bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–11–01
sixteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. A stress-adapted fiber state promotes clonal expansion of deleted mitochondrial DNA.
  2. Mitochondrial DNA replication and genome stability: From mechanisms to therapeutic strategies.
  3. Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
  4. Augmenting intercellular mitochondrial transfer for tissue repair and rejuvenation.
  5. A Pediatric Case of Homocystinuria Due to MTHFR Deficiency with Early Clinical Features Resembling Leigh Encephalopathy.
  6. Identification of substrates of the human mitochondrial ClpXP protease and its implications for Perrault syndrome.
  7. Animal Model Selection and Deep Phenotyping in Mitochondrial Genetic Diseases: Connecting Human Variants, Multisystem Pathology, and Preclinical Evidence.
  8. Mitochondrial Genomic Variation in Rare and Metabolic Diseases: From Heteroplasmy to Precision Medicine.
  9. Elevated mitochondrial metabolism in Down syndrome iPSCs reduces commitment to neuroectoderm.
  10. Early-Onset Levodopa-Responsive Parkinsonism with Normal Brain MRI Revealing Aceruloplasminemia.
  11. Lactate takes a shortcut into mitochondria to power the heart.
  12. The AMPK signaling pathway in cell metabolism and human diseases.
  13. Biomaterials Targeting Mitochondrial NAD+ Metabolism for Tissue Regeneration.
  14. Structural and biochemical characterization of disease-associated mutations in the human mitochondrial processing peptidase α-subunit.
  15. Mitochondrial dysfunction in diabetic neuropathy: a core pathogenic hub and therapeutic implications.
  16. Survey of the human proteostasis network: the ubiquitin-proteasome system.
  1. Cell Rep. 2026 Oct 29. pii: S2211-1247(26)01073-9. [Epub ahead of print]45(11): 117995
    A stress-adapted fiber state promotes clonal expansion of deleted mitochondrial DNA.
    Diego Perez-Rodriguez, Ilaria Dalla Rosa, Anastasia Magoulopoulou, Sara Ricciardi, Samantha Davidson, Rebecca Lasalandra, Renata Kabiljo, Aine Moylett, Tamara Hill, Tengfei Wan, Aleck W E Jones, Chloe F Moss, Charlotte Zierz, Melissa L Salazar, Radha Desai, Shar-Yin N Huang, Yves Pommier, Monika Hofer, Robert D S Pitceathly, Martin A M Reijns, Joanna Poulton, Christos Proukakis, J Paul Simons, Mats Nilsson, Robert W Taylor, Ian J Holt, Antonella Spinazzola.
      Mitochondrial DNA (mtDNA) depletion and multiple deletions frequently coexist in mitochondrial disease, neurodegeneration, and aging, yet how the two relate and why deletions accumulate focally remain unresolved. Here, longitudinal bulk and in situ analyses of Mpv17-/- murine muscle reveal that a compensatory rise in mitochondrial transcripts per mtDNA initially offsets severe, uniform mtDNA depletion, preserving the respiratory chain. However, this response carries a delayed cost: by six months transcripts decline, mtDNA deletions emerge, and respiratory-deficient fibers appear. Paradoxically, fibers harboring deletions accumulate supra-physiological amounts of mtDNA, despite prior depletion. This expansion is invariably accompanied by elevated Hsp60, and the same holds in human mitochondrial myopathy. We propose that depletion reprograms mitochondrial DNA and RNA metabolism, inadvertently promoting deletion formation and creating an Hsp60-high fiber state permissive for clonal expansion. Therefore, depletion and multiple deletions can be sequential phases of a common degenerative process, relevant also to aging and neurodegeneration.
    Keywords:  CP: molecular biology; Hsp60; clonal expansion; mTORC1; mitochondrial DNA; mitochondrial DNA deletions; mitochondrial DNA depletion; mitochondrial myopathy; nanopore sequencing of mitochondrial DNA; single-fiber analysis; stress response
    DOI:  https://doi.org/10.1016/j.celrep.2026.117995
  2. Biochim Biophys Acta Mol Cell Res. 2026 Oct 24. pii: S0167-4889(26)00140-0. [Epub ahead of print] 120241
    Mitochondrial DNA replication and genome stability: From mechanisms to therapeutic strategies.
