bims-mitmed 2026-08-16 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–08–16
fourteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Management of patients with thymidine kinase 2 deficiency: where are we now?
Exploring Heteroplasmic Variants in mtDNA: Insights from Single-Cell Transcriptomics.
Physiologically Regulated Frataxin Gene Replacement Restores Neurological Function in a Mouse Model of Friedreich Ataxia.
Regulation and roles of mammalian mitophagy.
From Common Pathway to Divergent Diseases: Metabolic Aspects of Inborn Errors of CoA Biosynthesis.
The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
Polyunsaturated fatty acid sequestration protects against mitochondrial dysfunction-induced ferroptosis.
Adaptation of OXPHOS biogenesis to cellular requirements.
Polystyrene nanoplastics induce fetal growth restriction via a novel NMNAT3 depletion cascade disrupting placental mitochondrial energetics and activating ferritinophagic ferroptosis.
Mitochondrial respiratory supercomplexes associated with longevity in mammals.
Isolation, Purification, and Characterization of Functional Mitochondria Derived from Mouse Skeletal Muscle for Mitochondrial Transplantation.
AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.
Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions.
Design and development of lipid nanoparticle formulations for brain gene therapy.

Expert Opin Pharmacother. 2026 Aug 15.

Management of patients with thymidine kinase 2 deficiency: where are we now?

Cristina Domínguez-González.



Keywords:  TK2 deficiency; doxecitine; doxribtimine; mitochondrial DNA depletion syndrome; mitochondrial myopathy

DOI:  https://doi.org/10.1080/14656566.2026.2720613
Cells. 2026 Aug 03. pii: 1403. [Epub ahead of print]15(15):

Exploring Heteroplasmic Variants in mtDNA: Insights from Single-Cell Transcriptomics.

Marco Barresi, Ivano Di Meo, Alessia Nasca, Eleonora Lamantea, Andrea Legati, Daniele Ghezzi.

  Mitochondrial DNA (mtDNA) heteroplasmy, which is the coexistence of wild-type and mutant mtDNA variants within the same cell, plays a critical role in modulating cellular phenotypes, disease severity, and penetrance. Bulk RNA sequencing cannot detect cell-to-cell heteroplasmy variability, limiting our understanding of the pathological mechanisms of mtDNA variants. In this study, we leveraged single-cell RNA sequencing (scRNA-seq) combined with a robust bioinformatics pipeline to characterize mtDNA heteroplasmy. We employed four fibroblast lines from patients harboring heteroplasmic mtDNA pathogenic variants in genes encoding respiratory complex I subunits. While RNA heteroplasmy corresponded to DNA-based measurements at the bulk level, single-cell analysis uncovered a diverged distribution in three out of four lines: most cells had near-homoplasmic (wild-type or mutant) mtDNA, with few cells showing intermediate levels. Furthermore, we found that high mutation levels correlate with transcriptional profile changes, although these responses were highly sample-specific, suggesting that the nuclear background and cellular context critically influence mitochondrial dysfunction and compensatory mechanisms. Our findings highlight the potential of single-cell technologies to better understand the complex link between mtDNA genetic diversity and mitochondrial phenotypic variability and to study crucial aspects of mitochondrial biology and pathology, such as clonal dynamics, at single-cell resolution.

Keywords:  heteroplasmy; mitochondrial DNA; mtDNA variant; single-cell transcriptomics

DOI:  https://doi.org/10.3390/cells15151403
Hum Gene Ther. 2026 Aug 09. 10430342261474315

Physiologically Regulated Frataxin Gene Replacement Restores Neurological Function in a Mouse Model of Friedreich Ataxia.

Federica Pilotto, Laure Dall'Agnol, Laurence Reutenauer, Marie Paschaki, Hélène Puccio.

  Friedreich ataxia (FA) is a progressive neurodegenerative disorder caused by reduced expression of frataxin (FXN), a mitochondrial protein essential for iron-sulfur (Fe-S) cluster biogenesis. Although gene therapy strategies aimed at restoring FXN have shown promise, excessive expression can lead to mitochondrial dysfunction, emphasizing the importance of maintaining FXN within a physiological range. Here, we evaluated a gene therapy approach based on a human mini-frataxin construct (miniFXN7) incorporating an endogenous regulatory element to enable controlled FXN expression. The construct was delivered systemically using an AAV-PHP.eB vector in the Pvalb-cKO mouse model of FA. MiniFXN7 treatment resulted in widespread neuronal transduction and restoration of FXN expression toward a near-physiological range in the neuronal populations examined. Treated mice exhibited sustained improvements in motor coordination and proprioceptive function, including normalization of H-reflex responses. At the cellular level, miniFXN7 restored succinate dehydrogenase activity, a mitochondrial Fe-S enzyme, and was associated with partial normalization of mitochondrial morphology. In parallel, neuronal integrity was preserved and astrogliosis reduced across the cerebellum. These findings demonstrate that physiologically regulated FXN replacement is sufficient to achieve substantial functional rescue in FA, supporting a gene therapy strategy based on a transgene expression driven by endogenous regulatory elements.

