bims-mitmed 2026-04-12 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–04–12
25 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial DNA analysis in a cohort of stillbirths with brainstem and cardiac conduction system abnormalities.
Ophthalmic manifestations of mitochondrial disorders.
A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
Optimized ND4 allotopic expression for gene therapy of Leber's hereditary optic neuropathy.
Exercise induces sex-specific assembly of mitochondrial supercomplexes.
Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.
Transforming the natural course of infantile onset thymidine kinase 2 deficiency through early nucleoside replacement therapy.
Longitudinal analysis shows GAA1 length and baseline clinical status as robust predictors of progression in Friedreich ataxia.
Mitochondrial iNOS blocks itaconate production by interacting with IRG1.
Mitochondrial transplantation in lung diseases: From mechanisms to application prospects.
Mitochondria Transplantation Preserves Retinal Ganglion Cells and Promotes CNS Axonal Regeneration.
Mitochondrial transplantation for osteoarthritis: from molecular mechanisms to clinical translation.
The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
Mitochondria transfer in tissue homeostasis and diseases.
Mitochondrial Transfer: From Bench to Bedside.
Mitochondria-Derived Vesicles and Mitochondrial Extracellular Vesicles in Health and Cardiovascular Disease.
Fluorescence-Based Quantification of Mitochondrial Damage in Human Airway Smooth Muscle Cells.
Mechanisms of human mitochondrial leaderless mRNA translation initiation.
Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
MitoPerturb-Seq identifies links between nuclear and mitochondrial genomes in single cells.
Leucine catabolic enzyme AUH regulates BAT thermogenesis via PPARγ HMGylation and RNA-binding function in male mice.
Melatonin attenuates Drp1-mediated excessive mitochondrial fission through upregulation of SIRT1 in granulosa cells in PCOS.
Synergistic Neurotoxicity of environmental Cadmium and Paraquat in Parkinsonism: Unveiling the Mito-ROS/OPA1/Caspase-3/GSDME-driven Apoptosis Axis.

Mitochondrion. 2026 Apr 02. pii: S1567-7249(26)00042-5. [Epub ahead of print]89 102152

Mitochondrial DNA analysis in a cohort of stillbirths with brainstem and cardiac conduction system abnormalities.

Mauro Lecca, Nicolò Mele, Patrizia Leonardi, Giulia Ottaviani, Edoardo Errichiello.

  Stillbirth (SB) accounts for over 60% of perinatal deaths in high-income countries, with a significant portion of cases remaining unexplained following thorough anatomopathological investigation. Mitochondrial DNA (mtDNA) alterations were analyzed in 42 SB cases with brainstem and cardiac conduction system (CCS) anomalies and in 32 control fetuses without these anomalies. DNA extracted from brainstem tissues was analyzed in both groups. In addition, unaffected tissues from the SB cases were examined for intra-individual comparison. The analysis included mtDNA sequencing, haplogroup determination, copy number (CN) quantification, and evaluation of displacement loop (D-loop) instability and methylation. Across the entire SB cohort, a total of 158 variants were identified, with a significant enrichment of variants observed in cases without CCS anomalies (p = 0.024). Affected brainstem tissues exhibited significantly higher mtDNA-CN compared with both control brainstem tissues (p < 0.0001) and unaffected tissues (p = 0.005), with levels higher in mild lesions than in severe lesions (p = 0.02). D-loop instability was identified in 37% of cases, and D-loop methylation levels were consistently higher in affected brainstem tissues compared with both control brainstem tissues (p < 0.0001) and unaffected tissues (p = 0.0001). These findings support mitochondrial dysfunction as a key contributor to fetal demise and mtDNA-CN as a potential biomarker for SB.

Keywords:  Brainstem; Methylation; Stillbirth (SB); cardiac conduction system (CCS); displacement loop (D-loop); mitochondrial DNA (mtDNA); mitochondrial DNA copy number (mtDNA-CN)

DOI:  https://doi.org/10.1016/j.mito.2026.102152
Prog Retin Eye Res. 2026 Apr 03. pii: S1350-9462(26)00032-7. [Epub ahead of print] 101466

Ophthalmic manifestations of mitochondrial disorders.

Megan F Baxter, Grace A Borchert, Emma L Blakely, Claire W Ruan, Robert E MacLaren, Robert McFarland, Robert W Taylor.