    Maria Falkenberg, Claes M Gustafsson.
      Replication of the mitochondrial genome is essential to sustain cellular energy conversion, and defects in this process cause severe, progressive mitochondrial diseases that have long lacked curative treatment. This is now beginning to change: mechanistic insight into the replication machinery has started to translate into therapy, with the first disease-modifying treatment recently approved and others entering clinical evaluation. Here we review the molecular mechanisms of mitochondrial DNA replication, with emphasis on replication initiation, deletion formation, and replication completion, and discuss how insights into these processes are opening new therapeutic possibilities for treating mitochondrial disease.
    Keywords:  DNA replication; Deletion formation; Mitochondrial disease; POLG; Treatment
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120241
  3. Nat Metab. 2026 Oct 27.
    Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
    Ruobing Cui, Keun Woo Ryu, Yi Fu, Ziad Bakouny, Dayi Li, Tamar Kavlashvili, Agnel Sfeir, Craig B Thompson.
      Mutations in mitochondrial DNA (mtDNA) impair ETC activity and oxidative phosphorylation, but their phenotypic consequences vary with heteroplasmy levels. Whether increasing mtDNA heteroplasmy creates metabolic dependencies not present in respiratory-competent cells remains unknown. Here, we show that low pyruvate carboxylase (PC) expression creates an asparagine dependency in high-mtDNA-heteroplasmy, respiration-compromised cells. In isogenic cells carrying similar mtDNA deletions, respiration declines linearly with increasing heteroplasmy, whereas redox imbalance emerges only above 50% heteroplasmy. Above 70% heteroplasmy, integrated stress-response-associated translational defects emerge, which can be reversed by either exogenous asparagine or PC overexpression. Asparagine dependence inversely correlates with PC expression across respiration-deficient cells. Consistent with this pattern, patient-derived thyroid tumour cells harbouring a high-heteroplasmy complex I mutation and low PC levels exhibit asparagine auxotrophy and sensitivity to L-asparaginase. Together, these findings demonstrate a role for mitochondrial PC in cellular asparagine synthesis under conditions of compromised respiratory activity.
    DOI:  https://doi.org/10.1038/s42255-026-01651-4
  4. Sci Adv. 2026 Oct 30. 12(44): eaeg5364
    Augmenting intercellular mitochondrial transfer for tissue repair and rejuvenation.
    John Soukar, Kayli Jones, Natalie M Garza, Valeria Duran Salas, Shounak Roy, Vishal M Gohil, Akhilesh K Gaharwar.
      Cells exhibit innate reparative communication, enabling the exchange of bioactive molecules and, in some cases, entire organelles. Harnessing this endogenous process of intercellular organelle transfer represents an emerging therapeutic paradigm for restoring cellular function in diseases driven by organelle dysfunction. Mitochondrial transfer has gained prominence for its ability to restore bioenergetic capacity, mitigate oxidative stress, and rescue metabolic function in cells with impaired mitochondrial activity. Given that genetic or acquired defects in mitochondrial function are associated with diverse pathologies, including neurodegeneration, cardiovascular diseases, metabolic disorders, skeletal muscle defects, immune dysregulation, and age-associated decline, mitochondrial transfer offers broad therapeutic potential. Mitochondrial transfer seeks to deliver functional mitochondria to injured cells to reestablish metabolic competence. However, insufficient organelle trafficking and limited control over transfer dynamics remain critical barriers to clinical translation. Recent biotechnological developments aimed at enhancing donor-recipient connectivity, increasing mitochondrial availability, and modulating transfer machinery have begun to address some of these key challenges. This review highlights recent advances in mitochondrial transfer bioengineering, emerging therapeutic applications, and key challenges that must be resolved to enable clinical deployment.
