bims-mitmed 2026-09-13 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–09–13
eleven papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Allotopic Expression of ND6 Restores Vision in a Mitochondrial Disease Model.
Progress and perspectives in primary mitochondrial myopathy: Highlights from the 2025 mitochondrial medicine masterclass with a focus on TK2 deficiency.
Metabolic regulation of mitochondrial DNA (mtDNA) homeostasis.
Endothelial-mitochondrial coupling in mitochondrial disease: A systematic review and quantitative synthesis of vascular, biochemical, and oxidative bioenergetic dysfunction.
Acute and Chronic Pancreatitis in Mitochondrial Disease: A Systematic Review.
Differential activation of TCA cycle activity and PDH flux by dichloroacetate in skeletal muscle measured by hyperpolarized [2-13C,3-2H3]pyruvate.
Childhood proteomic signatures that predict adult cardiometabolic disease.
Primary Mitochondrial-Disorders-Associated Nephropathy in Adulthood.
Resolving cell lineages and gene functions in the developing mouse gastrointestinal tract using in utero transduction.
Clinical base editing for β-hemoglobinopathies across different genetic backgrounds.
Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.

JCI Insight. 2026 Sep 08. pii: e209108. [Epub ahead of print]

Allotopic Expression of ND6 Restores Vision in a Mitochondrial Disease Model.

Cheng Ai, Huiying Li, Jing Wu, Tianwei Zhou, Jing Wang, Shao-Hui Pan, Jun Yu, Douglas C Wallace, Min-Xin Guan.

  Mutations in mitochondrial DNA (mtDNA) cause various mitochondrial diseases that are currently incurable. Allotopic expression of nuclear-recoded mitochondrial genes represents a promising therapeutic strategy, given its demonstrated capacity to restore mitochondrial function in human cell models harboring mtDNA mutations. However, the in vivo evaluation of allotopic gene therapy has been hindered by optimization challenges and the lack of appropriate animal models. Here, we overcome these limitations by utilizing an optimized AAV2-ND6 construct with codon optimization and mitochondrial targeting sequence in a mouse model bearing the homoplasmic ND6P25L mutation, which recapitulates Leber hereditary optic neuropathy (LHON). High-dose administration of the AAV2-ND6 construct resulted in robust, sustained expression within the retina and optic nerve without apparent systemic toxicity. Strikingly, We compared the therapeutic efficacy in mutant mice at different ages and pre-symptomatic intervention with AAV2-ND6 effectively attenuated disease progression, mitigated retinal cellular deficiencies and optic nerve damage, and restored visual function in ND6P25L mice. Mechanistically, allotopic ND6 expression markedly rescued the mitochondrial dysfunction, corrected dysregulated retinol metabolism and phototransduction pathways, and suppressed apoptotic processes in the mutant retina. Our study validates the safety and therapeutic potential of allotopic expression in vivo and provide critical mechanistic insights into its role in treating LHON and other mitochondrial diseases.

Keywords:  Gene therapy; Genetics; Mitochondria; Ophthalmology; Retinopathy

DOI:  https://doi.org/10.1172/jci.insight.209108
Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261478640

Progress and perspectives in primary mitochondrial myopathy: Highlights from the 2025 mitochondrial medicine masterclass with a focus on TK2 deficiency.

Austin Larson, Jared Goettemoeller, Ken Goettemoeller, Linda Goettemoeller, Amy Goldstein, Nikki Huggan, Amel Karaa, Megan Leahey, Fernando Scaglia, Philip Yeske, Zarazuela Zolkipli-Cunningham, Michio Hirano.