  Mitochondrial diseases are the most common group of inherited neurometabolic disorders and frequently involve multiple organ systems with high energy demands. Ophthalmic manifestations are a common occurrence in affected individuals and may be the earliest or predominant clinical feature. However, the marked clinical heterogeneity of mitochondrial eye disease often delays recognition and therefore diagnosis. Mitochondria play a central role in cellular metabolism through the process of oxidative phosphorylation. Genetic mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) can impair this key metabolic process leading to clinical disease. Diagnosing such mitochondrial diseases is however often complicated - the same genetic change can result in different symptoms (variable expressivity); different genes can cause similar conditions (allelic and locus heterogeneity); a single genetic change may affect multiple body systems (pleiotropy); and the proportion of affected mitochondrial DNA molecules can vary between tissues (mtDNA heteroplasmy). While the diagnostic process will certainly be influenced by the initial clinical presentation, perhaps more important is clinician awareness and early consideration of an underlying mitochondrial disorder. Early and accurate molecular genetic diagnosis is both available and essential, not only for prognostication and management, but also for reproductive counselling, access to appropriate clinical trials, cascade testing of relevant family members and consideration of emerging mitochondrial therapeutics(1,2). In this review, we summarise the biochemical and genetic foundations of mitochondrial eye disease, describe the spectrum of clinical phenotypes, outline diagnostic approaches and considerations, and highlight the importance of precise early diagnosis in guiding management and reproductive decision-making.

Keywords:  mitochondria; mitochondrial counselling; ophthalmology

DOI:  https://doi.org/10.1016/j.preteyeres.2026.101466
Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2535453123

A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.

Weiwei Fan, Tae Gyu Oh, Lillian Crossley, Hunter Robbins, Mingxiao He, Yang Dai, Morgan L Truitt, Annette R Atkins, Michael Downes, Ronald M Evans.

  Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell-based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell-embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.

Keywords:  ES cell; aggregation; mouse model; mtDNA; transgenesis

DOI:  https://doi.org/10.1073/pnas.2535453123
Cell Commun Signal. 2026 Apr 06.

Small but mighty: mitochondrial DNA at the centre of retrograde signalling.

Eve Harding, Veronica Bazzani, Carlo Vascotto.



Keywords:  Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial-derived Peptides; Mitochondrial-derived non-coding RNAs; Retrograde signalling

DOI:  https://doi.org/10.1186/s12964-026-02858-4
Front Bioeng Biotechnol. 2026 ;14 1765995

Optimized ND4 allotopic expression for gene therapy of Leber's hereditary optic neuropathy.

Evgeniy V Lapshin, Alexander D Egorov, Alexander S Malogolovkin, Nizami B Gasanov, Svetlana A Smirnikhina, Vyacheslav Yu Tabakov, Alexander V Karabelsky.

  Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by central vision loss, primarily resulting from mutations disrupting the electron transport chain. The most prevalent LHON-causing mutation is mt.11778G>A in the mitochondrial MT-ND4 gene, which encodes a critical subunit of complex I. Allotopic expression, a promising gene therapy strategy, aims to deliver a functional nuclear version of ND4 into the cell nucleus and target the resulting protein to the mitochondria. The efficiency of this approach critically depends on the mitochondrial targeting signal used. In this study, we screened five different MTS sequences to optimize the allotopic expression of ND4 in a HEK-293 cellular model of LHON harboring the mt.11778G>A mutation. We identified MTS-cox8k as the most effective signal for restoring mitochondrial function. Treatment with this construct significantly mitigated key pathological hallmarks: reactive oxygen species decreased by 72%, mitochondrial calcium levels dropped by 47%, and mitochondrial membrane potential (ΔΨm) increased by 38%. These results underscore the therapeutic potential of allotopic ND4 expression and highlight the critical importance of MTS optimization for developing effective treatments for mitochondrial diseases like LHON.

Keywords:  Leber’s neuropathy; gene therapy; mitochondrial function test; mitochondrial localization; mitochondrial transport

DOI:  https://doi.org/10.3389/fbioe.2026.1765995
Cell Rep. 2026 Apr 03. pii: S2211-1247(26)00295-0. [Epub ahead of print]45(4): 117217

Exercise induces sex-specific assembly of mitochondrial supercomplexes.

Jesús R Huertas, Jerónimo Aragón-Vela, Andreas Breenfeldt Andersen, Jacob Bejder, Lars Nybo, Nikolai B Nordsborg, Andrea Rodríguez-Carrillo, José A Enriquez, Sara Cogliati, Rafael A Casuso.

  The mitochondrial respiratory complexes of the electron transport chain (ETC) form supramolecular structures known as supercomplexes (SCs) whose functions remain partially understood. An increase in carbohydrate oxidation, such as that induced by high-intensity contractions within skeletal muscle (SKM), has been proposed to promote the assembly of high molecular weight SCs (HMWSCs). Here, healthy, active young subjects (7 females and 9 males) performed a moderate- followed by a high-intensity exercise bout. We found that males increased the assembly of complex III (CIII) into SCs, particularly HMWSCs, in an intensity-dependent manner within SKM. Females showed a stable content of both HMWSCs and I+III2 SCs during exercise. In contrast, the assembly of CIV into SCs was not promoted by exercise in either sex. These findings indicate that the ETC complex organization can be modulated by exercise, and the mitochondrial supercomplex assembly in human SKM appears to be regulated in a sex-specific manner.

Keywords:  CP: metabolism; CP: molecular biology; electron transport chain; electron transport chain remodeling; high-intensity exercise; human muscle bioenergetics; lactate; mitochondrial complexes; sex-specific mitochondrial adaptation; sexual dimorphism; skeletal muscle; skeletal muscle metabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.117217
J Neurol. 2026 Apr 10. pii: 263. [Epub ahead of print]273(5):

Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.

