bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–10–04
sixteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Advances in diagnosis of mitochondrial dysfunction and primary mitochondrial disease.
  2. Mitochondrial pearling: membrane biophysics, Ca2+-dependent regulation, mtDNA nucleoid dynamics, and emerging links to mitochondrial quality control and neurological disorders.
  3. A selective inhibitor reveals roles for LONP1 in mitochondrial proteostasis and OXPHOS dependencies.
  4. Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.
  5. Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ.
  6. Mitochondria before we knew them.
  7. Lightning Strikes Twice in the Same Place: Mitochondrial Myopathy and Malignant Hyperthermia-A Case Report.
  8. Successful live birth after preimplantation genetic testing for combined nuclear RNASEH2C and mitochondrial MT-TL1 variants.
  9. Conserved and divergent mitochondrial assemblies in kinetoplastid parasites.
  10. Direct Pharmacological Activation of AMPK Extends Lifespan in Yeast, Worms and Flies.
  11. Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
  12. Decoding mitochondrial proteomes of diverse eukaryotes.
  13. CLPP loss confers sex-specific protection from renal ischemia reperfusion injury.
  14. SIRT6-COX6A1 axis mediates prenatal 6:2 FTOH-induced neuronal damage via mitochondrial dysfunction.
  15. Mitochondrial proteome of Acanthamoeba delineates aerobic and anaerobic pathways dynamically regulated by oxygen.
  16. Comparative analysis of mitochondrial proteomes across the tree of life.
  1. Dis Model Mech. 2026 Sep 01. pii: dmm052804. [Epub ahead of print]19(9):
    Advances in diagnosis of mitochondrial dysfunction and primary mitochondrial disease.
    Melis Kose, Elizabeth McCormick, James T Peterson, Colleen Muraresku, Angela Viaene, Zarazuela Zolkipli-Cunningham, Marni J Falk.
      Mitochondria are critical cellular organelles engaged in energy production, diverse intermediary metabolic functions and signaling. Inherited genetic disorders directly affecting mitochondrial structure and/or function, known collectively as primary mitochondrial diseases, are among the most complex and heterogeneous inherited conditions, involving dual-genome origin, multisystem manifestations and widely variable clinical severity. These diseases can follow different inheritance patterns and are caused by pathogenic variants in nearly 400 genes encoded by either the mitochondrial or nuclear genome, which commonly impair proteins or RNAs in distinct molecular pathways, resulting in defective energy production by disrupting oxidative phosphorylation. Mitochondrial diseases are challenging to accurately diagnose because of their extensive clinical variability and common features with other metabolic and neuromuscular disorders, as well as limitations in existing diagnostic tools. However, advances in molecular genetics, imaging and systems biology have transformed the diagnostic landscape, enabling more comprehensive and integrative approaches. This Review provides an overview of mitochondrial physiology and outlines the current state of diagnostic strategies, ranging from conventional biochemical assessments and tissue-based analyses to next-generation genome-wide sequencing and the emerging omics technologies. We discuss how combining classical and modern methods can improve diagnostic accuracy and inform clinical decision making. Additionally, we highlight the need for continued refinement of diagnostic frameworks to better support personalized management and future therapeutic development in mitochondrial medicine.
    Keywords:  Mitochondrial diagnostics; Mitochondrial disease biomarkers; Multi-omics; Primary mitochondrial disease; mtDNA sequencing
    DOI:  https://doi.org/10.1242/dmm.052804
  2. Front Cell Dev Biol. 2026 ;14 1943282
    Mitochondrial pearling: membrane biophysics, Ca2+-dependent regulation, mtDNA nucleoid dynamics, and emerging links to mitochondrial quality control and neurological disorders.
    Ye Chen, Fajuan Tang, Xihong Li.
