bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–10–25
fifteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
  2. Context-specific hypermetabolism in humans with mitochondrial defects.
  3. Mitochondrial dysfunction in neurology: biomarkers and clinical implications.
  4. BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
  5. GRP75-dependent SIMPA mediates inter-organellar quality control.
  6. Placental mitochondrial impairment in preeclampsia patients.
  7. HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
  8. Mitophagy coordinates organelle crosstalk in health and diseases.
  9. PRKN dephosphorylation by PTEN-L couples mitophagy inhibition to GSDME pyroptosis suppression.
  10. Cold activates a BH2 metabolic network promoting longevity and proteostasis.
  11. Rethinking mitochondrial isolation for the next generation of mitochondrial therapies.
  12. Natural products targeting mitochondrial homeostasis: a four-dimensional framework integrating dynamics, mitophagy, pharmacokinetics, and translational safety.
  13. Stathmin 1 regulates mitophagy and non-proliferative cellular function in hematopoietic stem and progenitor cells.
  14. A Micropeptide Component of the OGDH Complex Modulates ATP Production in the TCA Cycle.
  15. Mitochondrial remodeling in heart failure with reduced ejection fraction.
  1. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613074123
    Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
    Tak Shun Fung, Elias Tzoc-Pacheco, Ruobing Cui, Shelby Brown, Simon Schwörer, Tullia Lindsten, Craig B Thompson, Keunwoo Ryu.
      When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.
    Keywords:  GLS; P5CS; metabolism; mitochondria; mtDNA
    DOI:  https://doi.org/10.1073/pnas.2613074123
  2. Cell Press Blue. 2026 Oct 07. pii: 100129. [Epub ahead of print]
    Context-specific hypermetabolism in humans with mitochondrial defects.
    Evan D Shaulson, Alexander J Sercel, Shannon Rausser, Samantha Leonard, Kathryn Whyte, Faris Zuraikat, Heather Seid, Qiuhan Huang, Alex Junker, Darshana Kapri, Mangesh Kurade, David Shire, Joanna Chen, Caroline Trumpff, Catherine Kelly, Natalia Bobba-Alves, Kris Englestad, Herman Pontzer, Wei Shen, Seth A Creasy, Edward L Melanson, Michael Rosenbaum, Marie-Pierre St-Onge, Dympna Gallagher, Michio Hirano, Martin Picard.
      Pathogenic mitochondrial DNA (mtDNA) defects test how impaired oxidative phosphorylation reshapes human energy expenditure. We studied adults with confirmed mtDNA defects (MitoD) and healthy controls using whole-room indirect calorimetry, doubly labeled water, quantitative magnetic resonance, actigraphy, autonomic monitoring, mood assessments, plasma inflammatory markers, and growth differentiation factor 15 (GDF15). Under behaviorally clamped conditions, fat-free mass-adjusted 24-h energy expenditure (24-h EE) was consistently higher in MitoD, with higher non-resting expenditure per unit wrist acceleration by day, and blunted sleep-related metabolic suppression at night. In contrast, free-living total daily energy expenditure (TDEE) was similar between groups despite lower physical activity in MitoD, consistent with behavioral compensation within a constrained energy budget. Plasma GDF15 was ~5-fold higher in MitoD and tracked with disease severity, systemic inflammation, fatigue, energetic burden, and lower habitual activity. These findings identify a persistent energetic burden in MitoD that is buffered in daily life and associated with elevated GDF15.
    Keywords:  GDF15; doubly labeled water; energy expenditure; fatigue; hypermetabolism; metabolic phenotyping; mitochondrial disease; resting energy expenditure; sickness behavior; whole-room indirect calorimetry
    DOI:  https://doi.org/10.1016/j.cpblue.2026.100129
  3. Nat Rev Neurol. 2026 Oct 23.
    Mitochondrial dysfunction in neurology: biomarkers and clinical implications.
    Elena Rossini, Matteo Garibaldi, Michael G Hanna, Robert D S Pitceathly, Chiara Pizzamiglio.
      Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of disease progression and therapeutic response. Primary mitochondrial diseases are presented as proof-of-concept models of impaired oxidative phosphorylation, providing a framework for biomarker identification and validation with translational relevance to other neurological diseases. Mitochondrial biomarkers can be broadly categorized into four domains: fluid biomarkers, reflecting metabolic alterations and stress signalling; genetic biomarkers, capturing mitochondrial DNA integrity and dynamics; multi-omics approaches, integrating transcriptomic, proteomic and metabolomic signatures; and imaging biomarkers, enabling in vivo assessment of structural and functional consequences of mitochondrial dysfunction. Across disorders, these biomarkers reveal shared disturbances in bioenergetics, redox homeostasis, mitochondrial genome maintenance and inflammatory signalling. However, clinical implementation remains limited by methodological heterogeneity, biological variability and reduced disease specificity. Integrated, multimodal biomarker strategies, combined with longitudinal validation, will be essential for supporting precision medicine and guiding the development of therapies to target mitochondrial pathways in neurology.
    DOI:  https://doi.org/10.1038/s41582-026-01274-z
  4. Science. 2026 Oct 22. 394(6822): eaea2181
    BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
    Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.
      The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.
    DOI:  https://doi.org/10.1126/science.aea2181
  5. Nature. 2026 Oct 21.
    GRP75-dependent SIMPA mediates inter-organellar quality control.
    Fan Yu, Lingyu Jiang, Hanyu Liu, Song Yang, Yuan Yuan, Hongzhen Jin, Jinming Liu, Xi Liu, Yu Dong, Dongfeng Ren, Jie Kang, Yan Huang, Qi Meng, Feng Bai, Yanjun Li, Shuoguo Li, Huadong Liu, Wei Zhao, Jia Xiao, Quan Chen.
      Mitochondria are bound by a double membrane and are semiautonomous organelles, rendering them highly vulnerable to global and internal proteostatic stress1. Multiple surveillance mechanisms at proteostatic and inter-organellar levels have evolved to maintain mitochondrial integrity and cellular health2-7. However, the precise mechanisms by which proteostatic damage relays stress signals across organelles and how the quality surveillance machinery coordinates these functions remain unknown. Here we report that under proteostatic stress, damaged mitochondrial proteins are sequestered to form stress-induced mitochondrial protein aggregates (SIMPAs) that activate specific quality control mechanisms in a spatially confined manner without perturbing the mitochondrial network. Quantitative proteomic and correlative light-electron microscopy analysis revealed that SIMPA mediates inter-organellar communication via mitochondria-endoplasmic reticulum contact sites or mitochondrial-associated membranes. Mechanistically, GRP75 coordinates SIMPA biogenesis and focally activates endoplasmic reticulum unfolded protein response pathways via mitochondria-endoplasmic reticulum contact sites or mitochondrial-associated membranes for the targeted clearance of SIMPAs. Functionally, in both cellular and liver disease models, we found that a GRP75-dependent SIMPA signalling cascade attenuates mitochondrial stress and preserves mitochondrial integrity under proteotoxic stress. Overall, we show that SIMPAs, functioning as protein condensates, serve as a central cross-compartment communication hub for mitochondrial quality control, supporting cellular and organismal fitness.
    DOI:  https://doi.org/10.1038/s41586-026-10733-y
  6. Hypertens Pregnancy. 2026 Dec 31. 45(1): 2734436
    Placental mitochondrial impairment in preeclampsia patients.
    Ramana Vaka, Elizabeth Hinton, Kristin Edwards, Babbette LaMarca.
      Preeclampsia is a pregnancy-specific hypertensive disorder characterized by new-onset hypertension after 20 weeks of gestation, accompanied by end-organ dysfunction with or without proteinuria. Affecting approximately 5-7% of pregnancies worldwide, it remains a leading cause of maternal and fetal morbidity and mortality. Despite decades of research, the underlying pathophysiology of preeclampsia remains incompletely understood. However, increasing evidence implicates placental mitochondrial oxidative stress in its pathogenesis. In this review, we summarize the current literature pertaining to ultrastructural evidence of mitochondrial damage, defects in oxidative phosphorylation and electron transport chain activity, and alterations in reactive oxygen species production, antioxidant defense, and mitochondrial biogenesis. Finally, we discuss translational considerations and highlight how therapeutic strategies targeted at restoring mitochondrial function may represent a promising approach for managing preeclampsia.