Ignazio Giuseppe Arena, Shamini Saravanabavan, Rita Horvath, Jelle van den Ameele.

  Primary mitochondrial diseases (PMDs) represent a clinically and genetically heterogeneous group of disorders characterized by impaired oxidative phosphorylation and multisystem involvement, commonly affecting the nervous system. As therapeutic development accelerates, there is a growing need for robust biomarkers capable of supporting diagnosis, stratifying patient subgroups, monitoring disease progression, and providing sensitive pharmacodynamic readouts for clinical trials. This review summarizes recent advances in three major non-invasive biomarker domains relevant to PMDs: circulating serum and molecular biomarkers, functional and digital endpoints, and neuroimaging modalities. Circulating markers, such as FGF21, GDF15, NfL, and NAD⁺-related signatures, have each been proposed for diagnosis and to follow disease progression, while multi-omics approaches are paving the way toward integrated molecular phenotyping. Digital health technologies, including accelerometry and gait analytics, enable objective quantification of real-world functional impairment, although disease-specific validation remains an unmet need. Neuroimaging offers mechanistic insights through metabolic (MRS, CEST), perfusion (ASL), and molecular modalities (mitochondrial PET tracers). Cutting-edge tools, such as Multi-Spectral Optoacoustic Tomography (MSOT), Raman spectroscopy, and Near-Infrared Spectroscopy (NIRS), promise real-time or spatially resolved assessment of mitochondrial function. Together, these developments outline multidimensional biomarker approaches for PMDs, with the potential to directly measure target engagement and clinically meaningful phenotypes in future therapeutic trials. Future progress will depend on longitudinal validation, harmonized acquisition protocols, and the integration of multimodal platforms to support upcoming therapeutic trials and precision medicine strategies.

Keywords:  Biomarkers; Clinical trials; Digital health technologies; Functional endpoints; Magnetic resonance imaging; Mitochondrial disease; Neuroimaging; Phenotyping; Positron emission tomography; Precision medicine; Wearable devices

DOI:  https://doi.org/10.1007/s00415-026-13794-1
J Neuromuscul Dis. 2026 Apr 07. 22143602261433223

Transforming the natural course of infantile onset thymidine kinase 2 deficiency through early nucleoside replacement therapy.

Gulcin Akinci, Javid Sardarzada, Haluk Topaloglu.

   BACKGROUND: Thymidine kinase 2 (TK2) deficiency is an ultra-rare, severe mitochondrial myopathy caused by pathogenic variants in TK2 and characterized by a wide range of ages at onset. The infantile form, presenting before 2 years of age, is the most rapidly progressive and is associated with a high risk of early mortality. We describe the clinical outcomes of early nucleoside therapy in a series of children with infantile-onset TK2 deficiency.
METHODS: We retrospectively reviewed four children with genetically confirmed infantile-onset TK2 deficiency treated with oral deoxycytidine/deoxythymidine (dC/dT) through an Early Access Program at two centers. Dosing was escalated to 800 mg/kg/day as tolerated. Patients were followed at baseline, Month 1, and regular intervals thereafter. Outcomes included neurological examinations, eight motor milestones, and respiratory and feeding support. Safety laboratory results, neuroimaging, and biopsy findings were reviewed.
RESULTS: Treatment began at 19-24 months (median duration 26 months; range: 4-81). All presented within the first year with hypotonia, motor regression, and respiratory and/or bulbar involvement. Two required invasive ventilation and three required tube feeding before therapy. After dC/dT initiation, all improved with no further milestone loss. Three achieved independent ambulation and stair climbing; the fourth, at 4 months of therapy, has begun unassisted walking. Both tracheostomized patients were weaned from ventilation, and enteral feeding was discontinued in all three within 1-6 months. Only mild dose-related diarrhea occurred in one patient.
CONCLUSION: Early nucleoside therapy halts disease progression and restores motor function in infantile-onset TK2 deficiency, the most severe form of the disease.

Keywords:  infantile-onset; mitochondrial myopathy; mtDNA depletion syndrome; nucleoside therapy; thymidine kinase 2 deficiency

DOI:  https://doi.org/10.1177/22143602261433223
J Neurol. 2026 Apr 09. pii: 259. [Epub ahead of print]273(5):

Longitudinal analysis shows GAA1 length and baseline clinical status as robust predictors of progression in Friedreich ataxia.

Leire Manrique, Francisco Martínez-Dubarbie, Ana L Pelayo-Negro, Natalia Benitez-Calle, María Victoria Sanchez-Pelaez, Daniel Cota-Gonzalez, Ruben Loza, Raquel Martinez-Díaz, Juan Irure-Ventura, Coro Sanchez-Quintana, Ivelisse Sanchez, Antoni Matilla-Dueñas, Jon Infante.

