bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–08–09
fourteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Progressive mitochondrial and autophagic dysfunction during RGC development driven by a LHON-associated mitochondrial tRNAThr mutation.
  2. Drug safety in patients with mitochondrial disease: an observational cohort study.
  3. The Plasmodium heme detoxification protein functions in mitochondrial protein synthesis.
  4. Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease.
  5. Mitochondria with (distinct) personality.
  6. Cancer prevalence in primary mitochondrial disease patients and their families.
  7. The coordinated actions of metformin in the intestine and liver improves hyperglycemia.
  8. Hydroxyhydroquinone as a novel modulator of mitochondrial metabolism with potential to restore CoQ10 homeostasis.
  9. A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
  10. Mitochondria-targeted therapeutic strategies in assisted reproduction: challenges and potential solutions.
  11. Mitochondrial electron transport chain is essential for acute inflammatory stress responses in mouse fibroblasts.
  12. Tau-induced mitochondrial reverse electron transport drives neurodegeneration.
  13. Multilevel impairment of mitochondrial respiration in inclusion body myositis.
  14. Mitochondrial homeostasis dysregulation: Potential mechanisms of Alzheimer's disease mediated by TDP-43.
  1. Cell Signal. 2026 Aug 02. pii: S0898-6568(26)00436-5. [Epub ahead of print]148 112778
    Progressive mitochondrial and autophagic dysfunction during RGC development driven by a LHON-associated mitochondrial tRNAThr mutation.
    Wei Guan, Wenxu Li, Zijun Li, Lu Peng, Shidan Shao, Juanjuan Zhang.
      Leber's hereditary optic neuropathy (LHON) is a genetically inherited disease of the eye triggered by mtDNA mutations, leading to degeneration of RGCs. We previously reported that the mitochondrial tRNAThr (MT-TT) 15927G > A homoplasmic mutation disrupted the base pairing (28C-42G) conserved in the anticodon stem of tRNAThr, impairing t6A modification, aminoacylation, and steady-state tRNAThr levels, ultimately resulting in mitochondrial dysfunction. However, the absence of suitable animal and cell models for LHON has delayed efforts to elucidate disease pathophysiology, particularly tissue-specific effects. In this study, RGC-like cells were generated from iPSCs derived from a Chinese family member carrying the m.15927G > A mutation and from a control subject without this mutation. Mitochondrial dysfunction and autophagy/mitophagy defects were investigated at three differentiation stages: iPSCs, NPCs, and RGC-like cells. Both iPSCs and NPCs harboring this mutation exhibited abnormal mitochondrial dynamics, mitochondrial dysfunction, and defects in autophagy and mitophagy. RGC-like cells carrying the mutation showed significant abnormalities, including shorter neurites, imbalanced mitochondrial dynamics, elevated ROS production, reduced mitochondrial membrane potential, and impaired autophagy and mitophagy. These results indicate that the m.15927G > A mutation induces progressive mitochondrial dysfunction and developmental defects in RGCs, providing new insights into LHON pathogenesis and establishing a valuable model for future therapeutic development.
    Keywords:  Autophagy; Induced pluripotent stem cells (iPSCs); Leber's hereditary optic neuropathy (LHON); Neural progenitor cells (NPCs); Retinal ganglion cells (RGCs)
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112778
  2. Neurol Sci. 2026 Aug 06. pii: 683. [Epub ahead of print]47(9):
    Drug safety in patients with mitochondrial disease: an observational cohort study.
    Oskar Järvinen, Mika H Martikainen.
       BACKGROUND: Mitochondrial diseases are common inherited neurometabolic disorders and frequently involve the nervous system, yet their multisystem nature often necessitates complex pharmacological management. Many commonly prescribed medications have off-target effects on mitochondrial function, and patients with mitochondrial disease may be particularly vulnerable to such effects due to impaired energy metabolism. However, systematic data on medication safety in this patient group remain scarce.