    DOI:  https://doi.org/10.1126/sciadv.aeg5364
  5. Children (Basel). 2026 Sep 30. pii: 1332. [Epub ahead of print]13(10):
    A Pediatric Case of Homocystinuria Due to MTHFR Deficiency with Early Clinical Features Resembling Leigh Encephalopathy.
    Tatsunori Itabashi, Jiro Abe, Midori Nakajima, Yuki Ueda, Kiyoshi Egawa, Masayoshi Nagao, Atsuhito Takeda.
      Background: Leigh encephalopathy is one of the most common phenotypes of mitochondrial diseases. It is characterized by progressive psychomotor regression, accompanied by elevated lactate/pyruvate ratios in blood and cerebrospinal fluid (CSF) and lactate on MRS, and symmetric lesions in the bilateral basal ganglia on brain MRI. A clinical diagnosis is made based on these findings and is confirmed by demonstrating mitochondrial dysfunction through genetic or enzymatic testing. However, some patients who present with clinical features of Leigh encephalopathy actually develop secondary mitochondrial dysfunction due to inborn errors of metabolism, thereby exhibiting a Leigh syndrome phenotype. Case Presentation: The patient was born at term without perinatal complications. Poor feeding was noted from two months of age, and microcephaly and hypotonia were identified at the 4-month health checkup. At 5 months, the patient was admitted for further evaluation. CSF analysis revealed an elevated lactate-to-pyruvate ratio of 21. Brain MRI demonstrated symmetrical T2-weighted hyperintensities in the bilateral basal ganglia, and MR spectroscopy detected a lactate peak in the same region. Based on clinical findings, CSF results, and MRI features, Leigh encephalopathy was suspected. At 9 months, mitochondrial DNA sequencing of skeletal muscle showed no significant mutations, and skeletal muscle biopsy revealed no findings suggestive of neuromuscular disease. At 7 years of age, two weeks after contracting COVID-19, the patient was admitted to the hospital with acute metabolic decompensation characterized by acidosis and complicated by a small intraventricular hemorrhage. Tandem mass spectrometry performed during the episode suggested homocystinuria due to MTHFR deficiency. Subsequent trio-based genetic testing revealed compound heterozygous variants in MTHFR. Measurement of MTHFR enzyme activity revealed a profound reduction, confirming the diagnosis of homocystinuria due to MTHFR deficiency. After initiation of specific metabolic therapy, including betaine, both urinary and plasma homocysteine levels decreased, and clinical symptoms improved. Conclusions: Homocystinuria due to MTHFR deficiency may cause secondary mitochondrial dysfunction, leading to a Leigh syndrome phenotype. When Leigh encephalopathy is suspected, metabolic screening should be performed to avoid missing potentially treatable diseases.
    Keywords:  Leigh encephalopathy; Leigh syndrome spectrum; homocystinuria due to MTHFR deficiency; methylenetetrahydrofolate reductase (MTHFR)
    DOI:  https://doi.org/10.3390/children13101332
  6. Nat Commun. 2026 09 24. pii: 11098. [Epub ahead of print]17(1):
    Identification of substrates of the human mitochondrial ClpXP protease and its implications for Perrault syndrome.
    Mazen E Aljghami, Trevor M Morey, Mark F Mabanglo, Jonathan J Meyrick, Huw B Thomas, Jiacheng Yu, Arveen Tahmasebi, King Lam Lai, Benjamin Bernard Armando Raymond, Matthias Trost, Robert W Taylor, Raymond T O'Keefe, William G Newman, Uwe Richter, Walid A Houry.