      Mitochondrial dynamics has long been interpreted primarily through fission and fusion, yet tubular mitochondria can also undergo rapid pearling, a phenomenon in which elongated mitochondria reorganize into a beads-on-a-string morphology while retaining a continuous imaged contour. The occurrence and biological relevance of mitochondrial pearling require careful study. The dimensionless tension-bending ratio used to organize these observations is a heuristic analogy to single-membrane tubes, not a validated quantitative model of the mitochondrial double membrane. Evidence does not yet establish a continuous sequence from pearling through coordinated outer- and inner-membrane scission to mitophagy or intercellular mitochondrial transfer; those links are therefore presented as hypotheses and testable predictions. We use the provisional term "candidate disease-associated sustained pearling phenotype" only for within-study events that meet dynamic pearling criteria and show longer duration or delayed/failed reversal relative to appropriately matched controls. No universal duration threshold or validated pearling-defined disease entity currently exists. Event duration, wavelength, un-pearling kinetics, separate outer- and inner-membrane continuity, and the fate of individual pearls should be measured together to determine whether sustained events are incidental, adaptive, or causally involved in disease.
    Keywords:  Ca2+; mitochondrial pearling; mitochondrial transfer; mitophagy; mtDNA nucleoid; neurological disease; sustained pearling phenotype
    DOI:  https://doi.org/10.3389/fcell.2026.1943282
  3. Life Sci Alliance. 2026 Dec;pii: e202503535. [Epub ahead of print]9(12):
    A selective inhibitor reveals roles for LONP1 in mitochondrial proteostasis and OXPHOS dependencies.
    Zsolt Szilagyi, Pauline Michon, Carlos Pardo-Hernández, Mãdãlina Sãcultanu, Javier Miralles Fusté, Andrew M Griffin, Paul S Charifson, Cindy Phan, Yonghong Shi, Gunther Kern, Gabriel Martinez Botella, Thomas A Keating, Bertil Macao, Nils-Göran Larsson, Maria Falkenberg, Jeremy Green, Claes M Gustafsson.
      Lon protease 1 (LONP1) is a conserved hexameric protease implicated in mitochondrial disorders and cancer progression. In this study, we present PZL-26, a potent and selective small-molecule inhibitor that targets LONP1 without affecting the proteasome, leading to selective accumulation of mitochondrial proteins. Using PZL-26 in a whole-genome CRISPR-Cas9 screen, we identified genes essential for cell survival under protease inhibition, supporting a role for LONP1 in key mitochondrial processes, including complex I biogenesis, mitochondrial transcription, and translation. Our CRISPR screen results are consistent with proteomics analysis, with both approaches converging on the same mitochondrial pathways and highlighting functional interactions between LONP1 and other mitochondrial proteases, including potential compensatory mechanisms. These findings establish PZL-26 as an effective tool for exploring LONP1 function and pave the way for future therapeutic strategies targeting LONP1 in mitochondrial diseases and cancer.
    DOI:  https://doi.org/10.26508/lsa.202503535
  4. Science. 2026 Oct;394(6819): eadz4797
    Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.
    Iuliia Karavaeva, Astrid Linde Basse, Samuel A J Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F Havelund, Marie Sophie Isidor, Adam Chatoff, Andrea Andress Huacachino, Hannah J Richter, Meghna Birla, Sabina Chubanava, Yann Deleye, Rini Arianti, David Tandio, Sarah E Utzon, Zafir Kaiser, Yachen Shen, Ditte Neess, Hannes Embring, Dilip Menon, Olivia J Conway, Frederike Sass, Fabian Finger, Lidia Argemi-Muntadas, Tao Ma, Elahu G Sustarsic, Cecilie Kynding Kristensen, Rebecca L McIntyre, Genesee J Martinez, Anna Sofie Husted, Matthew J Emmett, Zachary A Kipp, Mikkel Frost, Mark P Jedrychowski, Michel van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W McGarrah, Kaja Plucińska, Mohit K Midha, Andreas Prokesch, Paul Cohen, James G Granneman, Patrick Seale, Riekelt H Houtkooper, Jacob B Hansen, Steven P Gygi, Thue W Schwartz, Matthew P Gillum, Terry D Hinds, Raymond E Soccio, Phillip J White, Edmund R S Kunji, Thomas Moritz, Jonas T Treebak, Endre Kristóf, Susanne Mandrup, Brice Emanuelli, Nathaniel W Snyder, Daniel J Fazakerley, Lawrence Kazak, Nils J Færgeman, Mitchell A Lazar, Zachary Gerhart-Hines.
      Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid cycling. During the sleep phase, the adipocyte clock suppresses Slc25a34 expression through the REV-ERB transcriptional repressors. Entering the active phase, consuming lipid-rich diets, or exposure to cold abolishes REV-ERB repression, and lipolytic signals stimulate Slc25a34 transcription through the peroxisome proliferator-activated receptors. SLC25A34 is proposed to import oxaloacetate into mitochondria, dually supporting the tricarboxylic acid cycle and cytosolic acetyl-coenzyme A (acetyl-CoA) production. Elevated cytosolic acetyl-CoA then fuels the synthesis of lipids and promotes the transcription of genes enhancing mitochondrial oxidation. Thus, SLC25A34 confers circadian, dietary, and temperature control of adipocyte lipid metabolism.
    DOI:  https://doi.org/10.1126/science.adz4797
  5. Nat Aging. 2026 Sep 29.
    Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ.
    Fabian Finger, Mikkel Frost, Shinya Watanabe, Tao Ma, Taewook Kang, Dipsikha Biswas, Ruben Zapata-Perez, Vincent Anton, Lucile Dollet, Lasse K Markussen, Nanami Senoo, Iuliia Karavaeva, Astrid Linde Basse, Oksana Dmytriyeva, Tara TeSlaa, Jesper F Havelund, Amy M Ehrlich, Marta Moreno-Torres, Caio Yogi Yonamine, Nicoline R Andersen, Ida Blom, Francisco Garcia-Carrizo, Piyarat Siripoksup, Magnus Asping, Thomas S Nielsen, Marcus Nygård, Anders B Klein, Andrey Tvardovskiy, Trine S Nicolaisen, Carlos Durantez-Fernández, Klaus Qvortrup, Clara Prats, Joshua D Rabinowitz, Christoffer Clemmensen, Lykke Sylow, Juleen R Zierath, Jonas T Treebak, Tim J Schulz, Trisha J Grevengoed, Steven M Claypool, Julien Prudent, Rob C I Wüst, Susanne Mandrup, Riekelt H Houtkooper, Kei Sakamoto, Nils J Færgeman, Martin R Larsen, Katsuhiko Funai, Steen Larsen, Zachary Gerhart-Hines.
      Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthesis of the mitochondrial membrane lipid, cardiolipin, causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle. By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell autonomously orchestrate fiber-type adaptations in aging and myopathies.
    DOI:  https://doi.org/10.1038/s43587-026-01227-7
  6. Cell. 2026 Oct 01. pii: S0092-8674(26)01072-X. [Epub ahead of print]189(20): 6214-6216
    Mitochondria before we knew them.
    Courtney W Stairs, Ryan M R Gawryluk.
      In this issue of Cell, Chen et al. chart mitochondrial proteome diversity across eukaryotes, revealing an unexpectedly complex ancestral proteome alongside extensive lineage-specific innovation. Their broad phylogenetic reconstruction provides new insights into the mitochondrial proteome of the last eukaryotic common ancestor while unearthing a wealth of unexplored mitochondrial biology outside of traditional model systems.
    DOI:  https://doi.org/10.1016/j.cell.2026.09.003
  7. Case Rep Neurol Med. 2026 ;2026 5802797
    Lightning Strikes Twice in the Same Place: Mitochondrial Myopathy and Malignant Hyperthermia-A Case Report.
    Rafaela Souto E Souza de Melo, Jorge Kiyoshi Mitsunaga Júnior, André Macedo Serafim da Silva, Brandow Willy Souza, Joilson Moura Santos, Pamela Vieira Andrade, Acary Souza Bulle Oliveira, Claudia Ferreira da Rosa Sobreira, Mariz Vainzof, Helga Cristina Almeida da Silva.