    Keywords:  Bioenergetics; mitochondria; placenta; preeclampsia; reactive oxygen species
    DOI:  https://doi.org/10.1080/10641955.2026.2734436
  7. FASEB J. 2026 Oct 31. pii: e72407. [Epub ahead of print]40(20):
    HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
    Ko Suzuki, Jun-Ichiro Takahashi, Kiriko Kaneko, Kazumichi Furuyama.
      Intracellular energy metabolism is strictly regulated by hormones and intracellular metabolites for the appropriate use of energy resources such as carbohydrates and fatty acids. Mitochondria are essential organelles in eukaryotic cells since they contain several metabolic machineries required for oxidative phosphorylation, such as the tricarboxylic cycle, electron transport chain, and fatty acid β-oxidation (FAO). Previously, we reported that FAO activity is increased in CLPX-knockout HepG2 cells (CLPX-KO cells). CLPX is the substrate recognition subunit of the mitochondrial protease ClpXP that regulates intracellular heme levels through the degradation of ALAS1 in the mitochondrial matrix. ALAS1 is the rate-limiting enzyme for heme biosynthesis; thus, we examined whether heme regulates FAO activity. We found that the inhibition of heme synthesis in CLPX-KO cells decreased FAO activity; in contrast, hemin treatment increased FAO activity in wild-type HepG2 cells (CLPX-WT cells). Furthermore, pretreatment of CLPX-WT cells with a chemical inhibitor or specific siRNA targeting the heme degradation enzyme HMOX1 blocked FAO activation induced by hemin, indicating that heme catabolites rather than heme itself are responsible for FAO activation by heme. Among the heme catabolites, we identified carbon monoxide (CO) as an essential metabolite for FAO activation through the activation of the LKB1/AMPK signaling pathway. In this manuscript, we revealed the previously unknown role of CO as an intrinsic inducer of mitochondrial FAO activity and revealed that an excess amount of heme increases FAO activity via CO production by HMOX1.
    Keywords:  AMP‐activated kinase; carbon monoxide; fatty acid oxidation; heme; heme oxygenase; mitochondria
    DOI:  https://doi.org/10.1096/fj.202603280R
  8. Signal Transduct Target Ther. 2026 Oct 20. pii: 458. [Epub ahead of print]11(1):
    Mitophagy coordinates organelle crosstalk in health and diseases.
    Mengyao Wu, Pengyi He, Yajun Lian, Tuo Zhang, Yiqi Wu, Lu Wang, Daolin Tang, Yongming Yao, Renqi Yao.
      Eukaryotic cells contain various membrane- and non-membrane-bound organelles, whose spatial and functional organization underpins intracellular homeostasis. Organelle coordination is governed by complex signaling and metabolic networks, often facilitated by direct physical contacts and molecular exchange. Mitochondria, as central hubs of bioenergetic and metabolic activity, are essential to functional coordination among cellular organelles. They engage in diverse cellular processes, encompassing ATP production, biosynthesis of key metabolites, calcium ion buffering, redox balance, and cellular turnover. To preserve their integrity and functionality, dysfunctional mitochondria undergo selective elimination via mitophagy, a specialized form of macroautophagy. Mitophagy plays dual roles in maintaining mitochondrial fidelity and actively shapes interorganelle communication. Through bidirectional signaling, mitophagy influences the activity of multiple organelles, including the endoplasmic reticulum, nucleus, lysosomes, peroxisomes, and lipid droplets. This interorganelle crosstalk is essential for adapting to metabolic stress, maintaining redox balance, and coordinating cell fate decisions. In this review, we explore the intricate signaling networks connecting mitophagy with various organelles and discuss how these interactions influence organ function and overall cellular health. We also highlight emerging small-molecule modulators of mitophagy, providing insight into potential therapeutic strategies aimed at restoring or enhancing organelle communication in pathological conditions.
    DOI:  https://doi.org/10.1038/s41392-026-02812-3
  9. Autophagy. 2026 Oct 20.
    PRKN dephosphorylation by PTEN-L couples mitophagy inhibition to GSDME pyroptosis suppression.
    Chenghao Yan, Xu Liu, Xinyu Gong, Xiaofang Wu, Haodong Xu, Liming Wang.