      The ClpXP ATP-dependent unfoldase-protease complex plays important roles in maintaining protein homeostasis in the mitochondria. Pathogenic variants of CLPP have been identified in patients with Perrault syndrome type 3 (PRLTS3), a rare recessive mitochondrial disease characterized by sensorineural hearing loss, ovarian dysfunction, and neurological abnormalities. However, it remains unclear how these ClpP variants cause this disease. Here we identify three cellular substrates of ClpXP using proteomic analysis of PRLTS3 patient-derived fibroblasts, with follow up studies using induced pluripotent stem cells (iPSCs) and iPSC-derived neural progenitor cells, alongside in vitro biochemical assays. These substrates are: CHCHD2, a bi-organellar regulator of oxidative phosphorylation and mitochondrial stress responses; ALAS1, which catalyzes the rate-limiting step in heme biosynthesis; and TFAM, an essential mitochondrial transcription factor. Efficient degradation of these substrates by ClpXP requires the adaptor protein PDIP38. We propose that dysregulated cellular levels of these substrates might contribute to the etiology of PRLTS3.
    DOI:  https://doi.org/10.1038/s41467-026-77888-0
  7. Genes (Basel). 2026 Sep 22. pii: 1165. [Epub ahead of print]17(10):
    Animal Model Selection and Deep Phenotyping in Mitochondrial Genetic Diseases: Connecting Human Variants, Multisystem Pathology, and Preclinical Evidence.
    Nobuya Sasaki, Masaki Watanabe.
      Mitochondrial genetic diseases arise from variants in mitochondrial DNA (mtDNA) or nuclear genes required for mitochondrial function. Although many involve several organs, the predominant clinical manifestations may be confined to particular organs. Experimental models are used to investigate variant pathogenicity, organ vulnerability, disease progression, therapeutic response, and safety. We discuss how to select animal models and other experimental systems for specific research questions. We focus on genetically engineered mice (constitutive knockout, knock-in/humanized, conditional/tissue-specific, inducible, and heteroplasmic mtDNA models) and consider when yeast, worms, flies, zebrafish, rats, large animals, companion animals, and human in vitro models can complement or replace particular animal experiments. We define deep phenotyping by five minimum characteristics: longitudinal assessment across defined disease stages; prespecified relationships among molecular, mitochondrial, organ, and whole-animal measurements; integration of repeated and terminal endpoints; alignment with patient-relevant disease stages; and separation of primary from exploratory outcomes. Model selection depends on the experimental objective and the evidence needed to address it. We also propose a multidomain framework that distinguishes target engagement, molecular correction, downstream pharmacodynamic responses, organ function, and whole-animal or patient-relevant benefit without assuming that effective treatments must improve every domain sequentially. We also discuss reporting practices, the 3Rs (Replacement, Reduction, and Refinement), and the implications of mtDNA editing, iPSC-derived systems, organoids, and automated phenotyping for study design.
    Keywords:  3Rs; animal model; deep phenotyping; heteroplasmy; mitochondrial disease; mouse model; mtDNA editing; preclinical research; reproducibility; translational research
    DOI:  https://doi.org/10.3390/genes17101165
  8. Life (Basel). 2026 Sep 23. pii: 1590. [Epub ahead of print]16(10):
    Mitochondrial Genomic Variation in Rare and Metabolic Diseases: From Heteroplasmy to Precision Medicine.
    Arijahir Alexis Mancio-Cárdenas, Humberto García-Ortiz, Francisco Barajas-Olmos, Cecilia Contreras-Cubas, Ximena Luna-González, Diego Ramírez-Martínez, Federico Centeno-Cruz, José Rafael Villafán-Bernal, Montserrat Ivonne Morales-Rivera, Beth Mitchell Gamez-Rangel, Angélica González-Oliver, Lorena Orozco, Angélica Martínez-Hernández.