      Mitochondrial disease predominantly affects tissues reliant on aerobic metabolism, with an incidence of 1 in 4000 individuals and a broad spectrum of clinical presentations. Malignant hyperthermia is a pharmacogenetic disease in which a hypermetabolic reaction is triggered in malignant hyperthermia-susceptible patients by specific anesthetic agents. We present a clinical case of a fatal atypical reaction to anesthesia, where mitochondrial dysfunction was identified in the mother, and a variant in the RYR1 gene was found in the asymptomatic father and a paternal first cousin with exercise-induced rhabdomyolysis. Our report highlights that patients with complex phenotypes may present with concomitant diseases, necessitating comprehensive and often competing management priorities.
    DOI:  https://doi.org/10.1155/crnm/5802797
  8. J Assist Reprod Genet. 2026 Oct 01.
    Successful live birth after preimplantation genetic testing for combined nuclear RNASEH2C and mitochondrial MT-TL1 variants.
    Xiao Hu, Yi Zhang, Zhenxing Wan, Jing Dai, Yifan Gu, Lu Zhou, Fei Gong, Guangxiu Lu, Yue-Qiu Tan, Juan Du, Ge Lin.
       INTRODUCTION: Preimplantation genetic testing (PGT) reduces reproductive risks for genetically high-risk families. To date, simultaneous PGT for nuclear and mitochondrial gene variants has rarely been reported. PGT targeting mitochondrial DNA (mtDNA) variants remains challenging and requires further clinical evidence.
    CASE REPORT: We herein report a 3-year-old girl with severe global developmental delay. The proband harbored compound heterozygous RNASEH2C variants (maternal c.194G > A and paternal c.433C > T) and a maternally inherited m.3250 T > C variant in MT-TL1 with 72.9% heteroplasmy. PGT was performed for her parents, including RNASEH2C haplotype phasing, m.3250 T > C variant load quantification, and chromosomal copy number variation analysis. All eight embryos exhibited lower m.3250 T > C heteroplasmy (0-17.8%) than the mother (20.2%-27.9%). One aneuploid embryo with 17.8% heteroplasmy was aliquoted into 16 specimens for technical validation, and consistent variant loads (18.2% ± 1.7%) were observed across all aliquots. An euploid embryo carrying heterozygous RNASEH2C c.194G > A and low-level m.3250 T > C heteroplasmy (1.8%) was transferred, resulting in the birth of a healthy boy with uneventful birth and two-year postnatal follow-up.
    CONCLUSIONS: This case represents a successful application of combined nuclear, mitochondrial, and chromosomal PGT in a family. Our findings provide valuable clinical evidence supporting blastocyst-stage PGT for mtDNA variants, indicating PGT to be a reliable reproductive option for females with low-level pathogenic mtDNA variants.
    Keywords:   MT-TL1 ; RNASEH2C ; Preimplantation genetic testing
    DOI:  https://doi.org/10.1007/s10815-026-04041-7
  9. Mol Cell. 2026 Oct 01. pii: S1097-2765(26)00620-9. [Epub ahead of print]86(19): 4043-4057.e7
    Conserved and divergent mitochondrial assemblies in kinetoplastid parasites.
    MitoCarta Tree of Life Consortium
      The mitochondrial proteomes of Leishmania tarentolae and Trypanosoma brucei contain ∼1,700 proteins, most of which lack homologs in higher eukaryotes. Here, we integrate complexome profiling and cryo-electron microscopy to define conserved and lineage-specific macromolecular assemblies that support mitochondrial functions in these kinetoplastid protozoa. Comparative analyses reveal species- and life-stage-dependent differences in the abundance and composition of respiratory, metabolic, RNA processing, and other complexes, refining and expanding current annotations. Structures of L. tarentolae respiratory complex III2 (CIII2), complex IV2 (CIV2), and complex V (CV) identify nine previously unrecognized nuclear-encoded subunits and resolve five mitochondrially encoded proteins, including products of pan-edited mRNAs. These reconstructions uncover architectural innovations: a subunit 8 of ubiquinol cytochrome-c reductase (QCR8) N-terminal extension that plugs the vestigial mitochondrial processing peptidase (MPP)α/β cavity in CIII2, a CIV2 dimer stabilized by an extensive clade-restricted interface, and a CV dimer containing the mitochondrially encoded ATP6 subunit. Together, our findings reveal how kinetoplastids assemble specialized mitochondrial machinery while incorporating diverged components into core modules shared across eukaryotes.