  Friedreich's ataxia (FRDA) is the most common early onset hereditary ataxia, caused by GAA repeat expansions in the FXN gene. The length of the shorter allele (GAA1) and age at onset are established determinants of disease severity, though additional biomarkers such as frataxin expression and neurofilament light chain (NfL) have been proposed. We conducted a 30-month prospective longitudinal study, including 25 FRDA patients and 16 heterozygous carriers, assessing clinical progression through SARA, FARS-ADL, INAS, EQ-5D, SCAFI, and CCFS scales. Baseline measures included GAA repeats, frataxin expression in fibroblasts, CSF NfL, and disease burden. Frataxin levels were significantly reduced in patients and correlated with GAA1 length and baseline severity. SARA, FARS-ADL, and INAS worsened significantly over time, while SCAFI and CCFS remained stable. GAA1 length and baseline SARA score emerged as the strongest predictors of progression. CSF NfL was elevated in younger patients and declined with age but did not correlate with severity or progression. These results support GAA1 length and baseline clinical status as robust predictors of progression and suggest limited utility of CSF NfL as a longitudinal biomarker particularly in later disease stages.

Keywords:  Biomarkers; Disease progression; Frataxin; Friedreich ataxia; Neurofilament light chain; SARA

DOI:  https://doi.org/10.1007/s00415-026-13812-2
Nat Metab. 2026 Apr 10.

Mitochondrial iNOS blocks itaconate production by interacting with IRG1.

Tomas Paulenda, Maxim N Artyomov.

DOI: https://doi.org/10.1038/s42255-026-01493-0
Genes Dis. 2026 Jul;13(4): 101856

Mitochondrial transplantation in lung diseases: From mechanisms to application prospects.

Haoneng Wu, Qiuran Zhao, Ying Zhao, Jinguang Bai, Junxi Pan, Songling Huang.

  Mitochondria are double-membrane organelles in eukaryotic cells, which play an important role in energy metabolism, cell cycle and apoptosis. Therefore, mitochondrial abnormalities can affect various physiological and pathological processes. Extensive research over a long period of time has shown that mitochondrial dysfunction is considered a hallmark of several diseases, including cardiovascular diseases, neurodegenerative diseases, respiratory diseases, and even cancer. Mitochondrial transplantation has emerged in recent years as a novel approach for treating mitochondria-related diseases. This therapy involves transferring viable, functionally intact mitochondria into cells or tissues, either directly or indirectly, to replace dysfunctional mitochondria and restore mitochondrial function, thereby achieving therapeutic goals. Research has indicated that mitochondrial transplantation can alleviate the progression of lung diseases and improve disease outcomes. In this review, we explore the mechanisms underlying mitochondrial dysfunction in lung disease and the potential application of mitochondrial transplantation in the treatment of lung disease.

Keywords:  Lung disease; Mitochondrial dysfunction; Mitochondrial transplantation; Oxidative stress; Respiratory system

DOI:  https://doi.org/10.1016/j.gendis.2025.101856
Free Radic Biol Med. 2026 Apr 06. pii: S0891-5849(26)00266-2. [Epub ahead of print]

Mitochondria Transplantation Preserves Retinal Ganglion Cells and Promotes CNS Axonal Regeneration.

Ajay Ashok, Kin-Sang Cho, Wai Lydia Tai, Lu Huang, Hio Tong Kam, Suman Chaudhary, Karen Chang, Sarita Pooranawattanakul, Julie Chen, Anton Lennikov, Dong Feng Chen.

  Mitochondrial dysfunction is a central driver of retinal ganglion cell (RGC) loss in glaucoma and other forms of optic neuropathies, leading to irreversible blindness. Here, we demonstrate that replenishing the mitochondrial pool through exogenous mitochondrial transplantation ("mitotherapy") in adult mice not only preserves neuronal survival but also promotes regenerative competence in the central nervous system (CNS). In aging or injured RGCs, we identified profound deficits in mitochondrial biogenesis, fission-fusion balance, and mitophagy. Transplantation of functional mitochondria in in vitro models of trophic deprivation and glutamate excitotoxicity restored mitochondrial homeostasis, improved energy production, reduced reactive oxygen species, enhanced RGC survival, and drove robust neurite outgrowth, with transplanted mitochondria actively trafficking to growth cones. This effect was dampened following inhibition of mitochondrial fusion indicating a pivotal role of fusion-dependent functional integration of exogenous mitochondria. Strikingly, intravitreal delivery of mitochondria in an optic nerve crush model of adult mice enabled their integration into RGCs, improved survival and electrophysiological responses, and supported axonal regeneration across the lesion site. These findings indicate that mitochondrial transplantation strategy rescues bioenergetic failure and supports a pro-regenerative activity of neurons, highlighting the potential of mitotherapy as a transformative approach for neurodegenerative eye diseases and CNS injuries.

Keywords:  Mitochondrial transplantation; PC12 cells; SH-SY5Y cells; nerve regeneration; neuroprotection; optic nerve crush; retinal ganglion cells

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.069
Front Immunol. 2026 ;17 1716906

Mitochondrial transplantation for osteoarthritis: from molecular mechanisms to clinical translation.

