bims-mitmed 2026-07-12 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–07–12
28 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Hypoxia rescues complex 1-associated disease caused by proteostatic defects.
Mitochondria setting the stage for ferroptosis.
Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.
Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.
Non-invasive urinary heteroplasmy screening outperforms blood testing for certain mitochondrial DNA variants in mitochondrial disease patients.
Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
Ligand-independent EPHA2 signaling sustains neural progenitors via ECSIT and NAD.
Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
Intercellular Mitochondrial Transfer and Mitochondrial Transplantation in Cardiovascular Disease.
Perianesthetic Complications in Genetic Mitochondrial Disease: A Review of Case Reports.
NAD+ modulates REST isoform expression and its downstream mitophagy in Alzheimer's disease.
SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
The role of mitochondrial proteases in inflammation and immunity.
Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.
Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
Late-Onset Leber Hereditary Optic Neuropathy: A Report of a Case and Review of the Literature.
Efficient in vivo cytosine base editing using virus-like particles with uracil DNA glycosylase inhibition.
AAV.hBAG3 Gene Therapy Improves Phenotype in a Valosin Containing Protein Mouse Model of Hereditary Inclusion Body Myositis.
ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.
The UFSP2-ODR4 complex spatially confines and dynamically controls UFM1 deconjugation to safeguard neuronal proteostasis.
Biallelic Loss-Of-Function Variant in ATP5ME Is Associated With Severe and Early Onset Oxidative Phosphorylation Deficiency.
Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.
The Role of PGC-1α in Neurodegenerative Diseases: Molecular Mechanisms, Translational Challenges, and Therapeutic Potential.
A metabolite-bridged complex between SerRS and SIRT2 couples NAD⁺ metabolism to translation control.
Remodeling of the mitochondrial quality control network: natural products intervening in diabetic retinopathy.
Precision Medicine in Neurodegeneration with Brain Iron Accumulation (NBIA) Disorders: An Update on Emerging Treatments.
Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.

Nat Metab. 2026 Jul 08.

Hypoxia rescues complex 1-associated disease caused by proteostatic defects.

Ankur Garg, Brandon R Desousa, Raju Roy, Amy Flis, Skyler Y Blume, Yohei Abe, Arthur A Melo, Ryan R Cupo, Gabriela Grigorean, Daniel R Southworth, James Shorter, Isha H Jain.

Impaired mitochondrial proteostasis underlies a broad spectrum of diseases, yet effective therapies remain limited. Here we show that deficiency of HTRA2, a mitochondrial intermembrane space protease, can be rescued by hypoxia therapy. Using an Htra2 mutant mouse model that displays severe neurodegeneration and early lethality, we find that continuous hypoxia rescues striatal degeneration and extends lifespan. Mechanistically, we demonstrate that HTRA2 forms a functional complex with the disaggregase CLPB. Loss of function of either protein drives aggregation of intermembrane space-facing subunits of complex I of the electron transport chain, resulting in secondary complex I dysfunction. These changes impair tissue oxygen consumption and probably cause pathological hyperoxia, which is corrected by hypoxia. Together, these findings define a proteostasis pathway linking intermembrane space quality control to complex I function and expand the potential of hypoxia therapy to secondary complex I disease.

DOI: https://doi.org/10.1038/s42255-026-01566-0
Trends Endocrinol Metab. 2026 Jul 07. pii: S1043-2760(26)00150-5. [Epub ahead of print]

Mitochondria setting the stage for ferroptosis.

Sofia Ahola.

  Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Recent advances challenge the view of ferroptosis as a predominantly cytosolic process and instead position mitochondria as central regulators of ferroptosis by coordinating iron metabolism, lipid composition, and redox homoeostasis. This review discusses ferroptosis from a mitochondrial perspective and examines its potential relevance to primary mitochondrial diseases, where defects in oxidative phosphorylation profoundly remodel cellular metabolism and redox homoeostasis. The review highlights emerging roles for mitochondrial iron-sulfur cluster biogenesis, coenzyme Q metabolism and trafficking, mitochondrial lipid remodelling, and stress-response signalling in shaping ferroptotic vulnerability. Finally, we discuss current evidence linking ferroptosis to mitochondrial pathology and the therapeutic opportunities arising from targeting ferroptosis pathways in mitochondrial disease.

Keywords:  coenzyme Q; ferroptosis; iron–sulfur cluster; lipid peroxidation; mitochondrial disease

DOI:  https://doi.org/10.1016/j.tem.2026.06.006
Protein Sci. 2026 Aug;35(8): e70703

Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.

Lena J Reichert, F-Nora Vögtle, Carlotta Peselj.

  Mitochondria respond to proteotoxic stress through the mitochondrial unfolded protein response, traditionally viewed as a transcriptional program that restores proteostasis by inducing chaperones and proteases. Emerging evidence indicates that mitochondrial membrane remodeling constitutes an additional adaptive component of this response. Regulated changes in mitochondrial lipid composition, particularly involving the signature phospholipid cardiolipin, support mitochondrial function during stress by stabilizing protein import machineries, promoting mitochondrial protein biogenesis, and facilitating recovery from dysfunction. In addition, stress originating in other organelles, especially the endoplasmic reticulum, reshapes mitochondrial membranes through altered lipid biosynthesis, inter-organelle lipid trafficking, and stress signaling pathways. These findings suggest that mitochondrial membrane remodeling represents a regulatory layer of organelle quality control integrated within interconnected stress response networks and may provide new opportunities to enhance mitochondrial resilience in disease.

Keywords:  ER–mitochondria crosstalk; cardiolipin; mitochondrial membrane remodeling; mitochondrial protein biogenesis; mitochondrial unfolded protein response (UPRmt); organelle stress signaling

DOI:  https://doi.org/10.1002/pro.70703
Nat Metab. 2026 Jul 08.

Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.

Anthony S Grillo.

DOI: https://doi.org/10.1038/s42255-026-01569-x
Mol Genet Metab. 2026 Jun 26. pii: S1096-7192(26)00481-6. [Epub ahead of print]148(4): 110198

Non-invasive urinary heteroplasmy screening outperforms blood testing for certain mitochondrial DNA variants in mitochondrial disease patients.

Atsuko Okazaki, Yukiko Yatsuka, Takuya Fushimi, Takanori Onuki, Yuko Aida, Hisato Aihara, Toshiyuki Imasawa, Akira Ohtake, Kei Murayama, Yasushi Okazaki.