  The inaugural United Mitochondrial Disease Foundation (UMDF) Mitochondrial Medicine 2025 Masterclass focused on primary mitochondrial diseases (PMDs) especially primary mitochondrial myopathies (PMMs) and thymidine kinase 2 deficiency (TK2d). The Masterclass featured leading US experts in the field, providing the latest scientific and clinical knowledge, as well as patients and caregivers sharing their lived experience of mitochondrial diseases. In this report, we summarize the key highlights of each presentation. An overview of PMM featuring the etiologies of different PMMs and key features of notable PMMs, was followed by a presentation discussing the practical clinical processes of diagnosing PMM, how the roles of clinicians have evolved as diagnostic technology has improved, and actions clinicians can take to maximize the chances of an early, accurate diagnosis. Real-world case studies highlighted variations in disease presentation among the wide range of PMMs, which was followed by an in-depth review of clinical assessments and symptom management for PMM across organ systems. Multisystemic disorders like PMM require multidisciplinary management, in both a chronic and acute setting, and two experts discussed the practical workflow for clinicians to build a multidisciplinary model of care at their hospitals, the roles and responsibilities of the lead coordinator and each subspecialist, and practical steps that clinicians can take to manage acute care coordination and decrease acute care utilization. A hypothetical case study of TK2d (based on real patients) brought together the different aspects of PMM discussed during the Masterclass, while the patient perspective presentations allowed patients and caregivers to discuss the real-world impact that the diagnostic and care journey had on them and their families. This Educational Masterclass provided detailed knowledge of PMM designed to provide the next generation of clinicians and investigators with practical, actionable guidance and resources they could utilize to make a difference in the lives of patients with PMM.

Keywords:  TK2d; mitochondrial disease; mitochondrial myopathy

DOI:  https://doi.org/10.1177/26330040261478640
Biochim Biophys Acta Mol Cell Res. 2026 Sep 06. pii: S0167-4889(26)00119-9. [Epub ahead of print]1873(8): 120220

Metabolic regulation of mitochondrial DNA (mtDNA) homeostasis.

Tânia Catarina Medeiros, Gaetano Calabrese.

  Mitochondria are central hubs of cellular metabolism that harbor their own genome (mtDNA), whose maintenance is essential for both cellular and organismal homeostasis. Unlike nuclear DNA, mtDNA replicates continuously throughout the cell cycle, rendering it particularly sensitive to changes in metabolic state. Emerging evidence indicates that mtDNA homeostasis is not governed solely by dedicated replication factors but is tightly coupled to cellular metabolism. In this review, we discuss how metabolic networks shape mtDNA maintenance through three interconnected layers: mitochondrial nucleotide pools, metabolic control of the replication machinery, and stress-response pathways. This conceptual framework underscores the direct role of metabolic state in governing mtDNA replication, stability, and quality control, with significant implications for mitochondrial disease and therapeutic strategies.

Keywords:  Integrated stress response (ISR); Metabolism; Mitochondrial DNA (mtDNA); Mitochondrial diseases; Nucleotides; Replication machinery

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120220
Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261480132

Endothelial-mitochondrial coupling in mitochondrial disease: A systematic review and quantitative synthesis of vascular, biochemical, and oxidative bioenergetic dysfunction.

Jose A Adams, Tiffany Ko, Laith R Sultan, Tejas Sarna, Daniel McGinn, Arkady Uryash, Jose R Lopez, Vinay Nadkarni, Rui Xiao, Marni J Falk, Harry Ischiropoulos, Zarazuela Zolkipli-Cunningham.

