13score 76mitochondrial dynamicssignalingneurobiology
PKA anchored at AKAP1 remakes mitochondrial shape; the same kinase on MAP2 is a structural microtubule brace
A SpyCatcher-SpyTag replacement lets researchers keep an AKAP’s environment and toggle type-II PKA RII anchoring. RII on AKAP79 or AKAP1 gives phosphorylation-dependent outcomes, including catalytic-subunit membrane recruitment and mitochondrial morphology regulation (AKAP1). RII on MAP2 straightens microtubules, widens bundles, and supports dendritic arborization without needing phosphorylation; the structural job wants an intact second cAMP-binding pocket and is recapitulated by native MAP2–RII. Anchored PKA is sometimes an enzyme and sometimes a cAMP-gated structural protein. Mitochondria are one of the enzymatic addresses.
Source preprint: PKA can adopt structural or enzymatic roles depending on its anchoring site
- 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
- biorxiv2026-09-08score 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
- biorxiv2026-08-17score 73neurobiologyredox biologypain
Schwann-cell p75NTR turns NGF into mitochondrial ROS and TRPA1-dependent persistent pain
Nerve growth factor (NGF) pain splits by receptor and cell. Neuronal TrkA carries acute nociception and heat hyperalgesia. Mechanical allodynia and cold hypersensitivity require p75NTR on Schwann cells. There, NGF and proNGF trigger p75NTR-dependent calcium release, TRPA1 activation, mitochondrial reactive oxygen species, and NOX1-dependent oxidative amplification. Blocking ROS or TRPA1, or deleting Trpa1 in Schwann cells, cuts mechanical and cold pain without touching the acute/heat TrkA program. Cleavage-resistant proNGF only evokes the p75NTR half.
Source preprint: Schwann cell p75NTR sustains persistent pain downstream to NGF through ROS-dependent TRPA1 signaling
- 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
- biorxiv2026-08-21score 72neurobiologymitoUPRquality control
Without ATFS-1, worm dopamine neurons need JMJD histone demethylases and TWK-14 to survive α-synuclein
α-Synuclein overexpression in C. elegans chronically turns on the mitochondrial unfolded-protein response and worsens dopaminergic neuron loss. A loss-of-function atfs-1 mutation, which disables that UPRmt transcription factor, is neuroprotective. An F3 screen in that protected background recovered nonsense alleles of the H3K27me3 demethylases jmjd-1.2 and jmjd-3.1 and of the K+ leak-channel gene twk-14. Depleting any of the three in dopamine neurons restores neurodegeneration in the α-syn + atfs-1(lf) background. Those gene products therefore confer protection from α-synuclein once UPRmt is off.
Source preprint: An atfs-1 loss-of-function screen identifies novel regulators of a-synuclein toxicity in C. elegans dopaminergic neurons
- biorxiv2026-08-19score 72neurobiologyredox biologyproteostasis
VCP inhibitor ML240 saves photoreceptors, not RPE, and keeps cytochrome c in inner segments
In a human iPSC-RPE plus porcine neuroretina co-culture, the cigarette-smoke oxidant hydroquinone (HQ) stresses both RPE and photoreceptors, drives caspase apoptosis, ER-associated degradation in photoreceptors, thinner outer nuclear layer, and shorter outer segments. The VCP inhibitor ML240 does not stop HQ apoptosis in iPSC-RPE, but it preserves photoreceptor outer-segment length and cone density. Proteomics show lower ERAD markers, higher antioxidant proteins, and preserved cytochrome c enrichment in inner segments, read as improved mitochondrial integrity.
Source preprint: VCP inhibition preserves photoreceptor integrity under hydroquinone-induced oxidative stress in a human iPSC-RPE/porcine neuroretina co-culture model
- biorxiv2026-08-14score 72neurobiologytherapeuticsophthalmology
Cumulative IOP above 19 mmHg times RGC death; a mitochondria-targeted peptide still cuts the hazard
In DBA/2J glaucoma mice, retinal ganglion cell (RGC) loss is modeled as a latent time-to-event process driven by monthly intraocular pressure (IOP). Across Cox and Andersen–Gill models, cumulative IOP burden above 19 mmHg dominates the hazard. Peak and contemporaneous IOP add little once sustained exposure is in the model. HDAP2, a mitochondria-targeted neuroprotective peptide, significantly reduces progression hazard after adjustment for that longitudinal IOP exposure, which argues for a pressure-independent, organelle-directed effect.
Source preprint: Modeling Retinal Ganglion Cell Degeneration from Longitudinal Intraocular Pressure Trajectories
- 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
- biorxiv2026-08-10score 72agingmitochondrial dynamicsneurobiology
Nuclear troponin I/UNC-27 turns on in adult muscle and its arrival fragments mitochondria
In C. elegans, sarcomeric transcripts start falling at the onset of adulthood. A visual screen for delayed muscle ageing maps to troponin I (unc-27), a contractile protein, at a single amino acid in a predicted nuclear localization signal. UNC-27 enters muscle nuclei from early adulthood via multiple NLS motifs. Blocking that nuclear entry preserves sarcomeric gene expression and delays proteostatic imbalance and mitochondrial fragmentation. Nuclear UNC-27 selectively regulates structural muscle-apparatus genes. Mammalian troponin I orthologues also carry NLS motifs.
Source preprint: A nuclear role for the contractile protein troponin I/UNC-27 in regulating muscle aging in C. elegans
- 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
- medrxiv2026-09-03score 64neurobiologyophthalmologypsychiatry
Shared genes between retina and psychiatry put mitochondria on the bipolar-disorder side
Retinal-layer genetics overlap major psychiatric disorders, most with ganglion-cell inner plexiform thickness (~60%). Pathway follow-up is disorder-specific: schizophrenia looks GABAergic and developmental; bipolar disorder looks mitochondrial with a weaker developmental component; depression looks synaptic and gene-expression. The eye is a window, and for bipolar it is an organelle window.
Source preprint: Molecular Underpinnings of Retinal Traits Shared with Major Psychiatric Disorders
- medrxiv2026-09-03score 46biomarkersneurobiology
A calpain-cut GFAP neoepitope beats total GFAP for Veteran MCI and Alzheimer triage
Across a Veteran TBI-MCI-Alzheimer continuum, a calpain-cleaved GFAP neoepitope (neoGFAP) outperforms total GFAP for separating MCI plus Alzheimer from non-Alzheimer subjects, especially after a plasma p-tau217 and amyloid-beta-42 gate. This is astroglial injury, not a mitochondrial paper.
Source preprint: Proteoform-resolved neoGFAP ™ as a diagnostic and prognostic biomarker across the TBI–MCI–AD continuum in Veterans
- biorxiv2026-09-04score 44neurobiologyimmunology
Chronic stress sex-splits brain-resident T cells into male type-1 and female type-17 programs
Unpredictable chronic mild stress makes both sexes look depressed, then diverges: females lose regional synapses, males lose hippocampal neurons. Brain-resident lymphocytes carry the cytokine split. Females enrich gamma-delta type-2/17 and inflammasome genes; males enrich alpha-beta and NKT type-1, CXCR3, IL27RA, and IFNgamma after stress. Mitochondria are not the measured object.
Source preprint: Chronic stress promotes sex-divergent Type 1, 2 and 17 responses in brain resident lymphocytes