    Keywords:  Leishmania; RNA editing; Trypanosoma; complexome profiling; cryo-EM; kinetoplastids; mass spectrometry; mitochondria; respiratory complexes
    DOI:  https://doi.org/10.1016/j.molcel.2026.08.031
  10. Aging Cell. 2026 Oct;25(10): e70721
    Direct Pharmacological Activation of AMPK Extends Lifespan in Yeast, Worms and Flies.
    Eliano Dos Santos, Marie Blickling, Fiona C Leiper, John-Patrick Alao, Claudia Lennicke, Andrea Foley, Jon R Wilson, Steven J Gamblin, Bénédicte Chazaud, Giovanna Lollo, Rémi Mounier, Gaëtan Juban, Charalampos Rallis, David Carling, Filipe Cabreiro, Helena M Cochemé.
      AMP-activated protein kinase (AMPK) is a key evolutionarily conserved sensor of energy homeostasis and plays a central role in metabolic health and disease. AMPK has also been implicated in ageing; however, most in vivo drug studies rely on the use of indirect activators, such as metformin, which have complex modes-of-action, therefore making conclusions on the specific role of AMPK more challenging. Here, we demonstrate that direct activation of AMPK with the compound 991 extends lifespan in Drosophila melanogaster, Caenorhabditis elegans and Schizosaccharomyces pombe. In mice, 991 treatment induces a pro-longevity proteomic profile, highlighting the potential for translation to mammals. Overall, our study provides important proof-of-principle for AMPK as a pharmacological target with longevity benefits.
    Keywords:   Caenorhabditis elegans ; Drosophila melanogaster ; Schizosaccharomyces pombe ; AMPK; ageing; energy metabolism; lifespan; pharmacology
    DOI:  https://doi.org/10.1111/acel.70721
  11. Nat Commun. 2026 08 31. pii: 10359. [Epub ahead of print]17(1):
    Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
    Krystle C Kalafut, Yann Cormerais, Madi Y Cissé, Samuel C Lapp, Karen E Inouye, Gökhan S Hotamışlıgil, Brendan D Manning.
      The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, and aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established regulatory mechanisms influencing mTORC1 activation, but the physiological signals that control mTORC1 at the organismal and tissue levels are less well-defined. mTORC1 is dynamically regulated by fasting and feeding in metabolic tissues, with both nutrients and insulin proposed to activate mTORC1 in response to feeding. Here, studies employing a liver-specific genetic mouse model demonstrate that AKT-mediated TSC2 phosphorylation is the predominant mechanism of hepatic mTORC1 induction by insulin but is dispensable for activation by feeding. Furthermore, postprandial activation of hepatic mTORC1 requires dietary protein, which dictates the insulin-responsiveness of the pathway. Contrary to dogma, hepatic mTORC1 signaling was not elevated in response to diet-induced obesity, despite overt impairments in insulin and glucose homeostasis, and blocking hepatic AKT-TSC-mTORC1 signaling did not affect these metabolic phenotypes. Evidence is also provided supporting a role for glucagon in hepatic mTORC1 suppression during fasting. This study reveals a hierarchy of physiological signals regulating hepatic mTORC1.
    DOI:  https://doi.org/10.1038/s41467-026-77216-6
  12. Cell. 2026 Oct 01. pii: S0092-8674(26)01076-7. [Epub ahead of print]189(20): 6243-6245
    Decoding mitochondrial proteomes of diverse eukaryotes.
    Vamsi K Mootha, Sarah E Calvo.
      Our textbook view of mitochondria, which has been shaped by studies in animals and yeast, fails to do justice to the organelle's broader eukaryotic diversity. While most mitochondria retain a tiny genome, the overwhelming majority of their proteins are nuclear-encoded and vary extensively across lineages. To map this diversity, the MitoCarta Tree of Life Consortium developed experimental and computational workflows to generate high-accuracy mitochondrial proteomes across diverse eukaryotes-helping to lay a foundation for comparative mitochondrial biology with broad implications for physiology, evolution, and disease.