   Introduction: Mitochondrial diseases are multisystem disorders in which defects in oxidative phosphorylation disrupt cellular bioenergetics and redox signaling across the vasculature and heart. Because mitochondrial function is closely linked to endothelial nitric oxide (NO) production, we hypothesized that mitochondrial diseases manifest as a NO-deficiency endotheliopathy affecting conduit and microvascular function. To evaluate this, we performed a systematic review with quantitative synthesis of human studies reporting vascular reactivity, biochemical NO production, or myocardial metabolic imaging, aiming to define the magnitude of impairment and responsiveness to NO-precursor therapy (l-arginine or l-citrulline).
Methods: Following PRISMA 2020 guidelines, we conducted a comprehensive search (inception-October 2025) identifying clinical studies of genetically or clinically confirmed mitochondrial disease with quantitative endothelial or bioenergetic endpoints. Eligible measures included flow-mediated dilation (FMD), reactive hyperemia index (RHI), passive-leg-movement (PLM) hyperemia, absolute synthesis rate of NO metabolites (ASR NOm), and positron emission tomography (PET)-derived myocardial oxidative indices (k mono , DP/k mono ). Quantitative synthesis used Hedges g for between-group comparisons and standardized mean change (SMC) for within-subject responses. Risk of bias was evaluated using ROBINS-I and a modified Newcastle-Ottawa Scale.
Results: Seven studies met these inclusion criteria, comprising 76 mitochondrial-disease subjects and 81 controls (ages 8-63 years). Across all vascular and metabolic domains, mitochondrial disease was associated with marked endothelial and bioenergetic impairment. Macro- and microvascular dysfunction, reflected by reduced FMD, RHI, and PLM hyperemia, demonstrated severe endothelium-specific abnormalities. Biochemical assays showed diminished NO synthesis. Myocardial PET imaging revealed reduced oxidative rate constants and increased energetic inefficiency despite preserved perfusion. Nitric oxide synthesis-precursor therapy was associated with improved endothelial reactivity (increased FMD, RHI, and ASR NOm) and significant, modest improvements in myocardial oxidative metabolism, consistent with partial restoration of endothelial NO signaling. Effect sizes collectively supported a reversible NO-deficiency endotheliopathy. The risk-of-bias assessment indicated moderate-to-good methodological quality, with limitations primarily related to small sample sizes and nonrandomized designs.
Conclusions: Mitochondrial disease is characterized by significant impairments in vascular reactivity, NO signaling, and myocardial bioenergetics. Improvements in endothelial function and NO synthesis following l-arginine or l-citrulline supplementation are consistent with a role for impaired endothelial NO signaling in the vascular manifestations of mitochondrial disease. These findings highlight the vascular endothelium as a potential therapeutic target and underscore the need for future clinical intervention trials that use standardized vascular and bioenergetic endpoints.

Keywords:  and stroke-like episodes (MELAS); flow mediated dilatation; lactic acidosis; mitochondrial disease; mitochondrial dysfunction; mitochondrial encephalomyopathy; nitric oxide; vascular endothelium

DOI:  https://doi.org/10.1177/26330040261480132
JIMD Rep. 2026 Sep;67(5): e70125

Acute and Chronic Pancreatitis in Mitochondrial Disease: A Systematic Review.

Olivia Hahl, Mika H Martikainen.

  Mitochondrial disease is a common inherited multisystem neurometabolic disorder. Pancreatic dysfunction is a recognised manifestation, most frequently presenting as mitochondrial diabetes. Although pancreatitis cases have been reported in association with mitochondrial disease, acute and chronic pancreatitis in this context remain poorly characterised. Following the PRISMA framework, we performed a systematic literature review to identify all published cases in which acute or chronic pancreatitis occurred in individuals with a genetically confirmed mitochondrial disease. Literature search yielded 604 publications, of which 19 fit the inclusion criteria. During revision two additional publications were identified, one of which fit the inclusion criteria. These 20 reports described 24 individuals with mitochondrial disease and documented history of acute or chronic pancreatitis. Mean age at first recorded pancreatitis was 13 years, with median age 10 years (range 3 months to 53 years). Pancreatitis was recurrent or chronic in 63% of cases. The most reported presenting symptoms were abdominal pain (38%) and vomiting (33%). None had established pancreatitis risk factors such as gallstones or alcohol misuse. In those who underwent imaging, no structural abnormalities of the pancreas or biliary tree were identified. Most frequent genetic aetiologies were large-scale mitochondrial DNA (mtDNA) deletions and the m.3243A>G mtDNA variant (29% each). Six patients (25%) died shortly after hospital admission with pancreatitis. Pancreatitis associated with mitochondrial disease often presents in childhood and is frequently recurrent or chronic. Although uncommon, it represents a clinically significant and potentially life-threatening complication that warrants increased awareness.

Keywords:  m.3243A>G; mitochondrial DNA; mitochondrial disease; pancreatitis; systematic review

DOI:  https://doi.org/10.1002/jmd2.70125
iScience. 2026 Sep 18. 29(9): 117325

Differential activation of TCA cycle activity and PDH flux by dichloroacetate in skeletal muscle measured by hyperpolarized [2-13C,3-2H3]pyruvate.