   BACKGROUND: Mitochondrial diseases present diagnostic challenges due to variations in heteroplasmy levels of mitochondrial DNA (mtDNA) in different tissues. Current diagnostic approaches primarily rely on blood testing, which may miss pathogenic variants present at higher levels in other accessible tissues.
METHODS: We analyzed tissue samples from 164 individuals (125 probands and 39 family members) with genetically confirmed mitochondrial diseases using droplet digital PCR (ddPCR). We quantified heteroplasmy levels in five tissue types: blood, urine, cardiac muscle, skeletal muscle, and kidney tissue.
RESULTS: Among the 108 blood samples and 87 urine samples from patients carrying the m.3243A>G variant, urine samples demonstrated significantly higher heteroplasmy levels than blood samples (median: 76.6% [interquartile range (IQR): 50.8-91.8%] vs. 20.9% [IQR: 11.3-41.4%], p < 0.001). In a paired analysis of 80 patients with the m.3243 A > G variant who provided both blood and urine samples, urine heteroplasmy exceeded blood levels in all cases (median difference: 44.6% [interquartile range (IQR): 26.9-56.7%], p < 0.001). Moderate positive correlations were observed between blood and urine heteroplasmy (all variants: r = 0.68, n = 94 pairs; m.3243 A > G: r = 0.66, n = 80 pairs; both p < 0.001). Using an exploratory 10% heteroplasmy threshold based on prior reports for m.3243A>G, blood classified 24 of the 94 paired cases (25%, or one in four patients) as <10% while urine was ≥10%. Cardiac tissue exhibited the highest heteroplasmy levels (mean: 86% ±8% in m.3243A>G patients), though this likely reflects selection bias, as cardiac biopsies were obtained only from patients with cardiac involvement.
CONCLUSIONS: Urine specimens demonstrate higher heteroplasmy levels and more often place individuals above an exploratory 10% heteroplasmy threshold compared with blood specimens for certain mitochondrial DNA (mtDNA) variants, most notably m.3243A>G. Using this exploratory threshold, 24 of 94 paired blood-urine samples (25%) had blood heteroplasmy <10% while urine heteroplasmy was ≥10%, supporting the use of urine as an important noninvasive complementary specimen, and in many cases a preferred specimen, for suspected m.3243A>G. However, blood testing remains appropriate for variants that typically show high blood heteroplasmy and a relatively high threshold for clinical expressivity, such as m.8993 T > G. These findings support the implementation of urine-based screening protocols for suspected m.3243A>G cases, which may reduce underestimation of variant load and improve diagnostic evaluation.

Keywords:  Droplet digital PCR; Heteroplasmy; Inherited metabolic disorder; Mitochondrial disease; Tissue-specific diagnosis; m.3243A>G

DOI:  https://doi.org/10.1016/j.ymgme.2026.110198
Aging (Albany NY). 2026 Jul 06. 18(1): 787-812

Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.

Yash Flora, Dhriti Shastri, Kathryn R DeLeo, K Adam Bohnert.

  Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans, and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: the mitochondrion. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF-16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11-defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. We also found that experimental perturbation of mitochondria precipitated faster pexophagy with aging, implying bidirectionality in signaling between these two organelles. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.

Keywords:  cellular aging; inter-organelle crosstalk; lifespan; mitochondrial tubulation; pexophagy

DOI:  https://doi.org/10.18632/aging.206395
EMBO Rep. 2026 Jul 10.

Ligand-independent EPHA2 signaling sustains neural progenitors via ECSIT and NAD.

Tran Diem Nghi, Truong Thi My Nhung, Seunghyun Kim, Jonghyeok Yun, Nguyen Tran Nam Tien, Ara Lee, Minkyo Jung, Eun Jin Jang, Bon Seong Goo, Jin Yeong Yoo, Sung Ryong Shin, Ji Young Mun, Kyeng Min Park, Nguyen Phuoc Long, Cana Park, Sang Ki Park.

Embryonic neural stem and progenitor cells occupy a specialized niche along the lateral ventricles, where receptors on their apical membrane sense extracellular cues essential for preserving progenitor identity. How such surface signals are coupled to mitochondrial metabolism remains unclear. Here, we identify EPHA2 as a receptor enriched in cortical progenitors and show that disruption of its non-canonical, ligand-independent signaling compromises progenitor maintenance in vivo. EPHA2 perturbation reduces mitochondrial respiration, Complex I activity, and mitochondrial NAD+ regeneration, and is accompanied by lower mitochondrial abundance of the Complex I assembly factor ECSIT. Restoring mitochondrial NAD+ regeneration with MTS-LbNOX, or restoring mitochondrial ECSIT with ECSIT WT-but not a mitochondrial targeting-deficient mutant-attenuates the progenitor defects caused by EPHA2 perturbation. Maternal supplementation with NAD+ or its precursor NMN similarly mitigates these developmental defects. We further identify a PP2A-sensitive ECSIT phospho-state, including T179, that is consistent with regulated mitochondrial ECSIT accumulation downstream of EPHA2. Together, these findings support a model in which EPHA2 helps maintain embryonic cortical progenitors by sustaining ECSIT-dependent Complex I-linked mitochondrial redox homeostasis.

DOI: https://doi.org/10.1038/s44319-026-00858-6
J Cell Biol. 2026 Sep 07. pii: e202511211. [Epub ahead of print]225(9):

Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.

Emily Glover, Beth Wiseman, Celyn Dugdale, Charlie Humphery, Lorena Sueiro Ballesteros, Lorna Hodgson, Kevin Wilkinson, Ian Collinson.

Mitochondrial protein import is critical for organelle biogenesis, maintenance, and regeneration-essential for cellular homeostasis. Import dysfunction compromises cellular energy supplies, which is damaging to cells, particularly those with high energetic demands like neurons. Previously, we have shown that import failure is rescued by intercellular mitochondrial transfer (IMT) via tunnelling nanotubes (TNTs) however, the fate of the transferred mitochondria and the mechanistic basis for rescue were unresolved. Here, we show that bidirectional mitochondrial trafficking between cells harboring import-defective and import-competent mitochondria is distinct in terms of their regulation and ensuing consequences. Transferred import-defective mitochondria are highly fragmented and destined for canonical lysosomal degradation. In contrast, reactive oxygen species (ROS)-producing mitochondria at the periphery of cells with import-competent mitochondria are transferred into neighboring cells undergoing import failure. These new arrivals then accumulate within previously uncharacterized "mitochondrial degradation bodies" (MDBs). We speculate that the cooperation of these distinct cases of TNT-mediated conventional and noncanonical "trans-mitophagy" instigates mitochondrial regeneration, and thereby rescues mitochondrial function.