Ying Liu, Yang Liu, Na Zhang, Haizhuan An, Liangyu Mi, Yanan Gao, Ke Xu.

  Osteoarthritis (OA) is the most prevalent chronic degenerative joint disorder worldwide, characterized by progressive cartilage degradation, subchondral bone remodeling, synovial inflammation, and impaired mobility. Growing evidence has established mitochondrial dysfunction-including impaired oxidative phosphorylation (OXPHOS), excessive reactive oxygen species (ROS) generation, disrupted mitochondrial dynamics, and dysregulated mitophagy-as an early and pivotal driver of OA pathogenesis. These bioenergetic failures not only disrupt chondrocyte metabolism but also amplify inflammation, matrix degradation, and cell death. In recent years, mitochondrial transplantation has emerged as a revolutionary therapeutic paradigm, aiming to restore cellular homeostasis by delivering functional mitochondria into damaged chondrocytes. This review systematically summarizes the molecular mechanisms of mitochondrial dysfunction in OA and highlights three major therapeutic strategies: (1) cell-based approaches, particularly mesenchymal stem cell (MSC)-mediated mitochondrial transfer via tunneling nanotubes (TNTs) or extracellular vesicles (EVs); (2) cell-free approaches, utilizing purified mitochondria or MitoEVs for direct transplantation; and (3) engineered mitochondrial transplantation, integrating bioengineering, nanotechnology, and genetic modification to enhance mitochondrial quality, delivery efficiency, and therapeutic persistence. We further discuss opportunities and challenges in clinical translation, including standardization of mitochondrial preparation, optimization of delivery systems, immunological safety, and regulatory classification. Collectively, mitochondrial transplantation represents a disruptive strategy that directly addresses the bioenergetic collapse of chondrocytes and offers a promising avenue for disease-modifying therapy in OA. Future advances in mechanistic elucidation, technological optimization, and multicenter clinical trials will be crucial to transform "mitochondrial medicine" from experimental concept to clinical reality.

Keywords:  extracellular vesicles; mitochondrial dysfunction; mitochondrial transplantation; mitophagy; osteoarthritis; oxidative phosphorylation; regenerative medicine; stem cells

DOI:  https://doi.org/10.3389/fimmu.2026.1716906
Nat Commun. 2026 Apr 09.

The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.

Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-026-71630-6
Circ Res. 2026 Apr 10. 138(8): e326982

Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.

Gwang-Bum Im, Juan M Melero-Martin.

  Mitochondria are increasingly recognized as central regulators of vascular health, shaping endothelial cell function through roles that extend far beyond energy production. In addition to coordinating redox balance, calcium dynamics, and biosynthetic support, recent studies have revealed that mitochondria participate in intercellular communication, with evidence of transfer events emerging in vascular contexts. Parallel efforts have advanced the deliberate delivery of exogenous mitochondria from preclinical proof-of-principle studies to first-in-human trials, demonstrating that freshly isolated organelles can be harvested and administered in real-time to critically ill patients with favorable early outcomes. The mechanisms underlying these benefits remain incompletely defined, and strategies for efficient and scalable delivery are still emerging. In this review, we prioritize recent evidence linking mitochondrial function to endothelial cell physiology, highlight the nascent but growing field of mitochondrial transfer in the vasculature, and examine how mitochondrial transplantation is evolving from experimental concept to clinical translation. Together, these advances point to new therapeutic avenues for preserving vascular integrity and treating disease.

Keywords:  cell communication; endothelial cells; mitochondria; regenerative medicine; therapeutics

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326982
Int J Biol Sci. 2026 ;22(6): 3144-3173

Mitochondria transfer in tissue homeostasis and diseases.

Lei Qin, Donghao Gan, Zecai Chen, Zhen Xu, Mingyue Wu, Bimin Gao, Yufeng Long, Xihong Mou, Wenqing Li, Weihong Yi, Guozhi Xiao.

  Mitochondria serve as the essential powerhouse for virtually all eukaryotic cells and have been implicated in other crucial functions in both physiological and disease contexts. As cytoplasmic organelles, mitochondria are segregated and transported from parent to daughter cells during division or differentiation, a process known as vertical mitochondria transfer (VMT). A growing body of literature indicates that various cell types can export mitochondria for delivery to developmentally unrelated cell types without division, a process termed horizontal mitochondria transfer (HMT). In this review, we summarize current understanding of the modes of mitochondria transfer and illustrate the phenomenon of HMT across different tissue backgrounds, including the immune, cardiovascular, respiratory, hepatic, renal, musculoskeletal, adipose, and reproductive systems. Moreover, updated applications and functions of mitochondria transfer are discussed. Additionally, we also highlight the therapeutic potential of mitochondria transfer in current preclinical and clinical trials for inherited mitochondrial diseases, cancer, wound healing, and injuries of the respiratory and central nervous systems.