Sung-Han Lin, Andrew Cho, Mai T Huynh, Zohreh Erfani, Blanka Kucejova, Sasanka Wathukara Dewage, Thomas Jue, Xiaorong Fu, Zoltán Kovács, Shawn C Burgess, Jae Mo Park.

  Despite the central role of skeletal muscle bioenergetics in whole-body metabolic health, assessing mitochondrial oxidative phosphorylation and tricarboxylic acid (TCA) cycle activity in vivo remains a major challenge. While hyperpolarized [1-13C]pyruvate has been used to probe pyruvate dehydrogenase (PDH) flux to approximate TCA cycle activity, this approach relies on the unreliable assumption that PDH and TCA cycle fluxes are tightly coupled. Here, we demonstrate that hyperpolarized [2-13C,3-2H3]pyruvate can track label-incorporation into TCA cycle-derived glutamate in rat skeletal muscle. Following intravenous dichloroacetate administration, we observed a greater increase in hyperpolarized [1-13C]acetyl-L-carnitine relative to [5-13C]glutamate, suggesting disproportionately increased PDH flux relative to TCA cycle flux. A similar trend was also observed in ex vivo GC-MS analysis of skeletal muscle tissue collected from rats injected with [U-13C3]pyruvate. Together, these findings highlight the complex interplay between PDH and TCA cycle fluxes and establish hyperpolarized [2-13C,3-2H3]pyruvate as a robust agent for assessing mitochondrial metabolism in skeletal muscle.

Keywords:  TCA cycle; acetyl-L-carnitine; dichloroacetate; hyperpolarized; oxidative phosphorylation; pyruvate; pyruvate dehydrogenase; skeletal muscle

DOI:  https://doi.org/10.1016/j.isci.2026.117325
Nat Metab. 2026 Sep 11.

Childhood proteomic signatures that predict adult cardiometabolic disease.

DOI: https://doi.org/10.1038/s42255-026-01588-8
Kidney Int Rep. 2026 Oct;11(10): 106999

Primary Mitochondrial-Disorders-Associated Nephropathy in Adulthood.

Hugo Bakis, Aurélien Trimouille, Maximilian Schwarz, Christian Combe, Idris Boudhabhay, Marie-Laure Martin-Négrier, Claire Rigothier.

  Oxidative phosphorylation (OXPHOS) is the main source of cellular adenosine triphosphate (ATP) production and depends on proteins encoded by both mitochondrial and nuclear DNA (nDNA). Pathogenic variants affecting this dual genetic control cause primary mitochondrial disorders (MIDs), which follow either maternal inheritance when they affect mitochondrial DNA (mtDNA) or autosomal inheritance when they affect nuclear-encoded mitochondrial proteins. Once considered predominantly pediatric conditions, these disorders are increasingly recognized in adults where their clinical presentation is heterogeneous and frequently underdiagnosed, requiring the involvement of various medical specialties.Because of their high energy requirements, kidneys are particularly vulnerable to primary MIDs. Tubular epithelial cells rely on OXPHOS for solute transport, whereas podocytes require sustained ATP production to preserve the glomerular filtration barrier. Although kidney involvement in adult primary MIDs has long been regarded as rare, emerging data indicate that primary MIDs-associated nephropathy (MIDAN) is more common than previously appreciated, yet remains under-recognized, as a cause of adult kidney disease. Renal manifestations include a broad spectrum of glomerular disorders-predominantly focal segmental glomerulosclerosis (FSGS), often associated with diabetes mellitus and sensorineural hearing impairment-as well as tubulo-interstitial nephritis (TIN), which may present as an isolated renal phenotype or as part of a multisystemic disorder.Advances in next-generation sequencing, including mitochondrial genome sequencing and exome or whole-genome sequencing, are transforming the diagnostic approach to MIDAN. Improved recognition of mitochondrial etiologies in adults with unexplained glomerular or tubulo-interstitial kidney disease is essential to optimize diagnosis, management, and genetic counseling.