DOI: https://doi.org/10.1083/jcb.202511211
Can J Cardiol. 2026 Jul 07. pii: S0828-282X(26)00654-9. [Epub ahead of print]

Intercellular Mitochondrial Transfer and Mitochondrial Transplantation in Cardiovascular Disease.

Fatemeh Farhid, Farshad Heydari, Michael R Hamblin, Saman Masoudifar, Amirhossein Sahebkar, Jalal Naghinezhad.

  Mitochondria have traditionally been regarded as intracellular powerhouses; however, they are now recognized as dynamic intercellular signaling organelles capable of moving between cells to coordinate tissue adaptation and repair. This Review examines the emergence of mitochondria transfer as a fundamental mechanism of cardiovascular communication, integrating current evidence for the exchange of intact mitochondria, mitochondrial DNA, and mitochondrial components among cardiomyocytes, endothelial cells, vascular smooth muscle cells, fibroblasts, and immune cells. We discuss the major routes of mitochondria transfer, including tunneling nanotubes, extracellular vesicles, gap junction-associated pathways, and extracellular mitochondrial release, together with the molecular machinery governing mitochondrial trafficking, such as MIRO proteins, TRAK adaptors, and cytoskeletal motor complexes. By reshaping cellular bioenergetics, redox homeostasis, metabolic signaling, and innate immune responses, transferred mitochondria exert profound effects on cardiovascular homeostasis and disease, influencing ischemia-reperfusion injury, heart failure, vascular remodeling, and inflammatory vascular disorders. We further evaluate recent advances in mitochondria transplantation, engineered mitochondrial donor platforms, and emerging imaging technologies that enable tracking of mitochondrial fate in vivo. Finally, we propose an integrated mechanistic framework in which the biological consequences of mitochondria transfer and mitochondria transplantation are determined by donor-recipient compatibility, mitochondrial quality, and the surrounding microenvironment, thereby explaining their context-dependent protective, maladaptive, and immunomodulatory effects. By identifying critical gaps in molecular mechanisms, methodological standardization, and clinical validation, this Review outlines a roadmap for translating mitochondria-based therapeutic strategies into precision cardiovascular medicine.

Keywords:  Bioenergetics; Cardiovascular disease; Extracellular vesicles; Heart failure; Mitochondrial transfer; Mitochondrial transplantation; Regenerative cardiology

DOI:  https://doi.org/10.1016/j.cjca.2026.06.032
Paediatr Anaesth. 2026 Jul 07.

Perianesthetic Complications in Genetic Mitochondrial Disease: A Review of Case Reports.

Brittany M Johnson, Simon C Johnson.

   BACKGROUND: Genetic mitochondrial diseases (GMDs) are a large group of genetically and clinically heterogeneous disorders caused by defects in genes encoding mitochondrial components. GMDs are grouped into named syndromes based on clinical presentation, for example, Leigh syndrome (LS). Surgical interventions are often required in GMDs, necessitating the use of general anesthesia (GA). Some GMD animal models show both a marked reduction in anesthetic concentrations necessary for sedation and toxic sequelae resulting from anesthetic exposures. Hypersensitivity to sedation by anesthetic agents, most notably volatile anesthetic agents (VAs), occurs in a subset of GMD patients, and some evidence suggests toxicities are also present. Reported complications of anesthesia in GMD are varied, including minor metabolic changes, acceleration of underlying disease, and death. The potential toxicity of anesthetics in the setting of GMDs has recently been underscored by deaths among pediatric and young adult patients of Venezuelan descent putatively linked to a specific mitochondrial DNA haplotype. Interpretation of clinical findings is limited by the lack of a thorough review of case reports for anesthetic exposures in GMD patients. Here, we provide a comprehensive review of published case reports for GMD patients undergoing anesthetic exposures.
METHODS: Using search terms "anesthesia mitochondrial disease," "anesthesia mitochondrial disease case report," and "anesthesia Leigh syndrome" we identified case reports published up to May 2025. Non-English articles were translated and included where possible. Only reports of GMD patients undergoing GA with total intravenous anesthesia (TIVA) or VAs containing outcome information were included, totaling 148 cases from 123 reports. We examined relationships between complications and GA type, clinical diagnosis, perianesthetic drugs, procedure length and type, and general demographics. We performed a narrative review of clinical and pre-clinical literature.
RESULTS: Overall complication rate was significantly higher in VA versus TIVA cases (42% vs. 18%, Fisher's exact p-value **p = 0.0022), as was rate of severe complications (*p = 0.01). Encephalomyelopathies, including LS, were overrepresented among cases resulting in death. Complication rate has remained relatively stable over time. Sex and age were not associated with significant differences in complication rate. Complication rate varied significantly by procedure type, and severe complications were associated with procedure length. While not statistically significant, older VAs had higher complication rates than newer VAs. Similarly, older neuromuscular blockade agents may be less safe than newer drugs. N2O and ketamine were notably safe among drugs used in TIVA procedures.
CONCLUSIONS: Available case-report data support the notion that GMD patients are at increased risk of a variety of perianesthetic complications. Clinical symptoms and procedure length appear most strongly predictive of severe complications. Clinical and pre-clinical findings suggest more research is needed to understand the mechanisms of toxicity and more detailed reporting is needed in clinical case reports to identify potential risk factors.

Keywords:  anesthesia; anesthetic complications; anesthetic outcomes; anesthetic toxicity; mitochondrial diseases

DOI:  https://doi.org/10.1002/pan.70257
Autophagy. 2026 Jul 09.

NAD+ modulates REST isoform expression and its downstream mitophagy in Alzheimer's disease.

Maria J Lagartos-Donate, Beatriz Escobar-Doncel, Caroline Shi-Qi Zhang, Evandro Fei Fang.

  Repressor Element 1-Silencing Transcription factor (REST) emerges as a metabolism-sensitive transcriptional hub that supports basal mitophagy, mitochondrial quality, and synaptic function in neurons. In Alzheimer's disease, REST becomes mislocalized and functionally impaired, coinciding with early defects in mitochondrial quality control. Activation of the NAD+ -SIRT1 axis enhances REST nuclear activity, restores its mitochondrial and neuroprotective gene programs, and attenuates pathological and cognitive decline in experimental AD models. Our study highlights REST as a promising target to preserve mitochondrial and neuronal function.Abbreviations:Alzheimer's disease, AD; Repressor Element 1-Silencing Transcription factor, REST; Nicotinamide Adenine Dinucleotide, NAD+.