Keywords:  Friedreich ataxia; Pvalb-cKO mouse; gene therapy; miniFXN7

DOI:  https://doi.org/10.1177/10430342261474315
Nat Rev Mol Cell Biol. 2026 Aug 14.

Regulation and roles of mammalian mitophagy.

Sascha Martens, Ian G Ganley.

Mitochondria are essential metabolic and signalling hubs exposed to stress, and mitochondrial damage is highly detrimental to the cell. Mitophagy - the autophagy of mitochondria - is a key mechanism that maintains both mitochondrial integrity and metabolic flexibility. Mitophagy occurs via multiple pathways that either involve activation of PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin, or are independent of PINK1 and Parkin. Recessive mutations in PINK1 and PKRN (the gene that encodes Parkin) cause early-onset Parkinson's disease and have provided key mechanistic insights into mitophagy. However, emerging findings indicate that mitophagy is also executed by other molecular routes. Despite these molecular advances in mitophagy characterization, the physiological roles of these pathways in mammals and the specific contexts or conditions in which they operate remain poorly defined. This Review summarizes current understanding of PINK1-Parkin-dependent and independent mitophagy pathways, highlighting mechanistic distinctions and coordinated regulation. We also examine physiological and pathological triggers of mitophagy, as well as the expanding therapeutic potential of targeting mitophagy in disease.

DOI: https://doi.org/10.1038/s41580-026-01012-9
J Inherit Metab Dis. 2026 Sep;49(5): e70239

From Common Pathway to Divergent Diseases: Metabolic Aspects of Inborn Errors of CoA Biosynthesis.

Ivano Di Meo, Yair Anikster, Valeria Tiranti, Arcangela Iuso.

  Coenzyme A (CoA) biosynthesis is a conserved, dynamically regulated pathway essential for mitochondrial energy production, fatty acid oxidation, lipid biosynthesis and protein acylation. Biallelic variants in PANK2, PPCS, PPCDC, and COASY cause rare inborn errors of CoA biosynthesis, associated with markedly different clinical phenotypes: PANK2 and COASY defects predominantly cause neurological disorders within or adjacent to the neurodegeneration with brain iron accumulation (NBIA) spectrum, whereas PPCS and PPCDC deficiencies present mainly as severe early-onset dilated cardiomyopathy. However, COASY variants can also cause pontocerebellar hypoplasia and riboflavin-responsive lipid storage myopathy. This review examines these four disorders from a metabolic perspective, integrating clinical features, experimental models, biochemical data and emerging therapeutic approaches. Current evidence indicates that disease pathogenesis cannot be explained only by global CoA depletion. Total CoA levels may be reduced in PPCS and PPCDC deficiency, but are often preserved under basal conditions in PKAN and COASY-related models. Instead, impaired compartment-specific CoA handling and failure to sustain CoA-dependent flux under increased metabolic demand are emerging as central pathogenic concepts. Perturbation of fatty acid handling, acyl-CoA/acylcarnitine balance, mitochondrial function, iron homeostasis, protein acylation and 4'-phosphopantetheinylation may contribute to tissue-selective vulnerability. Therapeutic strategies are therefore likely to require disease-specific approaches, including precursor bypass or PANK activation where pathway flux can be restored, early pantethine supplementation in cardiomyopathic forms, and downstream or gene-directed strategies for COASY-related disorders. Understanding CoA as a regulator of metabolic adaptability provides a unifying framework for interpreting both shared mechanisms and disease divergence.

Keywords:  COASY; PANK2; PPCDC; PPCS; coenzyme A (CoA); neurodegeneration with brain iron accumulation (NBIA)

DOI:  https://doi.org/10.1002/jimd.70239
Cells. 2026 Jul 29. pii: 1371. [Epub ahead of print]15(15):

The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.

Elena D Avdonina, Sergey I Kutsev, Aleksandr V Shestopalov.

  Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.

Keywords:  autophagy; fatty acid oxidation disorders; mitochondrial diseases; mitophagy; selective autophagy

DOI:  https://doi.org/10.3390/cells15151371
EMBO Rep. 2026 Aug 14.