    METHODS: In this retrospective, single-centre, cohort-based study at Turku University Hospital (Turku, Finland), we reviewed the medication data from all hospital stays and outpatient prescriptions of 44 mostly adult (20 women; mean age 50 years, range 12-83 years) patients with genetically and clinically confirmed mitochondrial disease for years 2010-2022. We used the Anatomical Therapeutic Chemical system for drug classification. Potential drug-drug interactions and potential adverse drug reactions were investigated. Special focus was on potential mitochondrial toxicity of drugs and clinically relevant drug-drug interactions.
    RESULTS: Altogether ~ 1000 individual medication entries were reviewed. We identified several common drugs with potentially adverse effects on mitochondria, including metformin, beta-blockers, statins, ciprofloxacin, fluoxetine, ibuprofen, and certain anti-seizure drugs. Medications generally considered contraindicated in mitochondrial disease were not observed. No high-risk drug interactions were detected. Additional finding of clinical relevance was the frequent use of analgesics.
    CONCLUSIONS: Further research regarding mitochondrial safety of several drug classes is needed for more evidence-based safety evaluations. Pain in the context of mitochondrial disease merits increased attention.
    Keywords:  Drug safety; Medication; Mitochondria; Mitochondrial disease; Pharmacological treatment
    DOI:  https://doi.org/10.1007/s10072-026-09298-5
  3. Nat Commun. 2026 Aug 07. pii: 8002. [Epub ahead of print]17(1):
    The Plasmodium heme detoxification protein functions in mitochondrial protein synthesis.
    Louis Sarrazin, Melissa R Rosenthal, Joachim Kloehn, Tanja Ziesmann, Yasmin Schmitz, Anna-Lena Sandtmann, Robert Domènech-Eres, Katharina Scholz-Höhn, Coralie Boulet, Ute Distler, Daniel E Goldberg, Joachim M Matz.
      Malaria blood-stage parasites digest ~80% of host cell hemoglobin within a degradative vacuole, releasing heme that is detoxified by sequestration into hemozoin crystals. Although essential for survival and a validated drug target, the mechanisms of heme biomineralization remain unclear. Here, we study the parasite's Heme Detoxification Protein (HDP), previously proposed to mediate hemozoin formation, using genetic, microscopic, bioenergetic, and proteomic approaches. Endogenous tagging reveals that HDP localizes to the mitochondrion, not the digestive vacuole. HDP inactivation has no effect on heme biomineralization, but causes mitochondrial depolarization, proguanil hypersensitivity, and developmental arrest, which is rescued by bypassing respiratory-chain-dependent pyrimidine biosynthesis. HDP knockout abolishes mitochondrial electron flow due to loss of complexes III and IV, consistent with impaired mitochondrial protein synthesis. Integration of structural modelling with quantitative proteomics places HDP within the mitoribosomal large subunit. Here, we show that HDP is essential for mitochondrial function and does not contribute to hemozoin formation.
    DOI:  https://doi.org/10.1038/s41467-026-76511-6
  4. J Transl Med. 2026 Jul 31. pii: 988. [Epub ahead of print]24(1):
    Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease.
    Anbin Chen, Tsering Yangzom, Gareth John Sullivan, Kristina Xiao Liang.
       BACKGROUND: POLG (DNA polymerase γ catalytic subunit)-related mitochondrial diseases are among the most severe primary mitochondrial disorders and are characterized by progressive neurodegeneration with prominent dopaminergic involvement. However, the cell type-specific mechanisms linking mitochondrial DNA instability to neuronal vulnerability remain incompletely defined.
    METHODS: Using patient-derived midbrain organoids and single-cell RNA sequencing, we investigated how POLG mutations alter mitochondrial and neuronal programs at subtype resolution. We analyzed dopaminergic neuronal populations and ventral midbrain neurons to define disease-associated transcriptional changes. To evaluate therapeutic improvement, POLG organoids were treated chronically with nicotinamide riboside (NR), followed by single-cell transcriptomic profiling and pathway enrichment analysis.