      Mitochondrial DNA (mtDNA) variation has traditionally been investigated in the context of human evolution and rare mitochondrial diseases; however, growing evidence suggests that it may also contribute to susceptibility to common metabolic disorders. This review integrates current knowledge of mitochondrial biology, mtDNA genetics, heteroplasmy, and the global distribution of mitochondrial haplogroups to examine their roles in health and disease. In this narrative review, we synthesized English-language studies identified through PubMed, Scopus, and Web of Science from January 1988 to May 2026, prioritizing evidence according to relevance, scientific contribution, recency, and historical significance. We summarize evidence showing how pathogenic variants (PVs) in mtDNA genes impair oxidative phosphorylation (OXPHOS), increase reactive oxygen species (ROS) production, and disrupt cellular bioenergetics, thereby contributing to the multisystem manifestations of mitochondrial diseases. We further discuss population-specific mitochondrial haplogroups and their reported population-specific associations with metabolic phenotypes, including obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD). Finally, we review recent advances in next-generation sequencing technologies and their contributions to the molecular diagnosis of mitochondrial diseases and the characterization of genotype-phenotype relationships. Collectively, current evidence supports a well-established pathogenic role for specific mtDNA variants in primary mitochondrial disorders, whereas the contributions of common polymorphisms and haplogroups to complex metabolic disease remain largely associative and require further replication and functional validation.
    Keywords:  bioenergetics; heteroplasmy; metabolic disorders; mitochondrial disease; next-generation sequencing; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/life16101590
  9. EMBO Rep. 2026 Oct 30.
    Elevated mitochondrial metabolism in Down syndrome iPSCs reduces commitment to neuroectoderm.
    Malay Chaklader, Guilherme Henrique Souza Bomfim, Jiankun Zhu, Neil Jeju, Theodore Nguyen, Yingli Duan, Brian F Niemeyer, Joaquin M Espinosa, Edwin Rosado-Olivieri, Weichun Lin, Rodrigo S Lacruz, Beverly A Rothermel.
      A key feature of Down syndrome (DS) is reduced neurogenesis. Here, we provide evidence that increased mitochondrial metabolism in DS stem cells reduces their ability to commit to neuroectoderm (NE), one of the earliest steps in the development of the nervous system. We show that mitochondria in induced pluripotent stem cells derived from individuals with DS (3S-iPSCs) have a higher membrane potential and increased capacity for calcium uptake via the mitochondrial calcium uniporter (MCU) compared to isogenic, euploid controls. Consequently, 3S-iPSCs proliferate faster and spend less time in G1 of the cell cycle. This reduces the opportunity for growth of a primary cilium, an important developmental signaling hub. Inhibiting MCU or slowing proliferation of 3S-iPSCs is sufficient to increase ciliation and improve commitment to NE. In summary, we provide evidence that a mitochondria-to-cilia signaling axis important during the earliest steps of neurogenesis is dysregulated in DS iPSCs.
    DOI:  https://doi.org/10.1038/s44319-026-00944-9
  10. Mov Disord Clin Pract. 2026 Oct 28.
    Early-Onset Levodopa-Responsive Parkinsonism with Normal Brain MRI Revealing Aceruloplasminemia.
    Sabrine Othmani, Francesca Pinna, Antonio Emanuele Elia, Claudia Frau, Elisa Ogana, Andrea Salis, Carla Bagella, Valeria Tiranti, Federica Invernizzi, Paolo Solla, Caterina Francesca Bagella.
      
    Keywords:  CP gene; aceruloplasminemia; dopamine transporter imaging; iron metabolism; parkinsonism
    DOI:  https://doi.org/10.1002/mdc3.70879
  11. Nature. 2026 Oct 28.
    Lactate takes a shortcut into mitochondria to power the heart.
    Trace Thome, Zolt Arany.
      
    Keywords:  Cell biology; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-026-03261-2
  12. Signal Transduct Target Ther. 2026 Oct 27. pii: 471. [Epub ahead of print]11(1):
    The AMPK signaling pathway in cell metabolism and human diseases.
    Zhengkui Zhang, Yuanzhuo Gu, HongChao He, Shilei Qiao, Yifan Shao, Xianming Long, Jun Huang, Long Zhang, Fangfang Zhou.