Keywords:  adult; glomerular disease; kidney disease; mitochondrial disorders; tubulo-interstitial nephritis

DOI:  https://doi.org/10.1016/j.ekir.2026.106999
Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2614077123

Resolving cell lineages and gene functions in the developing mouse gastrointestinal tract using in utero transduction.

Ziwei Liu, Krishnanand Padmanabhan, Jingyan He, Katrin Hector, Bettina Semsch, Jia Sun, Viktoria Knoflach, Sarantis Giatrellis, Johan Lorentz, Khachatur Dallakyan, Christian Göritz, Emma Rachel Andersson, Ulrika Marklund.

  How diverse cell lineages emerge and are genetically regulated during organogenesis are central questions in understanding the developmental origins of disease. However, the mouse gut, including its intrinsic enteric nervous system (ENS) derived from migratory neural crest, has remained difficult to experimentally target. Here, we introduce an in utero lentiviral nano-injection strategy that enables early and efficient access to progenitor cells of all major cell types within the developing gut as well as gut-innervating ganglia. Leveraging this approach in combination with DNA barcoding and single-cell transcriptomics, we resolve clonal relationships in all gut lineages, including epithelial, neural, immune, and mesenchymal cell types. Clonal coupling between distinct subsets of fibroblasts and either pericytes, mesothelial cells, or interstitial cells of Cajal, suggested a developmental logic whereby the mesenchymal compartment arises from a set of fate-biased progenitors. Yet, mesenchymal regionalization along the anterior-posterior axis establishes early, whereas the ENS displays broad clonal dispersion across gut regions and acquires subsequent regional identities. We further adapted the platform for temporally controlled cell-type specific gene manipulation and, as a proof-of-principle, show that induced expression of the proneural factor Ascl1 biases ENS progenitor cells toward neuronal differentiation. Together, this work provides insights into refined spatiotemporal lineage relationships within a multigerm-layer organ and establishes a broadly applicable in vivo framework for probing gene function during gastrointestinal and neural crest development.

Keywords:  enteric nervous system; gut patterning; in utero transduction; lineage tracing; neural crest development

DOI:  https://doi.org/10.1073/pnas.2614077123
Cell Stem Cell. 2026 Sep 07. pii: S1934-5909(26)00310-3. [Epub ahead of print]

Clinical base editing for β-hemoglobinopathies across different genetic backgrounds.

Rongrong Liu, Yongrong Lai, Lijie Wang, Xiaowen Qian, Xu-Kai Ma, Yaliang Li, Gaohui Yang, Lingling Shi, Zifeng Li, Jia Wei, Zhenbin Wei, Hongsheng Wang, Xuemei Zhou, Ling Yu, Bei Yang, Xiaowen Zhai, Xiaodun Mou, Li Yang, Jia Chen.

  β-Hemoglobinopathies are monogenic disorders. We previously applied a transformer base editor (tBE) to reactivate fetal hemoglobin (HbF) expression, and five Chinese transfusion-dependent β-thalassemia (TDT) patients achieved transfusion independence. However, the applicability of tBE to sickle cell disease (SCD) and genetically different TDT populations remained unknown. Here, we show a four-patient descriptive report from three trials, including one African SCD patient and three TDT patients carrying mutations common in South and Southeast Asia. All patients achieve hematopoietic recovery, and red blood cell transfusions are discontinued in all cases. After more than 12 months of follow-up, all patients show durable editing, sustained high-level pan-cellular HbF expression, and transfusion independence. No vaso-occlusive episodes occur in the SCD patient. No off-target mutations, malignancies, or deaths are observed. These initial results support the feasibility of applying tBE to treat SCD and the reported TDT genotypes, warranting broader evaluation across diverse populations. ClinicalTrials.gov identifiers are as follows: NCT06328764, NCT06065189, and NCT06565026.

Keywords:  base editing; fetal hemoglobin; gene editing; sickle cell disease; β-thalassemia

DOI:  https://doi.org/10.1016/j.stem.2026.08.009
JCI Insight. 2026 Sep 10. pii: e210523. [Epub ahead of print]

Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.

Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning.

  Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.

Keywords:  Endocrinology; Muscle biology; Signal transduction

DOI:  https://doi.org/10.1172/jci.insight.210523