Keywords:  Alzheimer’s disease; NAD+; REST; SIRT1; transcriptional regulation

DOI:  https://doi.org/10.1080/15548627.2026.2701599
Mol Neurobiol. 2026 Jul 10. pii: 753. [Epub ahead of print]63(1):

SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.

Qingya Wu, Dengying Fan, Jianhui Ren, Yafang Xing, Zhengzheng Chen, Haochen Jin, Yisheng Lu, Xiaopeng Wang, Hua Zheng.

  Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.

Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Neurodegenerative diseases; SUMOylation

DOI:  https://doi.org/10.1007/s12035-026-06050-0
Front Immunol. 2026 ;17 1761658

The role of mitochondrial proteases in inflammation and immunity.

Anna Rebeka Oliveira Ferreira, Emily A Day.

  The global rise in chronic inflammatory and autoimmune disorders has intensified research to understand cellular stress response pathways that drive immune dysregulation. Mitochondria have emerged not only as central hubs of cellular metabolism but also as active modulators of immunity and inflammation. Mitochondrial proteases are essential regulators of mitochondrial protein quality control, dynamics, and stress responses. By selectively degrading misfolded or damaged proteins, they maintain mitochondrial function and bioenergetic capacity. Beyond housekeeping roles, mitochondrial proteases also influence immune signaling by modulating mitochondrial stress pathways, reactive oxygen species production, and the release of mitochondrial-derived danger signals. Dysregulation of these proteases has been linked to chronic inflammation and contributes to the pathogenesis of inflammatory diseases. This review summarizes current knowledge on the role of mitochondrial proteases CLPXP, LONP1, i-AAA, m-AAA, as well as processing peptidase OMA1, in immune cells and inflammatory pathologies. We explore the molecular mechanisms by which these mitochondrial proteases regulate immune signaling, integrating the results from immune cells as well as other non-immune cell types, including those involved in cancer, neurodegeneration, renal injury, and other inflammatory pathologies. We explore mitochondrial proteases function as context-dependent regulators of immunometabolic signaling, with effects shaped by cell type, metabolic state, and stress conditions. Finally, we discuss emerging small molecules and drugs targeting mitochondrial proteases to highlight their potential therapeutic role in modulating inflammation. By situating mitochondrial proteases at the crossroads of immunometabolism and therapeutic intervention, this review underscores their untapped potential in the development of innovative anti-inflammatory strategies.

Keywords:  MAVS; cGAS-STING; immune cells; inflammatory disease; innate immunity; macrophages; mitochondrial dysfunction; mtDNA

DOI:  https://doi.org/10.3389/fimmu.2026.1761658
Front Aging. 2026 ;7 1830839

Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.

Nengneng Shi, Xiaojing Li.

  Mitochondrial transcription factor A (TFAM) is a nuclear-encoded mitochondrial protein that directly binds mitochondrial DNA (mtDNA) and contributes to mitochondrial genome maintenance. Beyond its established roles in mitochondrial transcription, mtDNA packaging, nucleoid organization, replication support, and copy number control, TFAM is increasingly recognized as a potential regulator of aging-related mitochondrial stress responses. Because mtDNA instability, respiratory dysfunction, reactive oxygen species imbalance, impaired autophagy, cellular senescence, and chronic inflammation are closely interconnected during aging, TFAM may occupy a proximal position linking mitochondrial genome homeostasis to broader aging biology. However, TFAM should not be viewed as a uniformly protective factor. Its effects appear to depend on TFAM abundance, TFAM-to-mtDNA stoichiometry, tissue type, metabolic state, mitochondrial import, LONP1-mediated turnover, and mitochondrial quality-control capacity. TFAM deficiency may compromise mtDNA maintenance, impair oxidative phosphorylation, increase mitochondrial ROS production, and promote mtDNA-driven innate immune activation. Conversely, excessive or dysregulated TFAM accumulation may lead to mtDNA hypercompaction, reduce mtDNA accessibility, and potentially produce maladaptive effects in specific disease contexts. In this review, we discuss the structural basis of TFAM-mtDNA interaction, the role of TFAM in mtDNA transcription, copy number control, genome protection, damage handling, inflammatory signaling, cellular senescence, systemic aging, and age-related diseases. We also highlight therapeutic opportunities, limitations, and unresolved questions, emphasizing that future strategies should aim to restore TFAM homeostasis rather than simply increase TFAM expression.

Keywords:  age-related disease; aging; inflammation; mitochondria; mitochondrial transcription factor A; oxidative stress

DOI:  https://doi.org/10.3389/fragi.2026.1830839
Neurosci Bull. 2026 Jul 07.

Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.

Guanqin Ma, Erlin Wang, Xiaoxu Yan, Xiang-Xiong Xu, Xiaohong Li, Xueling Ma, Wan-Hua Yang, Jianxiong Zeng, Xiaochun Xie.

  Mitochondrial dysfunction induces metabolic dysregulation in immune cells that is etiologically associated with age-related brain disorders. However, how dysfunctional mitochondria in microglia-the brain-resident immune cells-initially affect neurological function remains incompletely understood. Here, we demonstrate that dysfunctional mitochondria in microglia, induced by the conditional knockout of mitochondrial transcription factor A, act as triggers of metabolic dysregulation, cognitive aging, and neurodegeneration in adult mice. Notably, this metabolic disturbance induces a microglial transition to states associated with neuroinflammatory activation and neurodegenerative disease, thereby triggering multiple layers of pathological cascade reactions among other brain cell types and shaping a neuroinflammaging state at single-cell resolution. Mechanistically, mitochondrial dysfunction activates the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which mediates immune sensing of cytosolic DNA in microglia and contributes to inflammaging. We further present evidence that combined treatment aimed at restoring metabolic homeostasis and inhibiting neuroinflammatory cGAS-STING partially rescues age-related neurological dysfunction in mice. Collectively, our findings reveal a link between mitochondrial dysfunction in microglia and cognitive aging, underscoring the significance of tightly regulated metabolism in age-associated neurological diseases.

Keywords:  Microglia; Mitochondrial dysregulation; Neurodegeneration; Neuroinflammaging; cGAS–STING

DOI:  https://doi.org/10.1007/s12264-026-01657-8
Cureus. 2026 Jun;18(6): e110551

Late-Onset Leber Hereditary Optic Neuropathy: A Report of a Case and Review of the Literature.