Polyunsaturated fatty acid sequestration protects against mitochondrial dysfunction-induced ferroptosis.

Guillermo Puertas-Frías, María José Saucedo-Rodríguez, Kristýna Čunátová, Lukáš Alán, Patrik Hrbáč, Michal Knězů, Soňa Koníčková, Jakub Schimmer, Monika Krakovková, Marek Vrbacký, Tomáš Čajka, Ondřej Kuda, Erika Fernández-Vizarra, Massimo Zeviani, Hana Hansíková, Tomáš Honzík, Josef Houštěk, Petr Pecina, Tomáš Mráček, Alena Pecinová.

Impaired energy production is a hallmark of mitochondrial oxidative phosphorylation (OXPHOS) defects. However, secondary metabolic disturbances also represent an important trigger for pathologies originating from OXPHOS aberrations. Here we show that cells with OXPHOS deficiencies accumulate triacylglycerols enriched in polyunsaturated fatty acids (PUFAs), which are stored in lipid droplets. Sequestration of PUFAs is a critical component of a broader stress response, which also includes downregulation of cellular desaturases and upregulation of glutathione peroxidase 4 (GPX4). We demonstrate that this mechanism represents a physiologically relevant protective strategy, manifesting in cells under hypoxia and in immortalised fibroblasts derived from patients with primary mitochondrial complex IV deficiency. As a proof of principle, we observe elevated PUFA-enriched triacylglycerols in the plasma of patients with Myoclonic Epilepsy with Ragged Red Fibres (MERRF). Our findings reveal a novel protective mechanism against ferroptosis, which preserves membrane integrity when mitochondrial respiration is compromised.

DOI: https://doi.org/10.1038/s44319-026-00898-y
Protein Sci. 2026 Sep;35(9): e70763

Adaptation of OXPHOS biogenesis to cellular requirements.

Sven Dennerlein, Peter Rehling.

  Metabolic cues regulate the formation of the mitochondrial OXPHOS machinery. These regulatory processes are tightly linked to mitochondrial translation, proteolytic degradation of unassembled subunits, and the formation of supercomplexes, creating checkpoints at which nutrient availability, oxygen tension, and signaling pathways remodel OXPHOS content and activity. In particular, the cytochrome c oxidase (COX) assembly pathway is regulated at multiple steps of its biogenesis in response to cellular demands. COX consists of mitochondrially encoded catalytic core subunits and nuclear-encoded accessory subunits whose coordinated expression, cofactor insertion, and incorporation into the COX enzyme result in optimized electron transport capacity. Consequently, COX assembly depends on numerous dedicated factors and protein isoforms, many of which are expressed in a tissue-specific manner. Through these metabolically regulated processes, cells tune oxidative phosphorylation efficiency, limit reactive oxygen species production, and support context-specific metabolic programs in development, adaptation, and disease.

Keywords:  Cytochrome c Oxidase; OXPHOS; mitochondria

DOI:  https://doi.org/10.1002/pro.70763
Free Radic Biol Med. 2026 Aug 11. pii: S0891-5849(26)00999-8. [Epub ahead of print]255 744-762

Polystyrene nanoplastics induce fetal growth restriction via a novel NMNAT3 depletion cascade disrupting placental mitochondrial energetics and activating ferritinophagic ferroptosis.

Yijing He, Qinfeng Sun, Qianqian Yang, Hui Liu, Wenzhe Yang, Zhiyi Kong, Miaoyu Chen, Weihan Wang, Qiao Li, Shiqiang Ju.

  The escalating environmental prevalence of micro- and nanoplastics (NPs) poses a growing threat to maternal-fetal health, with the placenta being a particularly vulnerable interface. However, the precise metabolic mechanisms by which NPs compromise placental function and contribute to adverse pregnancy outcomes remain poorly understood. This study, employing untargeted metabolomics, reveals that gestational exposure to polystyrene nanoplastics (PS-NPs) severely disrupts placental nicotinamide (NAM) metabolism and impairs mitochondrial energetics. A key mechanistic discovery is the central role of NMNAT3, a mitochondrial NAD+ synthase. PS-NPs exposure downregulated NMNAT3, leading to NAD+ depletion, mitochondrial dysfunction, oxidative stress, and lipid peroxidation in trophoblasts, which collectively triggered ferritinophagy-mediated ferroptosis. Notably, NMNAT3 overexpression rescued these defects by suppressing ferritinophagy, limiting cytotoxic iron release, and inhibiting ferroptosis. Importantly, NAM, as a metabolic modulator, can inhibit ferroptosis and improve pregnancy outcomes by restoring NAD+ homeostasis. Collectively, our findings delineate a novel pathogenic axis wherein PS-NPs impair placental health via NMNAT3-dependent disruption of NAM metabolism and iron homeostasis, highlighting NAM supplementation as potential strategies to counteract nanoplastic-induced reproductive toxicity.