      Adenosine 5'-monophosphate-activated protein kinase (AMPK), a highly conserved energy-sensing kinase, plays a central role in maintaining cellular metabolic homeostasis, such as glucose/lipid metabolism, mitochondrial biogenesis, and autophagy, to counteract energetic stress. Beyond the canonical adenylate-dependent activation of AMPK by sensing the ATP:AMP/ADP ratio, emerging evidence reveals noncanonical activation mechanisms. Proper AMPK signaling is essential for physiological functions, whereas its dysregulation underlies various pathologies, including metabolic diseases, immune disorders, and cancer. This review systematically recapitulates the historical background and landmark discoveries of the AMPK field, including the discovery of AMPK, the structure of AMPK complex, upstream regulators and downstream substrates, and the transcriptional/posttranscriptional and posttranslational regulatory mechanisms. Furthermore, we delineate its roles in maintaining metabolic equilibrium, mitochondrial integrity, and immune competence across organ systems and highlight how dysregulated AMPK activity contributes to pathological diseases, encompassing alterations in its expression levels, intrinsic kinase activity, subcellular localization or upstream regulatory signaling cascades. Specifically, we focus on knock-in or knockout mouse models utilized to study AMPK-associated human diseases and the translational potential of AMPK-targeting agonists or antagonists across diverse pathological conditions. A deep understanding of the multidimensional regulatory network of AMPK and mechanistic insights with therapeutic innovations that we provide with this review will help address the challenges of complex metabolic diseases.
    DOI:  https://doi.org/10.1038/s41392-026-02790-6
  13. Adv Healthc Mater. 2026 Oct 26. pii: e71902. [Epub ahead of print]
    Biomaterials Targeting Mitochondrial NAD+ Metabolism for Tissue Regeneration.
    Xinyu Ma, Mengying Li, Tingyu Ren, Yuchao Li, Yufang Zhu, Yuxin Wang, Lei Han.
      Mitochondrial nicotinamide adenine dinucleotide (NAD+) has emerged as a pivotal regulator in tissue regeneration, central to cellular energy metabolism and redox homeostasis. It regulates key mitochondrial processes-including energy production, reactive oxygen species (ROS) scavenging, and cell death-primarily through the tricarboxylic acid cycle (TAC), oxidative phosphorylation, and sirtuin deacetylase activity. This coordinated regulation fosters a favorable metabolic and immune microenvironment conducive to tissue repair. Strategies to increase mitochondrial NAD+ levels, such as delivery, precursor supplementation (e.g., NR or NMN), catalytic conversion, and inhibition of NAD+-consuming enzymes, have demonstrated significant efficacy in promoting regeneration across diverse tissues, including bone, cartilage, tooth, skin, myocardium, muscle, nerve, and vascular. There is no review that systematically addresses the latest progress in the advances of biomaterials targeting mitochondrial NAD+ metabolism for tissue regeneration. This review fills the gap by outlining the central role of biomaterials targeting mitochondrial NAD+ in tissue regeneration. We introduce the biological functions and regulatory mechanisms of mitochondrial NAD+, highlight the intervention strategies to boost NAD+ levels, and summarize the applications across diverse regenerative contexts. Finally, we discuss prevailing challenges and future prospects, providing new theoretical and interventional insights for regenerative medicine.
    Keywords:  NAD+; biomaterials; metabolic homeostasis; mitochondrial; tissue regeneration
    DOI:  https://doi.org/10.1002/adhm.71902
  14. J Struct Biol. 2026 Oct 26. pii: S1047-8477(26)00100-0. [Epub ahead of print]218(4): 108384
    Structural and biochemical characterization of disease-associated mutations in the human mitochondrial processing peptidase α-subunit.
    Danielle M Simons, Sibei Qin, Kim Munro, Lindsay A Matthews, Christopher J Thibodeaux, Jean-François Trempe.