    RESULTS: POLG mutations induced a coordinated downregulation of genes associated with oxidative phosphorylation and synaptic signaling, particularly in terminally differentiated dopaminergic neurons. This transcriptional alteration involved genes encoding respiratory chain complexes I-V, mitochondrial translation machinery, and ATP synthase components, suggesting disruption of mitochondrial bioenergetic programs at the transcriptomic level. Among dopaminergic subtypes, DA2 neurons and ventral midbrain neurons showed the most pronounced transcriptional alterations, indicating maturation-dependent vulnerability. NR treatment was associated with altered expression of genes involved in oxidative phosphorylation, NADH dehydrogenase activity, respiratory chain assembly, and synaptic pathways. Following NR exposure, dopaminergic subpopulations exhibited changes in cell-type proportions and partial normalization of mitochondrial- and synaptic-related transcriptional programs.
    CONCLUSIONS: These findings identify transcriptional alterations in pathways related to mitochondrial respiration. The data further suggests that modulation of NAD⁺ metabolism is associated with transcriptional changes in mitochondrial and neuronal pathways in this disease context.
    Keywords:  Dopaminergic vulnerability; Midbrain organoids; NADH-dependent respiration; POLG disease; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1186/s12967-026-08706-w
  5. Mol Cell. 2026 Aug 06. pii: S1097-2765(26)00463-6. [Epub ahead of print]86(15): 2918-2923
    Mitochondria with (distinct) personality.
    Won Dong Lee, David J Pagliarini, Zhixing Chen, Aleksandra Trifunovic, Quan Chen, Janine Hertzog Santos, Aleksandra Filipovska, Payam A Gammage.
      Cells owe a lot to their mitochondria-to their many mitochondria. Recent discoveries and emerging technologies point to functional distinctions within that population. We asked a group of researchers about what mitochondrial heterogeneity means for understanding cellular and organismal physiology.
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.044
  6. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261471914
    Cancer prevalence in primary mitochondrial disease patients and their families.
    Shrey Dalwadi, Nicole M Engelhardt, Colleen C Muraresku, Kelsey Keith, Kathleen D Valverde, Katherine L Nathanson, Marni J Falk.
       Background: While somatic mitochondrial dysfunction occurs in diverse cancers, the association between oncogenesis and germline mitochondrial gene pathogenic variants remains unclear. Further, few clinical observations have been reported of cancer occurring in primary mitochondrial disease (PMD) patients.
    Objectives: To improve understanding of the potential modulating role for PMD gene disorders in cancer prevalence.
    Design: 727 individuals, including 100 with PMD, from 97 unrelated families were retrospectively surveyed to assess their history of individual cancer occurrence.
    Methods: We evaluated survey responses by characterizing the cancer prevalence among the study cohort and comparing to the general U.S. population via the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database. Odds ratio calculation was performed to determine the association of survey responses and cancer prevalence.
    Results: Although overall cancer prevalence in PMD probands and their families was elevated compared to the NCI SEER rate (8800 vs 5600 cases per 100,000), odds ratio calculation determined that PMD did not significantly increase the likelihood of developing cancer, with a non-significant trend observed toward less cancer occuring in PMD that needs to be explored in further studies. Cancer prevalence was significantly correlated with advanced age. Significantly reduced prevalence of prostate cancer was seen across the entire cohort. Surprisingly, while low absolute prevalence (n = 3), a 9-fold increased odds ratio of cancer was seen in POLG patients relative to those with other causes of PMD.
    Conclusion: No evidence of increased cancer odds was identified in a cohort of PMD patients and their close relatives. Interestingly, a possible inverse association, which did not reach statistical significance, was suggested between mitochondrial disease status and cancer odds. Future prospective investigations in larger PMD kindreds are warranted to validate and evaluate potential mechanistic relations between cancer prevalence and PMD.
    Keywords:  POLG; cancer; mitochondria; primary mitochondrial disease
    DOI:  https://doi.org/10.1177/26330040261471914
  7. Cell Rep. 2026 Aug 05. pii: S2211-1247(26)00869-7. [Epub ahead of print]45(8): 117791
    The coordinated actions of metformin in the intestine and liver improves hyperglycemia.
    Ling He, Hongying An, Karina Ramirez, Sally Radovick, Fredric E Wondisford.