Keywords:  Ferroptosis; NAM metabolism; NMNAT3; Placenta; Polystyrene nanoplastics

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.010
Front Aging. 2026 ;7 1876149

Mitochondrial respiratory supercomplexes associated with longevity in mammals.

Shinichiro Suzuki, Kazuhiro Ikeda, Toshihiko Takeiwa, Kuniko Horie, Satoshi Inoue.

  Because of population aging and morbidity expansion, extending healthspan has become a global challenge and it is required to elucidate molecular mechanisms underlying aging and age-related diseases. Mitochondrial dysfunction is a hallmark of aging, characterized by impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and metabolic imbalance. Therefore, maintaining mitochondrial homeostasis is essential for healthspan. Mitochondrial respiratory chain complexes organize into higher-order assemblies known as supercomplexes (SCs), which enable to efficient energy or ATP production with repressed ROS generation. Notably, the assembly and stability of these SCs likely decline in aged mammals. In addition, factors such as COX7RP/SCAF1 and mitochondrial lipid cardiolipin have emerged as key regulators of SC assembly. In this review, we summarize the molecular assembly, physiological roles, and longevity implications of SC in healthy mammals. We further discuss emerging evidence supporting SC modulation as a potential strategy for promoting healthy aging.

Keywords:  OXPHOS; lifespan; longevity; mitochondria; supercomplex

DOI:  https://doi.org/10.3389/fragi.2026.1876149
J Vis Exp. 2026 Jul 21.

Isolation, Purification, and Characterization of Functional Mitochondria Derived from Mouse Skeletal Muscle for Mitochondrial Transplantation.

Lu Zhao, Ningning Da, Jing Wang, Shiping Chang, Lele Shi, Congcong Guan, Lei Tian, Taiqiang Dai.

Mitochondria are essential organelles that regulate energy metabolism, signal transduction, and cellular homeostasis in eukaryotic cells. Mitochondrial dysfunction contributes to the pathogenesis of numerous diseases and has prompted the development of mitochondrial transplantation as a regenerative therapeutic strategy. The successful application of mitochondrial transplantation depends on the availability of highly purified and functionally intact mitochondria. Skeletal muscle is a suitable donor source due to its high mitochondrial content, metabolic activity, and accessibility. This study established a standardized, reproducible protocol for the isolation, purification, and characterization of functional mitochondria from mouse skeletal muscle and evaluated their use in mitochondrial transplantation. The procedure consisted of two major stages. First, mitochondria were isolated from the skeletal muscle of C57BL/6 mice using trypsin digestion followed by differential centrifugation. Second, the isolated mitochondria were characterized to evaluate purity, ultrastructure, and functional activity. Mitochondrial purity was assessed by bicinchoninic acid (BCA) protein quantification and Western blot analysis. Ultrastructural integrity was examined by transmission electron microscopy. Functional activity was evaluated using JC-1 and mitochondrial fluorescent labeling together with measurements of oxygen consumption, ATP production capacity, and respiratory control ratio using a high-resolution respirometry system. The isolated mitochondria exhibited preserved membrane potential, intact ultrastructure, and stable respiratory activity, indicating suitability for downstream functional studies and mitochondrial transplantation applications.

DOI: https://doi.org/10.3791/71551
J Physiol Biochem. 2026 Aug 12. pii: 78. [Epub ahead of print]82(1):

AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.

Wenjing Song, Zhifei Ke.

  Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that links cellular energy stress with metabolic adaptation, autophagy, redox homeostasis, and cell fate decisions. Necroptosis is a regulated lytic form of cell death driven by receptor-interacting serine/threonine kinases 1 and 3 (RIPK1 and RIPK3), with mixed lineage kinase domain-like protein (MLKL) serving as the terminal executor. Increasing evidence suggests that AMPK modulates necroptosis through multiple interconnected mechanisms. AMPK directly phosphorylates RIPK1, thereby influencing necroptotic signaling in a context- and time-dependent manner. Through the AMPK-mTOR axis, AMPK also regulates autophagy and mitophagy, affecting inhibitory control of RIPK1 and autophagic turnover of RIPK3. In parallel, AMPK suppresses necroptosis through SIRT1- and PGAM5-related pathways, limiting necrosome assembly, mitochondrial dysfunction, and Drp1-dependent mitochondrial fission. AMPK further shapes reactive oxygen species (ROS)-associated necroptotic responses through downstream effectors, including mTOR and Nrf2. In this review, we summarize recent advances in the mechanisms by which AMPK regulates necroptosis and highlight unresolved questions, including the cell-type-specific roles of AMPK subunits, the contribution of additional autophagy regulators, the balance between mTORC1-dependent protective signaling and RIPK3 stability, and the in vivo relevance of the AMPK-SIRT1-PGAM5 axis. Clarifying this regulatory network may facilitate the development of therapeutic strategies for necroptosis-related diseases, including metabolic disorders, ischemia-reperfusion injury, and neurodegeneration. Collectively, the available evidence indicates that AMPK acts as a context-dependent regulator of necroptosis rather than a universally protective kinase.