      The mitochondrial processing peptidase (MPP) is an essential heterodimeric protease responsible for cleavage of N-terminal mitochondrial targeting sequences (N-MTSs) from most nuclear-encoded mitochondrial proteins following import into the mitochondrial matrix. Pathogenic variants in the α-subunit of MPP (PMPCA) cause a spectrum of mitochondrial disorders, including spinocerebellar ataxia type 2 (SCAR2), encephalopathy, and severe neurodevelopmental disease; however, the molecular mechanisms underlying these phenotypes remain poorly understood. Here, we combined biochemical and structural approaches to characterize five disease-associated PMPCA variants (S96L, R185W, R268W, A377T, and G515R). Enzymatic analyses revealed variant-specific defects in substrate processing, with most mutations severely impairing cleavage of the rapidly processed substrate malate dehydrogenase 2. In contrast, several variants exhibited only modest impairment in the processing of the slowly cleaved substrate PINK1. Mass photometry demonstrated reduced heterodimerization of all variants, whereas circular dichroism identified varying degrees of structural destabilization, particularly for S96L and G515R. To define the structural basis of these defects, hydrogen-deuterium exchange mass spectrometry was performed on wild type MPP and selected variants. Pathogenic mutations altered substrate-induced conformational changes within previously characterized substrate-recognition elements, including the glycine-rich loop. Furthermore, we identified a previously unrecognized region, termed the INS loop, that exhibited substrate-dependent protection uniquely in the wild type enzyme but was consistently disrupted across pathogenic variants. Together, these findings demonstrate that PMPCA mutations impair MPP function through diverse mechanisms involving protein stability, dimerization, substrate selectivity, and allosteric conformational dynamics. Our work provides a mechanistic framework for understanding genotype-phenotype relationships in PMPCA-associated disease.
    Keywords:  Hydrogen‑deuterium exchange mass spectrometry; MPP; Mitochondria; PMPCA; Peptidase; SCAR2
    DOI:  https://doi.org/10.1016/j.jsb.2026.108384
  15. J Transl Med. 2026 Oct 17. pii: 1354. [Epub ahead of print]24(1):
    Mitochondrial dysfunction in diabetic neuropathy: a core pathogenic hub and therapeutic implications.
    Xiaotong Wu, Xiaobo Li, Nengjun Lou, Xianghua Zhuang, Shihong Chen.
       BACKGROUND: Diabetic neuropathy is a heterogeneous complication of diabetes in which sensory loss, neuropathic pain, autonomic dysfunction and distal axonal degeneration cannot be fully explained by hyperglycaemia alone. Because peripheral axons, Schwann cells and autonomic neurons depend on sustained bioenergetic support, mitochondrial injury has emerged as a central link between metabolic overload, neuroinflammation and progressive nerve dysfunction.
    MAIN BODY: This review synthesizes evidence that hyperglycaemia, lipotoxicity and microvascular stress impair electron transport, oxidative phosphorylation and mitochondrial DNA stability, leading to excessive reactive oxygen species generation, calcium dyshomeostasis, mitochondrial permeability transition pore opening and maladaptive metabolic reprogramming. Disrupted fission-fusion balance, defective axonal transport, impaired mitophagy and abnormal mitochondria-associated endoplasmic reticulum membranes further weaken mitochondrial quality control in long peripheral axons. These changes engage SARM1-related NAD+ depletion, inflammasome activation, cGAS-STING signalling, apoptosis and glial-neuronal metabolic failure, thereby connecting bioenergetic collapse with pain sensitisation, distal axonal degeneration and autonomic dysfunction. Across painful and painless diabetic peripheral neuropathy, corneal small-fibre neuropathy, autonomic neuropathy and diabetes-related central nervous system injury, mitochondrial mechanisms appear shared, but endpoints and dominant cell types differ. Translationally, exercise and dietary strategies, metabolic regulators, SARM1 and calcium-pathway targeting, mitophagy modulation, mitochondria-directed antioxidants, and traditional Chinese medicine or natural products are discussed as metabolism-oriented interventions. Current evidence supports target engagement in experimental systems, but human validation, tissue exposure data, structural nerve endpoints and high-quality disease-modifying trials remain insufficient.