      Metformin is the first-line oral anti-diabetic agent. Metformin concentrations in the intestine can reach up to 1.3 mM, while those in the portal vein are approximately 0.075 mM. It is unclear whether this metformin concentration difference contributes to metformin's antidiabetic effects. Here, we showed that high metformin concentrations upregulate G6PC expression through AMP-activated protein kinase (AMPK) activation to prevent glucose release in intestinal epithelial cells (IECs). The inhibition of mitochondrial activity by high metformin concentrations leads to drastically increased glucose utilization through glycolysis, along with lactate overproduction in the IECs. Subsequently, glycolytic metabolite lactate is released from IECs into portal vein and delivered to the liver. In the liver, low concentrations of metformin activate AMPK to promote mitochondrial fission and mitophagy to maintain a healthy mitochondrial population, resulting in increased lactate utilization in the mitochondria. These coordinated actions of metformin in the intestine and liver improve hyperglycemia in diabetes and obesity.
    Keywords:  CP: metabolism; insulin sensitivity; intestine epithelial cells; lactate overproduction; metformin action; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.celrep.2026.117791
  8. Mol Cell Biochem. 2026 Aug 07.
    Hydroxyhydroquinone as a novel modulator of mitochondrial metabolism with potential to restore CoQ10 homeostasis.
    Paulo Roberto Dos Santos, Joseph Rastegar, Mariana Roesch-Ely.
      Mitochondrial dysfunction is a hallmark of diverse metabolic and neurodegenerative disorders, often linked to impaired coenzyme Q10 (CoQ10) homeostasis. Here, we have evaluated the activity of hydroxyhydroquinone (HHQ) as a novel modulator of mitochondrial metabolism. Molecular simulations revealed that HHQ can act as an alternative aromatic substrate for human COQ2 in the CoQ10 biosynthetic pathway. In cultured cells, HHQ exposure (5.10- 5 mol.L- 1) enhanced complex I activity while maintaining stable ATP levels. HHQ reduced nitric oxide accumulation without altering superoxide dismutase activity, suggesting selective redox modulation. By bypassing the 4-hydroxybenzoic acid (PHBA) pathway, HHQ restores mitochondrial homeostasis and supports aerobic metabolism. These findings highlight HHQ as a small aromatic compound with strong redox potential that may favor metabolic functions driven by CoQ10 deficiency and mitochondrial dysfunction.
    Keywords:  Coenzyme Q; Hydroxyhydroquinone; Metabolism; Mitochondrial; Ubiquinone
    DOI:  https://doi.org/10.1007/s11010-026-05687-8
  9. Science. 2026 Aug 06. 393(6811): 601-606
    A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
    Christina Gladkova, Maria G Paez-Segala, William P Grant, Mark Kittisopikul, Samuel A Myers, Yuxiao Wang, Ronald D Vale.
      The cellular distribution of mitochondria in response to stress and local energy needs is governed by the relative activities of the microtubule-based molecular motors kinesin and dynein. The mechanism for switching between these two opposite-polarity microtubule motors remains unknown. In this study, we coupled a cellular synthetic cargo transport assay with AlphaFold2-guided mutagenesis to identify a regulatory helix in the mitochondrial adaptor protein [trafficking kinesin-binding protein (TRAK)] that mediates switching between kinesin- and dynein-driven transport. Differences in the helix sequence explained why two near-identical TRAK isoforms transported mitochondria in predominantly opposite directions. Phosphorylation of the regulatory helix by stress-activated kinases caused the activation of dynein and dissociation of kinesin. Our results reveal a molecular mechanism for coordinating the directional transport of mitochondria in response to intracellular signals.
    DOI:  https://doi.org/10.1126/science.aeh1475
  10. Hum Reprod. 2026 Aug 03. pii: deag118. [Epub ahead of print]
    Mitochondria-targeted therapeutic strategies in assisted reproduction: challenges and potential solutions.
    Raziye Melike Yildirim, Gizem Nur Sahin, Richard T Scott, Emre Seli.