Víctor J Altares, María Castro Rebollo, Julio González Martín-Moro.

  Leber hereditary optic neuropathy (LHON) constitutes a mitochondrial disorder characterized by subacute, bilateral central vision impairment, secondary to mitochondrial DNA (mtDNA) mutations. These mutations compromise Complex I, subsequently precipitating the degeneration of retinal ganglion cells (RGCs). While traditionally manifesting in young males, contemporary literature has documented a small number of cases of late-onset presentation. Numerous studies have suggested the existence of a distinct clinical phenotype, particularly concerning the funduscopic features of the optic disc. Elucidating this atypical manifestation is paramount to preclude diagnostic inaccuracies and to refine therapeutic intervention. In this context, we describe the case of a 70-year-old male presenting with progressive bilateral vision loss and diffuse thinning of the ganglion cell complex on optical coherence tomography (OCT), notably lacking the hyperaemic phase typical of younger patients. Genetic analysis confirmed the homoplasmic m.14484T>C mutation; however, despite the traditionally favourable prognosis associated with this variant, the patient progressed to permanent optic atrophy with no functional recovery. By reporting this case of late-onset LHON and providing a comprehensive review of clinical cases documented in recent literature, our objective is to ascertain whether late-onset presentation endows this clinical entity with additional distinguishing characteristics.

Keywords:  age-related; case report; late-onset; leber hereditary optic neuropathy; lhon; mitochondrial disease; optic disc findings; senile

DOI:  https://doi.org/10.7759/cureus.110551
Nat Biotechnol. 2026 Jul 10.

Efficient in vivo cytosine base editing using virus-like particles with uracil DNA glycosylase inhibition.

Junjie Zhu, Lin Ding, Kai-Ming Liu, Xingyu Zhu, Jifang Li, Buer Ha, Bao-Qing Gao, Xujiao Zhou, Chengfang Liu, Jia Wei, Shuangyu Ma, Wenchao Xu, Lingyun Kong, Jing Wu, Xiaodun Mou, Bei Yang, Lijie Wang, Jiaxu Hong, Li Yang, Jia Chen.

Virus-like particles (VLPs) are promising for delivering genome editors, yet the in vivo in vivo efficacy of VLP-mediated cytosine base editing remains limited. Here we identified insufficient inhibition of uracil DNA glycosylases as the underlying mechanism of low cytosine base editor (CBE) editing efficiencies in vivo. We engineered a previously reported CBE, transformer base editor (tBE), and developed a VLP delivery system to enhance the recruitment of uracil DNA glycosylase inhibitor proteins. tBE-VLPs achieved robust C-to-T editing in mouse liver and retina. A single injection achieved, on average, 46.0% editing at mPcsk9 and 64.2% at mHpd in the liver, as well as 24.2% at mVegfa in the retinal pigment epithelium, resulting in marked therapeutic benefits in mouse disease models. tBE-VLP4 induced no detectable off-target edits in vitro or in vivo and demonstrated superior specificity compared to AAV or lipid nanoparticle mRNA delivery. Our work establishes tBE-VLP4 as a precise, efficient system for in vivo cytosine base editing.

DOI: https://doi.org/10.1038/s41587-026-03227-9
Hum Gene Ther. 2026 Jul 09. 10430342261466685

AAV.hBAG3 Gene Therapy Improves Phenotype in a Valosin Containing Protein Mouse Model of Hereditary Inclusion Body Myositis.

Burcak Ozes, Lingying Tong, Morgan Myers, Kyle Moss, Edward Son, Tatyana A Vetter, Gabriela Vasquez-Martinez, Diana Zepeda-Orozco, Zarife Sahenk.

  Mutations in the valosin-containing protein (VCP) gene lead to a hereditary type of inclusion body myositis (hIBM), in which sarcoplasmic and myonuclear inclusions with TAR DNA-binding protein 43 (TDP-43) pathology and mitochondrial abnormalities are observed in histological analysis. Pathophysiological conditions in the cell cause the protein quality control system to depend on the autophagy-lysosome pathway (ALP) for degradation of accumulated misfolded proteins and mitochondrial turnover. BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP. Our aim was to ameliorate disease processes resulting from mitochondrial abnormalities and misfolded protein aggregation by upregulating the ALP through overexpression of human BAG3 (hBAG3). The VCP-A232E mouse, a model for hIBM, received AAVrh74.tMCK.hBAG3 systemically at 3 months of age, and outcome measures, including functional, histological, and molecular studies, were assessed 9 months post-gene delivery. hBAG3 treatment improved treadmill running distance and rotarod duration, reduced the number of TDP-43-positive aggregates, and decreased the number of fibers showing abnormalities in mitochondrial enzyme histochemistry, compared with the untreated cohort. Moreover, hBAG3 gene therapy resulted in improvements in mitophagy and mitochondrial homeostasis observed as increased levels in mitophagy markers Parkin and Bnip3, mitochondria biogenesis marker Pgc1α and mitochondrial DNA-encoded subunits of complex IV, Cox1 and Cox3. In addition, the LC-II/I ratio increased, indicating increased autophagic flux. Our study presents evidence that the strategy of supporting the ALP system by overexpressing BAG3 has potential therapeutic use for myodegenerative conditions associated with abnormal protein aggregates and mitochondrial turnover.

Keywords:  BAG3; IBM; VCP; autophagy; mitophagy

DOI:  https://doi.org/10.1177/10430342261466685
Cell Rep. 2026 Jul 09. pii: S2211-1247(26)00693-5. [Epub ahead of print]45(7): 117615

ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.

Anastasia Chugunova, Isabelle Schütz, Hannah Keresztes, Roksolana Kobylinska, Maria Novatchkova, Thomas Lendl, Marcus Strobl, Jörg Fallmann, David Márquez Oller, Michael Schutzbier, Gerhard Dürnberger, Richard Imre, Elisabeth Roitinger, Phylicia Kidd, Pawel Pasierbek, Alberto Moreno Cencerrado, Marlene Brandstetter, Thomas Köcher, Benedikt Agerer, Jakob-Wendelin Genger, Andreas Bergthaler, Andrea Pauli.