      Mitochondrial damage is a potent trigger of inflammatory cell death; however, how damaged mitochondria transduce stress signals to initiate cell death execution, and how this process is finely regulated, remain incompletely understood. We recently identified that the PINK1-PRKN axis, activated upon mitochondrial depolarization, not only initiates mitophagy but also drives pyroptosis via the ubiquitination and degradation of MCL1, which in turn promotes BAX and BAK1 activation, leading to CASP3 activation and GSDME cleavage. PTEN-L functions as a negative regulator of this pathway by directly dephosphorylating PRKN, which concurrently suppresses both mitophagy and pyroptosis, thereby coupling organelle quality control to inflammatory cell death.
    Keywords:  GSDME-dependent pyroptosis; PINK1-PRKN axis; PTEN-L dephosphorylation; mitochondrial damage; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2751925
  10. Nature. 2026 Oct 21.
    Cold activates a BH2 metabolic network promoting longevity and proteostasis.
    Hyun Ju Lee, Cansu Doğan, Seda Koyuncu, Markus Wehrmann, Murat Artan, Dunja Petrovic, Rute Loureiro, Amit Kumar Sahu, Joana Schnubel, Pavel Grobushkin, Dimitrios Prymidis, Theodoros Georgomanolis, Agnieszka Sokol, Ming Yang, Thorsten Hoppe, Christian Frezza, David Vilchez.
      Moderately cold temperatures extend lifespan and promote health across species1-3, yet the molecular mechanisms underlying these benefits remain unclear. Here we define a metabolite-driven, multi-tissue signalling system that links cold temperature to enhanced longevity and proteostasis in Caenorhabditis elegans. Cold temperature upregulates the biopterin-synthesis enzyme CAT-4 (GCH1 in humans), increasing production of dihydrobiopterin (BH2), a transportable reservoir for the bioactive cofactor tetrahydrobiopterin (BH4). BH2 is produced in muscle and transported to distal tissues, including the intestine and neurons, where it is converted into BH4 by the salvage enzyme DHFR-1. BH4 functions as an essential cofactor for phenylalanine hydroxylase PAH-1, promoting tyrosine synthesis and extending lifespan. This BH2-BH4 axis also prevents disease-related protein aggregation and subsequent neuronal dysfunction during ageing. Importantly, increasing BH2 synthesis specifically in muscle is sufficient to promote longevity and suppress pathological protein aggregation in distal tissues, even at normal or elevated temperatures. In human cells, BH2 or tyrosine supplementation reduces aggregation of polyQ-expanded proteins associated with Huntington's disease, as well as mutant variants of TDP-43 and FUS that cause amyotrophic lateral sclerosis. Together, these findings identify BH2 as a cold-induced metabolite of which the synthesis, intertissue transport and conversion into bioactive BH4 preserve organism-wide proteostasis and extend lifespan.
    DOI:  https://doi.org/10.1038/s41586-026-11152-9
  11. Front Physiol. 2026 ;17 1975105
    Rethinking mitochondrial isolation for the next generation of mitochondrial therapies.
    Ethan A Simpson, Celina Phan, Jason P Acker.
      Mitochondrial isolation is fundamental to the study of mitochondrial biology and is increasingly relevant to emerging therapeutic applications such as mitochondrial transplantation. However, isolation procedures can substantially influence mitochondrial yield, purity, structural integrity, and bioenergetic function, making method selection an important determinant of experimental and translational outcomes. This review examines current mitochondrial isolation strategies, including physical disruption, chemical permeabilization, emerging microfluidic and automated dissociation technologies, and downstream separation approaches such as differential centrifugation, density-gradient centrifugation, filtration, and immunoaffinity enrichment. Each approach offers distinct advantages and limitations depending on the biological source, processing requirements, and intended application. Conventional methods remain widely used because of their accessibility and flexibility, but may introduce operator variability, mechanical stress, contamination, or loss of mitochondrial function. More selective purification strategies can improve sample purity, although often at the cost of additional processing time, technical complexity, and reduced recovery. Emerging technologies, including standardized mechanical dissociation and microfluidic disruption, may provide greater control over mitochondrial release, but require broader validation across tissues and sample volumes. A persistent challenge across isolation workflows is balancing mitochondrial recovery with preservation of organelle integrity and function. Future progress will require standardized, scalable isolation strategies that consistently preserve mitochondrial quality across different biological sources and downstream applications. Continued refinement of these approaches will be essential for advancing mitochondrial research and supporting the development of mitochondrial-based therapies.