Keywords:  extracellular vesicles (EVs); gap junctions (GJs); horizontal mitochondria transfer; intercellular mitochondria transfer; tunneling nanotubes (TNT); vertical mitochondria transfer

DOI:  https://doi.org/10.7150/ijbs.129709
Circ Res. 2026 Apr 10. 138(8): e326984

Mitochondrial Transfer: From Bench to Bedside.

Gentaro Ikeda, Jiwen Li, Alyssa Wang, Amogha Medha Paleru, Phillip C Yang.

  Intercellular mitochondrial transfer has emerged as a fundamental mechanism of tissue adaptation and repair in the cardiovascular system, with major implications for cardiovascular, neurological, metabolic, and inflammatory diseases. Once thought to be static, mitochondria are now recognized as mobile organelles that move between cells via tunneling nanotubes, extracellular vesicles, and free mitochondria. These pathways support 2 complementary axes of mitochondrial communication: Rescue by Replenish, in which healthy mitochondria or mitochondrial components restore bioenergetics and stress resistance in recipient cells, and Relief by Release, in which damaged mitochondria are exported for degradation to preserve homeostasis and limit inflammation. We summarize the molecular machinery governing tunneling nanotube formation, mitochondria-derived vesicle biogenesis, extracellular vesicle sorting, and free mitochondrial release and uptake, and discuss how these processes shape organ function. Building on these mechanistic insights, we outline 4 translational strategies: (1) cell-based therapies that donate healthy mitochondria or scavenge damaged ones; cell-free approaches using (2) mitochondria-containing extracellular vesicles or (3) purified mitochondria; (4) pharmacological, nutritional, and lifestyle interventions that augment endogenous mitochondrial turnover and intercellular exchange. Finally, we discuss key barriers to clinical translation, including inflammatory and oncogenic risks, mitonuclear incompatibility, incomplete understanding of the fate and durability of transferred mitochondria, and the lack of standardized manufacturing, potency assays, and long-term storage methods. Continued integration of mechanistic biology with bioengineering and regulatory science will be essential to safely move mitochondrial transfer-based therapies from bench to bedside in cardiovascular medicine.

Keywords:  cell communication; energy metabolism; extracellular vesicles; homeostasis; inflammation; mitochondria; nanotubes

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326984
Circ Res. 2026 Apr 10. 138(8): e327357

Mitochondria-Derived Vesicles and Mitochondrial Extracellular Vesicles in Health and Cardiovascular Disease.

Erjola Rapushi, Anubhav Aryal, Tianyuan Yang, Zhixin Li, Xiaohong Wang, Guo-Chang Fan.

  Mitochondria-derived vesicles (MDVs) and mitochondrial extracellular vesicles (mitoEVs) represent 2 related extensions of mitochondrial dynamics that link organelle maintenance to communication within and between cells. MDVs are small vesicles that bud directly from mitochondria, selectively packaging components of the outer membrane, inner membrane, or matrix. They serve as a localized quality control mechanism that removes oxidized or damaged material without engaging the entire mitophagic machinery. After budding, MDVs typically enter the endolysosomal pathway, where they can fuse with late endosomes or lysosomes for cargo degradation. A subset of MDVs also targets other organelles, particularly peroxisomes, contributing to organelle crosstalk, lipid metabolism, and redox balance. By contrast, mitoEVs released into the extracellular space contain intact functional mitochondria, mitochondrial contents (proteins, DNAs/RNAs, lipids, and so on), and nonmitochondrial cargo (ie, mRNAs, noncoding RNAs, and so on), which can be transferred to recipient cells and subsequently induce either pathogenic or beneficial outcomes. Therefore, mitoEVs have been implicated in metabolic cooperation, immune regulation, tissue remodeling, and aging. Accordingly, this review summarizes recent progress on the diverse mechanisms for the biogenesis of MDVs and mitoEVs, as well as available protocols for their isolation. The roles of MDVs and mitoEVs in mediating mitochondrial quality/quantity control and multiple layers of crosstalk between intracellular organelles and different cell types in health and disease are highlighted. Last, mitoEV-mediated pathogenic effects and therapeutic potential in cardiovascular disease are also discussed.

Keywords:  cardiovascular diseases; extracellular vesicles; lipid metabolism; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327357
Am J Physiol Cell Physiol. 2026 Apr 09.

Fluorescence-Based Quantification of Mitochondrial Damage in Human Airway Smooth Muscle Cells.

Sanjana Mahadev Bhat, Gary C Sieck.