    DOI:  https://doi.org/10.1016/j.cell.2026.09.007
  13. Redox Biol. 2026 Sep 23. pii: S2213-2317(26)00411-8. [Epub ahead of print]97 104412
    CLPP loss confers sex-specific protection from renal ischemia reperfusion injury.
    Lea Isermann, Pedro Rojas-Morales, Katharina Senft, Nidhi Nair, Linda Baumann, Marijana Croon, Viktoria Katharina Lauterbach, Heike Göbel, Francesco Landini, Chiara Tuma, Ignacio Sottorff-Neculhueque, Mario Thevis, Michael Ignarski, Sebastian Brähler, Jan Riemer, Roman-Ulrich Müller, Aleksandra Trifunovic.
      Renal ischemia-reperfusion injury (IRI) is initiated by a burst of mitochondrial reactive oxygen species generated when ischemia-accumulated succinate is rapidly oxidised upon reperfusion, driving reverse electron transport and triggering lipid peroxidation-dependent tubular cell death. Here, we identify the mitochondrial matrix protease CLPP as an unexpected regulator of renal redox resilience. CLPP deficiency reduced succinate-driven mitochondrial H2O2 production and protected kidneys from functional decline, tubular necrosis, mitochondrial ultrastructural damage, and lipid peroxidation following IRI. Protection was most pronounced in females, in which CLPP loss established a constitutive antioxidant and detoxification programme prior to injury, characterised by increased glutathione and γ-glutamylcysteine abundance, enhanced NADPH-generating pentose phosphate pathway activity, sustained sulphur amino acid metabolism, and elevated capacity for lipid aldehyde detoxification. During reperfusion, these adaptations preserved thiol-redox buffering, limited 4-hydroxynonenal accumulation, and reduced oxidative modification of cysteine residues on proteins involved in complement, coagulation, fibrinolysis, and inflammatory signalling, thereby restricting ferroptotic lipid damage and downstream thrombo-inflammatory amplification. Although reduced reverse electron transport-derived ROS contributed to this phenotype, it was insufficient to account for the sex bias. While CLPP deficiency amplified an endogenous female antioxidant programme, male kidneys, lacking equivalent glutathione-centred preconditioning, showed only marginal benefit. These findings establish mitochondrial proteostasis as a determinant of sex-dependent redox adaptation and identify CLPP as a candidate target for preconditioning against predictable ischaemic insults, including kidney transplantation and cardiac surgery.
    Keywords:  Ferroptosis; Glutathione metabolism; Lipid peroxidation; Mitochondrial CLPP protease; Mitochondrial dysfunction; NRF2; Renal ischemia-reperfusion injury; Renal preconditioning; Sex differences
    DOI:  https://doi.org/10.1016/j.redox.2026.104412
  14. Ecotoxicol Environ Saf. 2026 Sep 30. pii: S0147-6513(26)01194-2. [Epub ahead of print]324 120864
    SIRT6-COX6A1 axis mediates prenatal 6:2 FTOH-induced neuronal damage via mitochondrial dysfunction.
    Yunhui Xia, Wenjun Tai, Jie Ding, Weidong Gan, Ping Hu, Dongmei Li.
      Prenatal exposure to 6:2 fluorotelomer alcohol (6:2 FTOH), an emerging environmental contaminant, raises concerns regarding developmental neurotoxicity, but the underlying mechanisms remain unclear. Combining network toxicology and transcriptomics in a prenatal mouse exposure model, we discovered that 6:2 FTOH suppressed silent information regulator 6 (SIRT6) expression in the developing brain, leading to hyperacetylation and autophagic degradation of cytochrome c oxidase subunit 6A1 (COX6A1), an essential element of the mitochondrial electron transport chain. This cascade reduced COX6A1 mitochondrial content, triggered mitochondrial dysfunction, and ultimately reduced neurotransmitter content. Molecular docking predicted favorable binding affinities between 6:2 FTOH and both SIRT6 and COX6A1. Importantly, restoring SIRT6 or COX6A1 expression in vitro reversed 6:2 FTOH-induced neurotoxicity. These findings reveal a novel mechanism where SIRT6-mediated deacetylation preserves COX6A1 stability and mitochondrial function, and demonstrate that an environmental contaminant can hijack this pathway to inflict neuronal damage. The SIRT6-COX6A1 axis represents a potential therapeutic target for neuronal damage induced by environmental contaminant.