    Keywords:  bioprocessing; isolation; mitochondria; oxidative injury; stabilization
    DOI:  https://doi.org/10.3389/fphys.2026.1975105
  12. Front Pharmacol. 2026 ;17 1911495
    Natural products targeting mitochondrial homeostasis: a four-dimensional framework integrating dynamics, mitophagy, pharmacokinetics, and translational safety.
    Zhi-Yun Xiang, Xiu-Hua Yang, Wen-Ying Lan, Xin-Yu Xiao, Qun Huang, Lin-Lin Yang.
       Background: Dysregulated mitochondrial dynamics, including fission, fusion, biogenesis, and mitophagy, underlie the pathogenesis of many diseases. Natural products have the potential for multi-target therapy, but insufficient understanding of their mechanisms of action and pharmacokinetic limitations hinder their clinical translation.
    Objective: This review proposes a regulatory framework covering the four dimensions of biogenesis, morphology, quality control, and defense, aiming to systematically clarify how natural products regulate mitochondrial function and critically evaluate their translational potential. The framework emphasizes that inter-organelle contact platforms, such as mitochondria-endoplasmic reticulum contact sites (MERCs) and mitochondrial-lysosomal contact sites (MLCs), are key sites through which natural products exert regulatory effects.
    Methods: Major scientific databases, including PubMed, Web of Science, and Scopus, were searched, and evidence on mechanisms, pharmacokinetics, and toxicology from preclinical and clinical studies was comprehensively reviewed.
    Results: Natural products can selectively regulate key mitochondrial pathways and regulatory nodes, including the AMPK/SIRT1/PGC-1α axis involved in mitochondrial biogenesis, the DRP1 axis involved in mitochondrial fission, and the PINK1/Parkin pathway involved in mitophagy. Representative metabolites include resveratrol, curcumin, and Coptis chinensis-derived alkaloids. A key finding of this review is that the intestinal microbiota plays an important role in converting low-bioavailability precursors, such as tannins, into systemically active metabolites, such as urolithin A (UA), thus inducing mitophagy. Although these metabolites usually show strong activity in vitro, their low oral bioavailability and rapid metabolism lead to significant pharmacokinetic/pharmacodynamic (PK/PD) mismatch, which remains a major obstacle to their clinical translation.
    Conclusion: Natural products are powerful multidimensional regulators of mitochondrial homeostasis. In order to fully realize their therapeutic potential, strategies must be adopted to overcome PK/PD mismatch, including the development of targeted delivery systems, in-depth analysis of microbiome-metabolite interactions, and the integration of artificial intelligence and CRISPR-based technological innovation to support precision therapy.
    Keywords:  gut microbiota–mitochondria axis; mitochondrial dynamics; mitohormesis; mitophagy; natural products; pharmacokinetics
    DOI:  https://doi.org/10.3389/fphar.2026.1911495
  13. iScience. 2026 Nov 20. 29(11): 117458
    Stathmin 1 regulates mitophagy and non-proliferative cellular function in hematopoietic stem and progenitor cells.
    Luana Chiquetto, Meg Schuetz, Qian Dong, Mia Warmka, Liana Valin, Ashley Jones, Patrick Hunt, Copper Petermeier, Jie Wang, Nate Roundy, Zev J Greenberg, Wei Yang, Christine R Zhang, Grant A Challen, Cliff J Luke, Robert A J Signer, Wandy L Beatty, Stephen Sykes, Weikai Li, David J Kast, Laura G Schuettpelz.
      Stathmin 1 is a cytoplasmic phosphoprotein that regulates microtubule dynamics. Stathmin 1 expression is a feature of proliferating cells, and it is overexpressed in many cancers, including leukemias. In contrast to its roles in proliferating cells, considerably less is known of stathmin 1 in quiescent cells. Importantly, stathmin 1 is highly expressed in hematopoietic stem and progenitor cells (HSPCs), and herein we found that stathmin 1 loss is associated with altered microtubule architecture and markedly impaired HSPC function. Transcriptomic studies suggested metabolic differences in Stmn1 -/- HSPCs, and further mechanistic studies revealed defective mitochondrial structure and function. Microtubules facilitate autophagosome formation and mitophagy, and indeed we found that this critical mitochondrial quality control process is impaired in Stmn1 -/- HSPCs. Finally, stimulation of autophagy improved Stmn1 -/- HSPC colony-forming ability. Together, these data identify a non-proliferative role for stathmin 1 in the regulation of HSPC mitochondrial quality control and cellular function.