  Increased mitochondrial activity is essential for embryo development. Although conserved across organisms, the molecular basis of this increase is unknown, as detailed biochemical analysis in vertebrates is hampered by the limited availability of material. Using zebrafish as a model for vertebrate development, we comprehensively profile mitochondrial activity, morphology, metabolome, proteome, and phospho-proteome, as well as respiratory chain activity. Our data show that the mitochondrial proteome undergoes major changes during embryogenesis. While respiratory chain complex levels remain largely constant, we identify a marked increase in mitochondrial-ER association during early embryogenesis. Moreover, time-lapse imaging of mitochondrial dynamics reveals a transition from fragmented to elongated mitochondria starting during somitogenesis. Overall, our systematic profiling of the molecular and morphological changes of mitochondria during embryogenesis provides a valuable resource for further investigation of mitochondrial function. Our study reveals that increased mitochondrial-ER interaction and changes in mitochondrial morphology may contribute to its regulation during vertebrate development.

Keywords:  CP: cell biology; CP: developmental biology; ER-mitochondrial interaction; metabolism; mitochondria; mitochondrial activation; proteomics; vertebrate embryogenesis; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2026.117615
CNS Neurosci Ther. 2026 Jul;32(7): e71013

Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.

Zou Pan, Li Yang, Haiyan Tang, Chen Chen, Qian Yang, Tenghui Wu, Fang He, Zhanwei Zhang, Fangyun Liu, Jing Peng.

   AIM: To delineate the clinical features of AFG3L2-related developmental and epileptic encephalopathy (DEE) and explore its pathogenic mechanisms.
METHODS: Whole-genome and blood transcriptome sequencing were performed in undiagnosed DEE patients. Patient-derived skin fibroblasts were established for the analysis of RNA and protein expression as well as for mitochondrial functional assays, including OPA1 processing, mtDNA copy number, membrane potential, ATP production, mitochondrial morphology analysis, and mitochondrial stress testing. Additionally, published AFG3L2-related epilepsy cases were systematically reviewed.
RESULTS: We identified four novel AFG3L2 variants in four DEE patients from two unrelated families, including splice-site/intronic variants in one family and exon-deletion/intronic variants in the other, fitting a recessive model of disease. In these patients, plus six additional previously reported DEE patients, symptoms included severe developmental delay, intractable seizures, microcephaly, generalized spasticity, and progressive cerebral atrophy. Transcriptome and fibroblast functional analyses revealed aberrant splicing, reduced AFG3L2 expression, defective OPA1 processing, decreased mtDNA content, impaired membrane potential and ATP production, fragmented mitochondrial networks, and diminished respiratory capacity, supporting a loss-of-function mechanism. Compared with spastic ataxia 5-usually involving null-missense or missense-missense genotypes-DEE predominantly features null-null combinations.
SIGNIFICANCE: We implicate AFG3L2 as a novel causative gene for DEE, likely through mitochondrial proteostasis failure and bioenergetic compromise, expanding the phenotypic and genotypic spectrum of AFG3L2-related disorders.

Keywords:   AFG3L2 ; developmental and epileptic encephalopathy; genomic and transcriptomic sequencing; mitochondrial dysfunction; m‐AAA protease

DOI:  https://doi.org/10.1002/cns.71013
Mol Cell. 2026 Jul 09. pii: S1097-2765(26)00415-6. [Epub ahead of print]

The UFSP2-ODR4 complex spatially confines and dynamically controls UFM1 deconjugation to safeguard neuronal proteostasis.

Gaoxin Mao, Sota Ito, Ryosuke Ishimura, Jun-Ichi Sakamaki, Ryohei Sasaki, Takefumi Uemura, Kei-Ichi Ishikawa, Satoko Komatsu-Hirota, Wado Akamatsu, Manabu Abe, Satoshi Waguri, Sunita Bijarnia-Mahay, Nobuo N Noda, Toshifumi Inada, Masaaki Komatsu.

  The ubiquitin-fold modifier 1 (UFM1) pathway is essential for endoplasmic-reticulum-associated ribosome quality control (ER-RQC) through UFMylation of the 60S ribosomal protein RPL26, but the regulation and physiological significance of UFM1 deconjugation remain poorly understood. Here, we identify the ER-anchored UFSP2-ODR4 complex as a spatially confined deUFMylation module critical for neuronal proteostasis. Structural modeling and biochemical analyses show that ODR4 recruits UFSP2 to the ER, enabling efficient deUFMylation of RPL26. Disruption of the UFSP2-ODR4 interaction causes the accumulation of UFMylated RPL26 and defective ER-RQC. Neural progenitor-specific knockin mice expressing a catalytically inactive UFSP2 mutant exhibit perinatal lethality, microcephaly, and neuronal apoptosis. We also identify a patient with biallelic UFC1 mutations that enhance UFL1 binding and induce hyper-UFMylation of RPL26 in patient-derived neurons. These findings establish spatially confined deUFMylation as a critical mechanism for safeguarding neuronal proteostasis.

Keywords:  ER-RQC; ODR4; UFC1; UFM1; UFSP2; endoplasmic-reticulum-ribosome quality control; neurodevelopmental disorders; neuronal proteostasis; ribosomal protein RPL26

DOI:  https://doi.org/10.1016/j.molcel.2026.06.026
J Inherit Metab Dis. 2026 Jul;49(4): e70222

Biallelic Loss-Of-Function Variant in ATP5ME Is Associated With Severe and Early Onset Oxidative Phosphorylation Deficiency.

Pranavi Hegde, Aakanksha Anand, Rita Rani, Namanpreet Kaur, Ami Shah, Shilpa Kulkarni, Janani Supraja Mallavaram, Raghavender Medishetti, Amoolya Kandettu, Huzail Shaikh, Shahyan Siddiqui, Purvi Majethia, Vivekananda Bhat, Periyasamy Radhakrishnan, Aarti Sevilimedu, Sanjiban Chakrabarty, Anju Shukla.