      Mitochondria are central to oocyte competence and early embryonic development, with roles that extend beyond energy production to include regulation of redox homeostasis, apoptosis and cellular aging. Mitochondrial dysfunction is increasingly recognized as a key contributor to diminished ovarian reserve, impaired embryo development, and accelerated reproductive aging. Mitochondria-targeted therapeutic strategies, including pharmacological approaches such as Coenzyme Q10, mitoquinone, resveratrol, rapamycin, and NAD+ precursors, as well as mitochondrial replacement techniques such as maternal spindle and pronuclear transfer, have shown promise in preclinical models; however, clinical outcomes remain heterogeneous and often inconclusive. This translational gap likely reflects critical limitations, including variability in therapeutic targets, suboptimal timing of intervention relative to oocyte development, and insufficiently powered or standardized clinical studies. Greater emphasis on well-defined, physiologically justified therapeutic targets, along with the use of physiologically relevant experimental systems, may improve therapeutic precision and efficacy. Rigorous evaluation of safety, particularly for interventions with pleiotropic effects or heritable consequences, remains essential. A more targeted, developmentally informed and systematically validated approach is needed to advance mitochondria-based therapies toward meaningful improvements in reproductive outcomes.
    Keywords:  embryo aneuploidy; mitochondrial dysfunction; mitochondrial replacement therapy; oocyte quality; ovarian reserve
    DOI:  https://doi.org/10.1093/humrep/deag118
  11. Sci Rep. 2026 Aug 05. pii: 24156. [Epub ahead of print]16(1):
    Mitochondrial electron transport chain is essential for acute inflammatory stress responses in mouse fibroblasts.
    Marie M Mühlon, Christina Schenkl, Lukas Harder, Luca Giordano, Julian M Voll, Christian Franke, Diana Dudziak, Torsten Doenst, Ralf A Claus, Marten Szibor.
      Fibroblasts are linked to stress responses in a broad number of diseases. Here, we used immortalized mouse embryonic fibroblasts (iMEFs) to elucidate their signaling behavior in response to proinflammatory lipopolysaccharides (LPS) and angiotensin II (Ang-II). To test for the role of the mitochondrial electron transport chain (ETC), iMEFs were cultured in glucose- and galactose-containing media promoting glycolysis and mitochondrial oxidative phosphorylation, respectively. In addition, we used alternative oxidase (AOX), a ubiquinol oxidoreductase that serves as a naturally evolved rescue mechanism in case of ETC disruption. We found that within 24 h of treatment, LPS upregulated a number of proinflammatory genes, namely Tlr4, Il6, Tgfb1, Nlrp3, Casp1, and Il1b; largely, the effect was more pronounced in galactose-containing media and attenuated by AOX. The increase in transcripts resulted partly in elevated cytokine secretion. Twenty-four hours of Ang-II treatment also induced these genes, albeit to a lesser degree and less sensitive to AOX. Cellular oxygen consumption rates (OCRs) were higher in galactose media but remained unaffected by either stimulus. Our results suggest that fibroblasts undergo a similar proinflammatory phenotypic shift in response to different stressors. This response is shaped by ETC activity, which, surprisingly, is not reflected in altered OCRs.
    Keywords:  Alternative oxidase; Electron transport chain; Fibroblasts; Inflammatory response; Mitochondria; Mouse
    DOI:  https://doi.org/10.1038/s41598-026-61303-1
  12. Neuron. 2026 Aug 06. pii: S0896-6273(26)00541-6. [Epub ahead of print]
    Tau-induced mitochondrial reverse electron transport drives neurodegeneration.
    Wen Li, Suman Rimal, Sunil Bhurtel, Lucas Yeung, Benjamin G Lu, Lea T Grinberg, Salvatore Spina, Maria Inmaculada Cobos Sillero, William W Seeley, Su Guo, Bingwei Lu.