  Mitochondrial quality control is essential for maintaining cellular homeostasis by balancing the removal of damaged mitochondria (mitophagy) with the generation of new mitochondria (mitochondrial biogenesis). A key feature of mitochondrial damage is loss of mitochondrial membrane potential (ΔΨm), which initiates mitophagy, enabling effective mitochondrial clearance. Although an array of tools exists to assess mitochondrial damage (depolarization), many rely on acute, non-physiological depolarization or provide semiquantitative measures of mitochondrial damage, limiting their ability to resolve intact versus damaged mitochondria within heterogeneous mitochondrial networks. Therefore, in the present study we developed and validated an imaging-based assay to quantify intact mitochondria in human airway smooth muscle (hASM) cells using dual-fluorescence labeling. This approach combines a ΔΨm-dependent (MitoTracker Red FM) dye with a ΔΨm-independent label (CellLight Mitochondria-GFP). Dual-labeled mitochondria in untreated hASM cells exhibited ~10% non-overlap between the two fluorescence signals, indicating presence of damaged (depolarized) mitochondria in homeostatic conditions. Dose- and time-dependent treatment with the mitochondrial uncoupler FCCP induced loss of membrane potential, confirmed by TMRM, and resulted in a marked reduction in fluorescence overlap, volume of intact mitochondria and increased mitochondrial fragmentation. Complementary analysis using the redox-sensitive reporter pMitoTimer was performed, where a shift in fluorescence signal from green to red is indicative of increased mitochondrial oxidative stress and rate of mitochondrial turnover. Together, these findings validate the dual-labeling strategy as a quantitative method to distinguish intact from damaged mitochondria in situ and as a useful tool for studying mitochondrial quality control, potentially translatable to various cell and disease models.

Keywords:  Confocal Imaging; Depolarization; Mitochondria; Mitochondrial Damage; Mitochondrial Membrane Potential

DOI:  https://doi.org/10.1152/ajpcell.00033.2026
Nat Commun. 2026 Apr 04.

Mechanisms of human mitochondrial leaderless mRNA translation initiation.

Shuangjie Shen, Yinghua Xu, Daniel L Kober, Jinfan Wang.

Mitochondrial translation is essential for cellular function, and its dysregulation is associated with mitochondrial disorders and cancer. However, the mechanisms by which human mitochondrial ribosomes initiate translation remain poorly understood, particularly because mitochondrial mRNAs generally lack the 5' untranslated regions that guide translation initiation in bacterial and cytoplasmic systems. Using real-time single-molecule fluorescence measurements, biochemical assays, and cryo-EM analysis, we show that human mitochondrial translation initiation occurs through two parallel pathways. In one pathway, leaderless mRNA first loads onto the 28S small subunit, followed by recruitment of the 39S large subunit to form the 55S initiation complex. In the second pathway, a preassembled 55S monosome directly loads onto leaderless mRNA. Both pathways require recruitment of mtIF2 and fMet-tRNAMet before mRNA binding. However, the monosome-loading pathway tolerates non-formylated Met-tRNAMet and is suppressed by mtIF3. Together, these findings define the heterogeneous pathways of human mitochondrial translation initiation on leaderless mRNAs.

DOI: https://doi.org/10.1038/s41467-026-71535-4
Circ Res. 2026 Apr 10. 138(8): e326985

Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.

Xi Fang, Åsa B Gustafsson.

  Mitochondria are highly dynamic, double-membraned organelles that generate the majority of ATP in cardiomyocytes while supporting cellular homeostasis and signal transduction. Accumulation of dysfunctional mitochondria can promote cardiomyocyte loss, impair contractile function, and ultimately lead to myocardial damage. To preserve mitochondrial integrity, cardiomyocytes rely on multilayered quality control mechanisms to remove defective mitochondria. Two major routes have emerged for this process: degradation, primarily via autophagy, and secretion via extracellular vesicles. This review summarizes the mechanisms of mitochondrial degradation and secretion in the heart and highlights their contributions to cardiac disease progression and potential as therapeutic targets.

Keywords:  extracellular vesicles; homeostasis; mitochondria; mitophagy; myocytes, cardiac

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326985
Nat Struct Mol Biol. 2026 Apr 09.

MitoPerturb-Seq identifies links between nuclear and mitochondrial genomes in single cells.

DOI: https://doi.org/10.1038/s41594-026-01780-0
Nat Commun. 2026 Apr 10.

Leucine catabolic enzyme AUH regulates BAT thermogenesis via PPARγ HMGylation and RNA-binding function in male mice.

Haizhou Jiang, Shihong Ni, Zi Li, Shanghai Chen, Xiaoying Li, Huijie Zhang, Wei L Shen, Xiaoxue Jiang, Peixiang Luo, Yousheng Shu, Feixiang Yuan, Kexin Tong, Fei Xiao, Feifan Guo.

A strong association between leucine and obesity has been well established; however, the role of leucine catabolic enzymes in adipose tissue remains largely unknown. Here, we show that knockdown of the leucine catabolic enzyme AU RNA-binding methylglutaconyl-CoA hydratase (AUH) in brown adipocytes reduces thermogenesis, while AUH over-expression has the opposite effect both in vivo and in vitro. Mechanistically, AUH partially promotes uncoupling protein 1 (UCP1) expression through its metabolite 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). HMG-CoA directly HMGylates peroxisome proliferator-activated receptor gamma (PPARγ) on lysine 386, enhancing its transcriptional activity to increase UCP1 expression. In addition, AUH binds to and stabilizes Ucp1 mRNA via its RNA-binding function. Moreover, we discovered that AUH promotes white adipose tissue browning; AUH expression in human white adipose tissue is inversely correlated with adiposity, and over-expression of AUH in adipose tissue protects male mice against high-fat diet-induced obesity. Collectively, these results provide new insights into the crosstalk between amino acid metabolism and thermogenesis and identify a novel post-translational modification of PPARγ.