  ATP synthase (complex V) catalyzes ATP synthesis and is composed of the F1 catalytic sector and the F0 proton-conducting sector. The e subunit of the F0 sector, encoded by ATP5ME, is essential for complex V dimerization and cristae organization; however, genetic variants in ATP5ME have not yet been implicated in human disease. We ascertained a 4-year-old male, born of a consanguineous marriage, who presented with neuroregression, feeding difficulty, spasticity, encephalopathy, bilateral sensorineural hearing loss and optic atrophy. Exome sequencing identified a biallelic 62 bp deletion, c.-48_14del in ATP5ME (NM_007100.4; NC_000004.12: g.674234_674295del), spanning the upstream sequence, the 5' untranslated region, and part of exon 1. Patient-derived fibroblasts exhibited markedly decreased ATP5ME transcript and protein levels, accompanied by a reduction in the expression of complex I, IV, and V subunits. In vitro assays demonstrated reduced activities of complexes I, IV, and V, impaired mitochondrial respiration, reduced reactive oxygen species levels, decreased mitochondrial membrane potential, and reduced ATP levels. Additionally, atp5me knockout zebrafish demonstrated a severe developmental phenotype characterized by craniofacial defects, reduced locomotion, and decreased ATP levels. This was accompanied by reduced protein levels of complex II and IV subunits, mild decrease in mtDNA, and upregulation of genes associated with glycolysis and oxidative stress. All observed phenotypes were rescued by human ATP5ME mRNA complementation, thereby validating the pathogenicity of ATP5ME deficiency in vivo.

Keywords:   ATP5ME ; ATP synthase; OXPHOS; complex V deficiency; mitochondrial bioenergetics; mitochondrial encephalopathy; oxidative phosphorylation; subunit e; zebrafish

DOI:  https://doi.org/10.1002/jimd.70222
Transl Neurodegener. 2026 Jul 08. pii: 30. [Epub ahead of print]15(1):

Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.

Yun Teng, Chao Luo, Qingbo Xu, Jingyao Mu, Lucy Teng, Hongjia Qian, Yinan Huang, Minmin Liu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Maiying Kong, Jun Yan, Michael L Merchant, Huang-Ge Zhang.

   BACKGROUND: Intercellular mitochondrial transfer is pivotal in both healthy and pathological states. Supplementing healthy mitochondria is emerging as a promising therapeutic approach for various diseases. Non-immunogenic edible plants, which contain mitochondria, offer a novel avenue for such therapies.
METHODS: Mitochondria were isolated from several commonly consumed edible plants (P-Mit) using differential centrifugation followed by sucrose gradient ultracentrifugation. The distribution of P-Mit, particularly in the brain, was examined with a mitochondrial membrane-potential dye and an imaging system. As a proof of concept, the molecular interactions underlying turmeric-derived mitochondria (T-Mit) uptake by microglia were elucidated through affinity precipitation coupled with mass spectrometry. By labeling with gold-nanoparticles in a distinct triangular or spherical shape followed by electron microscopy and energy dispersive spectroscopy analysis, we demonstrated the physical fusion of T-Mit and animal mitochondria in microglia. Mitochondrial functions such as superoxide levels, ATP-linked mitochondrial respiration, glycolysis and electron transport chain activity were assessed to determine the impact of T-Mit on aging-related microglial dysfunction. Next-generation small RNA sequencing revealed the underlying mechanism by which T-Mit-derived small RNAs modulate the expression of NADH dehydrogenase (ND) genes in microglia.
RESULTS: Orally administered T-Mit travelled from the gut to the brain in aged male mice, where they fused with microglial mitochondria (M-Mit), reprogramming M-Mit energy metabolism and reversing aging-related cognitive dysfunction. Specifically, T-Mit was taken up by microglia via the phagocytic receptor TREM2. Subsequently, T-Mit fused with M-Mit in a mitofusin 1-dependent manner. The T-Mit microRNAs Tae-miR319 and Osa-miR166a-3p then integrated into M-Mit, inhibiting the expression of complex I subunits ND4 and ND5. This inhibition alleviated reverse electron transport (RET) at complex I, reducing reactive oxygen species (ROS) production and facilitating ATP production, ultimately rescuing aging-related cognitive decline. Data from elderly human subjects also showed overactivation of the RET process and overproduction of ROS, accompanied by low ATP levels in microglia.
CONCLUSIONS: Our findings fundamentally alter our understanding of the regulation of mammalian mitochondrial biology by P-Mit and may lead to P-Mit-based transfer therapy for preventing or treating human mitochondrial disorder-related diseases.

Keywords:  Aging-related neurodegeneration; Cardiolipin; Cross-kingdom mitochondrial fusion; Microglia mitochondrial metabolism; Mitochondria transfer therapy; NADH dehydrogenase (Complex I); Plant mitochondrial microRNAs; Plant mitochondria; Reactive oxygen species (ROS); Reverse electron transport (RET)

DOI:  https://doi.org/10.1186/s40035-026-00565-1
Mol Neurobiol. 2026 Jul 10. pii: 755. [Epub ahead of print]63(1):

The Role of PGC-1α in Neurodegenerative Diseases: Molecular Mechanisms, Translational Challenges, and Therapeutic Potential.

Yang You, Daxin Duan, Qian Xiang.

  Neurodegenerative diseases (NDDs) are progressive disorders in which mitochondrial dysfunction, oxidative stress, proteostasis failure, neuroinflammation, and synaptic damage progressively interact to drive neuronal vulnerability. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) links metabolic adaptation to stress-response pathways that are repeatedly disrupted in Alzheimer's disease, Parkinson's disease, Huntington's disease, polyglutamine (PolyQ) disorders, and amyotrophic lateral sclerosis. Rather than providing only an updated catalogue of studies, this review organizes the evidence into a cross-disease rheostat framework that explains why PGC-1α modulation is protective in some settings but incomplete or maladaptive in others. Current findings indicate that PGC-1α supports mitochondrial biogenesis, oxidative phosphorylation, antioxidant defense, mitophagy, autophagy, protein quality control, and inflammatory balance. However, its effects are highly context dependent. In several models, restoration of PGC-1α-related signaling improves mitochondrial function and reduces neuronal injury, whereas broad, sustained, or cell-inappropriate activation may produce limited benefit or undesirable outcomes. These observations suggest that PGC-1α is not a simple neuroprotective switch, but a flexible regulatory hub whose therapeutic value depends on cell type, isoform profile, disease stage, and activation level. Emerging strategies, including small-molecule modulators, gene delivery, antisense-based approaches, nanoparticle systems, and exercise-related interventions, remain largely preclinical and face major barriers related to CNS delivery, pathway selectivity, dose and cell-type control, peripheral safety, and validated target-engagement biomarkers. Nevertheless, clinical translation requires stronger causal validation, reliable target-engagement biomarkers, selective delivery methods, and long-term safety assessment. Future research should focus on precision-based modulation of PGC-1α to determine when and how this pathway can be safely used for disease modification. Such a careful approach may help transform PGC-1α from a broad experimental target into a clinically relevant strategy for well-defined neurodegenerative phenotypes.