      Hyperphosphorylation and aggregation of tau are pathological hallmarks of tauopathies. Mitochondrial dysfunction is also a common feature of tauopathies. The mechanistic link between tau abnormalities and mitochondrial dysfunction and its relationship to the physiological function of tau, however, is unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species (ROS), reduces the NAD+/NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cell (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers resilience. Mechanistically, tau enters mitochondria and directly interacts with the complex I subunit NDUFS3 to promote RET in a phosphorylation-dependent manner. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Inhibition of RET ameliorates tau toxicity across species. RET regulation thus represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for various conditions characterized by tau abnormalities and mitochondrial dysfunction.
    Keywords:  Alzheimer’s disease; NAD(+)/NADH ratio; NDUFS3; ROS; complex I; mitochondria; phosphorylation; reverse electron transport; tau; tauopathy
    DOI:  https://doi.org/10.1016/j.neuron.2026.07.012
  13. Brain. 2026 Aug 02. pii: awag269. [Epub ahead of print]
    Multilevel impairment of mitochondrial respiration in inclusion body myositis.
    Ibrahim Shammas, Hazem Iaali, Jens O Watzlawik, Noemi Vidal Folch, Surendra Dasari, Graeme Preston, Thi Kim Oanh Nguyen, Wolfdieter Springer, Tamas Kozicz, Linda Hasadsri, Eugenia Trushina, Ian R Lanza, Elie Naddaf.
      Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary approaches from RNA level to high-resolution respirometry on permeabilized muscle fibers was employed. The relationship between mitochondrial respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine their clinical relevance. The study included a total of 67 patients with IBM and 45 controls. On high resolution respirometry of permeabilized muscle fibers, IBM samples exhibited reduced maximal mitochondrial respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, male patients had decreased State 3 intrinsic respiration, whereas female patients had greater intrinsic respiration under leak states. Complex I activity was decreased mainly in female patients, in whom complex II control ratio positively correlated with disease duration and severity. IBM was further associated with decreased RNA levels of all complexes, and lower protein expression of complex I, III, IV and V, likely related to the lower mtDNA content seen in IBM samples. Regarding the production of reactive oxygen species, IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that positively correlated with disease duration in female patients. Lastly, correlation analyses suggested that impaired mitochondrial respiration, altered mitophagy, and reduced mtDNA content are interconnected in IBM and maybe of clinical significance. IBM is characterized by multifaceted, clinically relevant impairments in mitochondrial respiration. Future studies should further explore underlying pathomechanisms and the variation of mitochondrial respiration by disease stage.
    Keywords:  aging; mitochondrial DNA abnormalities; mitophagy; myopathy; oxidative phosphorylation; oxidative stress
    DOI:  https://doi.org/10.1093/brain/awag269
  14. Ageing Res Rev. 2026 Aug 05. pii: S1568-1637(26)00282-5. [Epub ahead of print] 103290
    Mitochondrial homeostasis dysregulation: Potential mechanisms of Alzheimer's disease mediated by TDP-43.
    Wendi Huang, Juan Huang, Nanyu Kuang, Jingjing Wu, Fei Feng, Yong Luo, Nanqu Huang.
      Alzheimer's disease (AD) exhibits substantial clinical and pathological heterogeneity that is not fully explained by amyloid-β and tau pathology alone. TAR DNA-binding protein 43 (TDP-43) is increasingly recognized as a frequent copathology in AD, particularly in limbic regions, where its presence is associated with accelerated cognitive decline. Disruption of mitochondrial homeostasis is also an early and consistent feature of AD and contributes to neuronal vulnerability. In this review, we summarize current evidence linking TDP-43 pathology to impaired mitochondrial homeostasis in AD. We outline key features of mitochondrial homeostasis in neurons, review neuropathological and clinical data supporting the relevance of TDP-43 in AD, and synthesize emerging mechanisms by which TDP-43 may perturb mitochondrial homeostasis, including effects on expression, aggregation and localization, quality control, organelle dynamics, and endoplasmic reticulum-mitochondria communication.
    Keywords:  Alzheimer's Disease; Mitochondrial fission; Mitochondrial fusion; Mitochondrial homeostasis; Mitophagy; TDP-43
    DOI:  https://doi.org/10.1016/j.arr.2026.103290
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