    CONCLUSION: Mitochondrial dysfunction functions as a core pathogenic hub-rather than the sole cause-linking substrate overload, redox imbalance, calcium stress, organelle quality-control failure, inflammatory signalling, and axonal degeneration in diabetic neuropathy. The most actionable translational path is not symptomatic antioxidant use alone but biomarker-guided, mechanism-stratified trials that connect mitochondrial target modulation with small-fibre structure, nerve function, safety, and patient-centred outcomes.
    SEARCH STRATEGY AND EVIDENCE SELECTION: For this narrative review, PubMed was searched from database inception to 1 August 2026, supplemented by backward reference screening of relevant original studies and recent reviews. Search terms included "diabetic neuropathy", "diabetic peripheral neuropathy", "mitochondria", "oxidative phosphorylation", "oxidative stress", "mitophagy", "SARM1", "NLRP3", "cGAS-STING", and "mitochondria-associated endoplasmic reticulum membranes", alone and in combination. English-language original mechanistic, translational, observational, and interventional studies were prioritised; recent high-quality reviews were used for context and to identify primary studies. Evidence from other neurological disorders was retained only when direct DN evidence was limited and the study clarified biological plausibility. Because this is a narrative review, no formal risk-of-bias tool or GRADE assessment was applied; human, animal, and cellular evidence and major translational limitations are instead distinguished explicitly.
    Keywords:  Diabetic neuropathy; Mitochondrial dysfunction; Mitophagy; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1186/s12967-026-09015-y
  16. Autophagy. 2026 Oct 29. 1-33
    Survey of the human proteostasis network: the ubiquitin-proteasome system.
    Suzanne Elsasser, Evan T Powers, Thomas Stoeger, Xiaojing Sui, Roy D Kurtzbard, Patricia Martínez-Botía, Margaret A Wangeline, Alejandro Rodriguez Gama, Edward L Huttlin, Lisa P Elia, Jeffery W Kelly, Jason E Gestwicki, Judith Frydman, Steven Finkbeiner, Eugenia M Clerico, Richard I Morimoto, Miguel A Prado, Alfred C O Vertegaal, Kay Hofmann, Daniel Finley.
      Modification by ubiquitination governs the half-lives of thousands of proteins that are fated for elimination by either the proteasome or autophagy pathways, depending on the intricate architectures of ubiquitin modification. This system mediates quality control for individual proteins, protein complexes, and organelles, as well as myriad purely regulatory functions. Here we provide a comprehensive survey of the ubiquitin-proteasome system (UPS), the scope of which is at present poorly defined. The UPS, with the inclusion of pathways involving ubiquitin-like modifiers, comprises in our estimate over 1430 distinct components in humans, a vast set of activities whose collective impact on the biology of the cell is pervasive. The UPS is an integral component of the proteostasis network (PN), the remainder of which is surveyed in the accompanying reports. With the addition of molecular chaperones, proteins from autophagy-lysosome pathway, and related activities, the PN includes in total over 3150 components by our estimates. Comprehensive and systematic definition of these pathways should facilitate a range of ongoing investigations in the areas of genomics, proteomics, biochemistry, cell biology, and disease research.Abbreviations: APC, anaphase promoting complex; CDD, Conserved Domain Database; CRL, cullin RING ligase; DSB, double-strand break; DUB, deubiquitinating enzyme; ERAD, ER-associated degradation; PN, proteostasis network; RBR, RING-between-RING; RCR, RING-Cys-Relay; SPOC, Structure Prediction and Omics-informed Classifier; UB, ubiquitin; UBL, ubiquitin-like; UBLM, ubiquitin-like modifier; UEV, ubiquitin-conjugating enzyme variant; UPS, ubiquitin-proteasome system.
    Keywords:  Cullin; UFMylation; deubiquitination; sumoylation; ubiquitin ligase; ubiquitin-like modifier
    DOI:  https://doi.org/10.1080/15548627.2026.2741092
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