    Keywords:  autophagy; hematopoietic stem cells; metabolism; microtubules; mitophagy; stathmin
    DOI:  https://doi.org/10.1016/j.isci.2026.117458
  14. Adv Sci (Weinh). 2026 Oct 18. e77242
    A Micropeptide Component of the OGDH Complex Modulates ATP Production in the TCA Cycle.
    Xinqiang Yin, Weiyan Qi, Lifen Lin, Huilin Zheng, Guoxiang Zhao, Quan Chen, Guoqiang Shao, Yifan Wu, Jialiang Hu, Hanmei Xu.
      Since its elucidation, the tricarboxylic acid (TCA) cycle has been regarded as a fully defined enzymatic pathway. Here, we report the discovery of a previously unrecognized micropeptide component of this central metabolic system. Through analyzing ribosome profiling data from the mouse sORFs.org database, we discovered APPM (ATP production-promoting micropeptide), a 29-amino acid peptide encoded by a non-canonical small open reading frame within the mouse Ctsb gene. APPM localizes to the mitochondrial matrix and inner membrane, where it directly binds to the E1 subunit (OGDH) of the α-ketoglutarate dehydrogenase complex (OGDHc). This interaction modulates OGDHc enzymatic activity, thereby regulating NADH and ATP production. We identified tyrosine-13 as the critical residue mediating the APPM-OGDH interaction and functional activation. Exogenous APPM administration increased ATP levels in vivo and, in a mouse model of heart failure, restored cardiac function, outperforming the reference drug trimetazidine. Collectively, our findings identify APPM as the first micropeptide regulator of the OGDH complex, expanding the known repertoire of the TCA cycle and presenting a potential therapeutic strategy for diseases characterized by bioenergetic insufficiency.
    Keywords:  APPM; ATP synthesis; OGDHc; TCA cycle; mitochondrial function
    DOI:  https://doi.org/10.1002/advs.77242
  15. Front Physiol. 2026 ;17 1958014
    Mitochondrial remodeling in heart failure with reduced ejection fraction.
    Xin Chen.
      Extensive mitochondrial remodeling occurs during heart failure with reduced ejection fraction (HFrEF), yielding either protective adaptations that mitigate dysfunction or detrimental alterations that accelerate disease progression. Central to this remodeling are maladaptive metabolic reprogramming, featured by aberrant fuel preference and electron transport chain deficiency, which underlie the depletion of bioenergetic reserves. Concurrently, alterations in reactive oxygen species (ROS)-producing sites and antioxidant system elevate mitochondrial ROS production while diminishing ROS scavenging capacity, fostering a progressively deteriorating redox environment that perpetuates mitochondrial dysfunction. Additional maladaptive changes, including impaired mitochondrial biogenesis, fission-biased mitochondrial dynamics, mitophagy dysregulation, increased mitochondrial membrane permeability, and activation of pro-inflammatory responses, further disrupt mitochondrial homeostasis and exacerbate cardiac injury. Conversely, remodeling of the mitochondrial Ca2+ transport system provides adaptive restriction of mitochondrial Ca2+, conferring protection against apoptosis. In this review, I will summarize recent evidence demonstrating the molecular and pathophysiological mechanisms related to mitochondrial remodeling in HFrEF. I will delineate the signaling axes and factors that mediate distinct mitochondrial functions and specify how they are remodeled during the progression of heart failure. Different HFrEF etiologies are associated with distinct mitochondrial pathologies, and these will be comprehensively reviewed. I will also discuss the therapeutic potential of mitochondrial targeting in preclinical models and how these insights are translated into novel clinical strategies to improve heart failure management.
    Keywords:  electron transport chain; heart failure; metabolic reprogramming; mitochondrial dynamics; mitochondrial membrane permeability transition; mitochondrial remodeling; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3389/fphys.2026.1958014
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