Keywords:  AMPK; Autophagy; Mitochondrial fission; Mitophagy; Necroptosis; Oxidative stress

DOI:  https://doi.org/10.1007/s13105-026-01221-y
Cell. 2026 Aug 04. pii: S0092-8674(26)00821-4. [Epub ahead of print]

Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions.

Jessenya Mil, Jose A Soto, Abigail S Krall, Julia Peloggia, Sara Frigui, Olivia S Fong, Laila Sathe, Nedas Matulionis, Francesca Day, Linsey Stiles, Katrina P Montales, Daria J Azizad, Carlos E Gonzalez, Elisa Fazzari, Matthew X Li, Patricia R Nano, Antoni A Martija, Cesar A Perez-Ramirez, Claudia V Nguyen, Brittney Wick, Weihong Ge, Ryan L Kan, Madeline G Andrews, Maximilian Haeussler, Michael F Wells, Heather R Christofk, Aparna Bhaduri.

  Cortical development involves rapid progenitor expansion and cell diversification supported by tightly regulated metabolic programs, yet these programs remain largely uncharacterized in human development. Here, we generated a metabolic atlas of the early human cortex using primary tissue and stem cell-derived cortical organoids. We observed dynamic changes in core metabolic functions, including an unexpected increase in glycolysis and pentose phosphate pathway (PPP) activity during late neurogenesis. Manipulation of glucose availability in cortical organoids altered cell-type composition, increasing outer radial glia (oRG) and inhibitory neuron populations. Pharmacological and genetic inhibition of PPP enzymes recapitulated these cell fate changes. Ribose was sufficient to rescue radial glia (RG) gene expression changes, revert organoid cell-type composition, and restore levels of ATP and hypotaurine. These data identify a critical role for the PPP in modulating RG cell fate specification and generate a resource for future exploration of additional metabolic pathways in human cortical development.

Keywords:  cell fate; cortical development; cortical organoids; glycolysis; metabolism; metabolomics; neurodevelopment; pentose phosphate pathway; radial glia

DOI:  https://doi.org/10.1016/j.cell.2026.07.023
Mol Ther Nucleic Acids. 2026 Sep 08. 37(3): 103025

Design and development of lipid nanoparticle formulations for brain gene therapy.

Sarah B Thomson, Alissandra de Moura Gomes, Pardis Kazemian, Daniel Z Kurek, Jayesh A Kulkarni, Fariba Sadaati, Pamela K Wagner, Terri L Petkau, Marco A Ciufolini, Pieter R Cullis, Blair R Leavitt.

  Many genetic neurological diseases are caused by toxic gain-of-function of a mutant protein or loss-of-function of a wild-type protein. Treatment of these disorders may be feasible using gene therapy, which requires delivering therapeutic agents to affected brain regions and cells. Lipid nanoparticles (LNPs) have significant potential for this purpose: the clinical safety and efficacy of LNP systems is well-established, and neurons are amenable to LNP-mediated transfection. To adapt LNP technology for brain gene therapy applications, we iteratively designed LNPs to deliver nucleic acids to ex vivo primary neurons, and evaluated optimized formulations in vivo in the brain. Our approach improved ex vivo LNP potency over 1.7-fold for siRNA-containing systems and over 22-fold for mRNA-containing systems, and identified distinct compositions optimal for siRNA and mRNA delivery. We show that the activity of ex vivo-optimized LNPs is not always correlated with in vivo activity in murine striatum and establish the apparent pKa of ionizable cationic lipids as an important contributor to LNP efficacy in both model systems. Collectively, we demonstrate robust delivery of multiple macromolecular payloads to primary neurons ex vivo and to the brain in vivo and validate the utility of LNP systems for gene knockdown and protein replacement brain gene therapies.

Keywords:  MT: delivery strategies; brain gene therapy; lipid nanoparticles; nanomedicine; neurodegenerative disease; neurological disease

DOI:  https://doi.org/10.1016/j.omtn.2026.103025