Keywords:  Alzheimer’s disease; Neurodegenerative diseases; PGC-1α; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-026-06029-x
Nat Commun. 2026 Jul 08.

A metabolite-bridged complex between SerRS and SIRT2 couples NAD⁺ metabolism to translation control.

Qian Zhang, Huimin Zhang, Marscha Hirschi, Sheng Li, Gabriel C Lander, Jie Yang, Xiang-Lei Yang.

Cellular homeostasis requires tight coordination between metabolic and translational networks. Here we identify a direct molecular link between these processes through a cryo-EM structure of human cytosolic seryl-tRNA synthetase (SerRS) in complex with the NAD⁺-dependent deacetylase SIRT2. This interaction is promoted by the NAD⁺ metabolite ADP-ribose (ADPR), which acts as a molecular bridge between the two enzymes. Within the SIRT2 active site, ADPR engages SerRS residue K414 located in a flexible catalytic-domain loop. Acetylation of K414 is dispensable for binding. Functionally, complex formation inhibits SIRT2 deacetylase activity by blocking substrate access, while SIRT2 association suppresses SerRS aminoacylation activity by preventing tRNA binding. Thus, SerRS and SIRT2 mutually regulate each other, with ADPR enhancing while tRNA attenuating their interaction. Oxidative stress promotes this interaction via a PARP1-dependent pathway, revealing an ADPR-responsive regulatory module that couples metabolic state to translational output. This regulatory module is likely conserved across vertebrates.

DOI: https://doi.org/10.1038/s41467-026-75266-4
Front Pharmacol. 2026 ;17 1851846

Remodeling of the mitochondrial quality control network: natural products intervening in diabetic retinopathy.

Tingru Chen, Ruolan Wu, Xinyi Liu, Yutong Jiang, Qun Huang, Ninghui Wan.

  Diabetic retinopathy (DR) remains a leading cause of vision loss among working-age adults. Its pathogenesis is increasingly understood as the progressive dysregulation of the mitochondrial quality control (MQC) network, which encompasses mitochondrial dynamics, mitophagy, mitochondrial biogenesis, mitochondria-associated endoplasmic reticulum membranes (MAMs), and intercellular mitochondrial transfer. Under sustained hyperglycemia, this network shifts from compensatory imbalance to irreversible collapse, driving mitochondrial dysfunction, oxidative stress, inflammatory activation, and retinal neurovascular unit (NVU) injury, thus promoting progression from non-proliferative to proliferative DR. Because of their multitarget properties, natural products (NPs) can restore fusion-fission balance, modulate mitophagy in a stage-dependent manner, and promote mitochondrial biogenesis, thereby remodeling the MQC network. However, their clinical translation is constrained by low bioavailability, poor penetration of the blood-retinal barrier (BRB), and potential dose-dependent toxicity. Mitochondria-targeted nano-delivery systems, including liposomes, exosomes, and mitochondrial-derived vesicles, may improve retinal accumulation and mitochondrial targeting. Future studies should refine stage-specific mechanistic understanding, strengthen safety evaluation and structural optimization, and integrate single-cell omics with artificial intelligence to accelerate translation and enable early MQC-targeted intervention, with the potential to delay or even reverse the progression of DR. Critically, MQC-directed NP therapy should not be interpreted as uniformly pro-mitophagy, anti-fission, or pro-biogenesis; the therapeutic benefit depends on disease stage, cell type, autophagic flux integrity, target engagement, and retinal pharmacokinetic/pharmacodynamic exposure.

Keywords:  diabetic retinopathy; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; natural products

DOI:  https://doi.org/10.3389/fphar.2026.1851846
Mov Disord Clin Pract. 2026 Jul 10.

Precision Medicine in Neurodegeneration with Brain Iron Accumulation (NBIA) Disorders: An Update on Emerging Treatments.

Susanne A Schneider, Divyani Garg, Vassilena Iankova, Thomas Klopstock.

   BACKGROUND: Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of heritable, mostly recessive, progressive neurodegenerative diseases characterized by iron deposition in the basal ganglia and brainstem. There are no solid global epidemiological data on prevalence and incidence of NBIA subtypes, but registry data and expert opinion suggest PKAN, BPAN, PLAN, and MPAN are the most common subtypes. NBIA disorders present with a wide spectrum of clinical symptoms, including movement disorders (dystonia, parkinsonism, chorea), pyramidal involvement (eg, spasticity), speech and cognitive deficits, motor and cognitive slowing, and ocular abnormalities. Treatment remains symptomatic, though several new drugs are in development.
OBJECTIVES AND METHODS: Following our review published in 2021, this article provides an updated summary of recent developments. We discuss the rationale of new compounds, summarize clinical trials or-in their absence-preclinical studies for NBIA subtypes. The article is divided into two sections: one section on general approaches based on the shared feature of increased iron in the brain; and the second section on tailor-made, mechanistic treatments for the various NBIA subtypes targeting the specific molecular and cellular pathways of the affected enzyme including gene therapy.
RESULTS AND CONCLUSIONS: In summary, randomized controlled trials in NBIA have not yet demonstrated substantial benefit, neither for iron removal, in general, which appears to be clinically ineffective in most subtypes, except aceruloplasminemia; nor for subtype-specific approaches. Several ongoing studies are exploring more dedicated compounds in this exciting field.

Keywords:  NBIA; PKAN; PLAN; disease‐modifying; precision medicine

DOI:  https://doi.org/10.1002/mdc3.70736
Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2529208123

Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.

Stefano Bettinazzi, Avishikta Chakraborty, Finley Grover-Thomas, Damian K Dowling, M Florencia Camus.

  Mitochondrial decline is a hallmark of ageing, yet the role of intergenomic compatibility in shaping ageing trajectories remains poorly understood, particularly in an ecologically relevant framework. Hormetic interventions have been proposed as strategies to modulate metabolism and lifespan, but it is unknown how this operates in the context of mitonuclear discordance. Here, we demonstrate that mitonuclear mismatch accelerates age-related mitochondrial decline, elevates reactive oxygen species production, and shortens lifespan. Strikingly, early-life mitochondrial stress induced by dietary modulation counteracts these effects, promoting mitochondrial homeostasis and longevity. Our findings reveal mitonuclear interactions shaping ageing trajectories in natural populations and provide unique evidence that targeted interventions can act as a buffer against the detrimental impact of genetic discordance.

Keywords:  Drosophila; ageing; mitochondrial metabolism; mitohormesis; mitonuclear discordance

DOI:  https://doi.org/10.1073/pnas.2529208123