DOI: https://doi.org/10.1038/s41467-026-71581-y
Reproduction. 2026 Apr 06. pii: xaag041. [Epub ahead of print]

Melatonin attenuates Drp1-mediated excessive mitochondrial fission through upregulation of SIRT1 in granulosa cells in PCOS.

Jingyu Zhang, Yuting Zhang, Mengyun Li, Linhui Gao, Jidong Zhou, Liang Gao, Jianjun Zhou.

  Mitochondrial dysfunction in GCs has been implicated in PCOS pathogenesis. Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission is critical for maintaining intact mitochondrial function. This study aims to investigate whether mitochondrial fission contributes to mitochondrial dysfunction in the GCs of individuals with PCOS and the molecular effects of melatonin on mitochondrial fission. Transmission electron microscopy (TEM) of human GCs showed that the mitochondria exhibited a condensed and small spherical morphology with a tendency toward fragmentation in PCOS patients. At the molecular level, GCs from patients with PCOS presented significant increases in both the p-Drp1(Ser616)/(Ser637) ratio and mitochondrial fission factor (MFF). In a dihydrotestosterone (DHT)-induced PCOS-like mouse model, excessive mitochondrial fission in GCs was similarly observed, characterized by fragmented mitochondrial morphology via TEM and increased expression of the mitochondrion-localized Drp1 (mito-Drp1) protein. Similarly, in vitro experiments demonstrated that DHT treatment increased the expression of mito-Drp1, the p-Drp1(Ser616)/(Ser637) ratio, and MFF in KGN cells. Melatonin treatment effectively reversed these abnormalities, restoring mitochondrial morphology, reducing fission markers (mito-Drp1, the p-Drp1 ratio, and MFF), decreasing mitochondrial reactive oxygen species, and enhancing mitochondrial membrane potential. Mechanistically, melatonin upregulated SIRT1, which restored the imbalance of Drp1 phosphorylation and blocked its MFF-dependent mitochondrial recruitment, thereby attenuating Drp1-mediated excessive mitochondrial fission. Our findings reveal a novel protective mechanism of melatonin in PCOS via the SIRT1-Drp1 signaling axis, offering a potential therapeutic target for PCOS management.

Keywords:  Drp1; PCOS; SIRT1; melatonin; mitochondrial fission

DOI:  https://doi.org/10.1093/reprod/xaag041
Int J Biol Sci. 2026 ;22(6): 2885-2905

Synergistic Neurotoxicity of environmental Cadmium and Paraquat in Parkinsonism: Unveiling the Mito-ROS/OPA1/Caspase-3/GSDME-driven Apoptosis Axis.

Yufei Luo, Yingying Lu, Yancheng Tang, Xuejun Zhao, Junpu Wang, Yifan Liu, Sijia Jiang, Yuyuan Zhu, Jiaqi Qi, Linlin Xing, Chenghao Yan, Xu Liu, Cainian Huang, Haiji Wang, Haodong Xu, Liming Wang.

  The increasing environmental presence of cadmium (Cd) and paraquat (PQ), driven by industrial emissions and overuse of herbicide, poses heightened risks for neurodegenerative disorders. Although each of these toxins can independently induce neuronal damage, the synergistic neurotoxic effects resulting from chronic, low-dose co-exposure to Cd and PQ remain inadequately understood. This study demonstrates that exposure to subtoxic levels of Cd and PQ concurrently induces neuronal cell death and contributes to Parkinson's disease (PD)-like symptoms. Mechanistically, chronic co-exposure to Cd and PQ triggers a marked overproduction of mitochondrial ROS (mito-ROS), which impairs OPA1 processing and results in mitochondrial fragmentation. This mitochondrial dysfunction subsequently triggers caspase-3 activation, leading to GSDME cleavage and its translocation to the mitochondria, ultimately promoting neuronal apoptosis. Furthermore, our in vivo studies demonstrate significant mitochondrial dysfunction and loss of nigrostriatal dopaminergic neurons, resulting in motor deficits and cognitive impairments in mice co-exposed to these toxins. Collectively, our findings reveal a novel molecular mechanism involving the mito-ROS/OPA1/caspase-3/GSDME pathway in environmentally-induced PD-like pathology, thereby offering potential therapeutic insights for PD treatment.

Keywords:  OPA1 cleavage; Parkinsonian neurodegeneration; cadmium-paraquat co-exposure; caspase-3/GSDME axis; mitochondrial apoptosis; reactive oxygen species

DOI:  https://doi.org/10.7150/ijbs.126979