    Keywords:  6:2 fluorotelomer alcohol; Mitochondrial dysfunction; Molecular docking; Network toxicology; Neurodevelopmental deficits
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.120864
  15. Cell. 2026 Oct 01. pii: S0092-8674(26)01067-6. [Epub ahead of print]189(20): 6246-6266.e19
    Mitochondrial proteome of Acanthamoeba delineates aerobic and anaerobic pathways dynamically regulated by oxygen.
    MitoCarta Tree of Life Consortium
      Acanthamoeba castellanii causes infectious blindness and resides in a key evolutionary outgroup to humans and fungi. Its divergent mitochondria are of outstanding interest due to their predicted aerobic and anaerobic functions with potential for drug targeting. However, a detailed delineation of its bioenergetic machinery, its activities, and their regulation remains lacking. Here, we integrate mitochondrial immunoprecipitation, density gradient purification, mass spectrometry, protein correlation profiling, and microscopy to generate a high-confidence inventory of the Acanthamoeba mitoproteome. The resulting AcMitoCarta contains 1,122 proteins, including 381 lacking readily identifiable homologs in human and yeast mitochondria. Complexome analysis highlights 20 macromolecular assemblies. Complementary proteomic and transcriptomic profiling reveals extensive rewiring of the organelle's bioenergetic machinery by oxygen, including induction of an anaerobic pyruvate:ferredoxin oxidoreductase-to-hydrogenase pathway under anoxia. We experimentally demonstrate that Acanthamoeba can produce H2 gas under anoxic conditions via a mitochondria-localized, oxygen-labile hydrogenase. AcMitoCarta establishes a framework for dissecting the interplay between aerobic and anaerobic energy metabolism.
    Keywords:  ATP synthase; Acanthamoeba; BN-PAGE-MS; HCP; HGT; HupA; HydA; HydE; HydF; HydG; MDH; NDH2; NirK; PFOR; SDHB; TFAM; complex I; hybrid cluster protein; mitochondria; mitochondrial ribosome
    DOI:  https://doi.org/10.1016/j.cell.2026.08.056
  16. Cell. 2026 Oct 01. pii: S0092-8674(26)01002-0. [Epub ahead of print]189(20): 6285-6306.e13
    Comparative analysis of mitochondrial proteomes across the tree of life.
    MitoCarta Tree of Life Consortium
      Mitochondria arose from the endosymbiosis of a bacterium with an archaea-related host cell about 2 billion years ago. To understand their origins and evolution, we compared experimentally defined mitoproteomes from the MitoCarta Tree of Life project. Across eight organisms, we identified 8,619 distinct mitochondrial proteins within 3,199 families, of which 43% lack Pfam domains. We report 33 protein families conserved in eukaryotic pathogens yet absent in humans, representing promising candidate targets for protozoan infectious diseases. Leveraging our experimentally defined mitoproteomes, we retrained a classifier based on a protein language model to predict mitoproteomes of ∼200 eukaryotes. From this expanded set, we detail the evolutionary trajectories of mitochondria, ranging from clade-specific gene family expansions to extreme mitoproteome reductions seemingly en route to complete organelle loss. Finally, we reconstruct the last eukaryotic common ancestor (LECA) mitoproteome, revealing that LECA possessed a complex mitochondrion capable of both aerobic and anaerobic metabolism.
    Keywords:  calcium; eukaryogenesis; evolution; last eukaryotic common ancestor; mitochondria; mitoproteome; oxygen; parasite; pathogen; phylogenetics
    DOI:  https://doi.org/10.1016/j.cell.2026.08.029
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