bims-mimcad 2025-02-02 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2025–02–02
twelve papers selected by
Henver Brunetta, Karolinska Institutet

Semaglutide administration protects cardiomyocytes in db/db mice via energetic improvement and mitochondrial quality control.
WBSCR16 is essential for mitochondrial 16S rRNA processing in mammals.
Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.
Investigating the role of adipose tissue in mobility and aging: design and methods of the Adipose Tissue ancillary to the Study of Muscle, Mobility and Aging (SOMMA-AT).
Mitochondrial respiration in white adipose tissue is dependent on body mass index and tissue location in patients undergoing oncological or parietal digestive surgery.
Near-universal prevalence of central adiposity in heart failure with preserved ejection fraction: the PARAGON-HF trial.
Utility of the C-peptide/insulin molar ratio for distinguishing type A insulin resistance syndrome from type 2 diabetes.
CIDEC/FSP27 exacerbates obesity-related abdominal aortic aneurysm by promoting perivascular adipose tissue inflammation.
Estimating direct tissue effects versus weight loss effects of incretin-based drugs for obesity on various chronic conditions.
Toward a New SUMMIT in Heart Failure with Preserved Ejection Fraction.
SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.

Acta Pharmacol Sin. 2025 Jan 24.

Semaglutide administration protects cardiomyocytes in db/db mice via energetic improvement and mitochondrial quality control.

Meng-Yun Tian, Ji-Qin Yang, Jin-Chuan Hu, Shan Lu, Yong Ji.

  Diabetic cardiomyopathy causes end-stage heart failure, resulting in high morbidity and mortality in type 2 diabetes mellitus (T2DM) patients. Long-term treatment targeting metabolism is an emerging field in the treatment of diabetic cardiomyopathy. Semaglutide, an agonist of the glucagon-like peptide 1 receptor, is clinically approved for the treatment of T2DM and provides cardiac benefits in patients. However, the cardioprotective mechanism of semaglutide, especially its direct effects on cardiomyocytes (CMs), is not fully understood. Here, we used 8-week diabetic and obese db/db mice treated with semaglutide (200 μg·kg·d-1, i.p.) to study its direct effect on CMs and the underlying mechanisms. Our results revealed that the consecutive application of semaglutide improved cardiac function. Increased AMPK and ULK1 phosphorylation levels were detected, accompanied by elevated [Ca2+]mito. Seahorse analysis revealed that semaglutide increases ATP production via elevated basal and maximum respiration rates as well as spare respiration capacity in CMs. Transmission electron microscopy revealed improved mitochondrial morphology in the cardiomyocytes of db/db mice. On the other hand, Western blot analysis revealed increased Parkin and LC3 protein expression, indicating mitophagy in CMs. Collectively, our findings demonstrate that semaglutide directly protects CMs from high-glucose damage by promoting AMPK-dependent ATP production as well as ULK1-mediated mitophagy in db/db mice.

Keywords:   db/db mice; diabetic cardiomyopathy; mitochondrial calcium; mitophagy; semaglutide

DOI:  https://doi.org/10.1038/s41401-024-01448-9
Nucleic Acids Res. 2025 Jan 24. pii: gkae1325. [Epub ahead of print]53(3):

WBSCR16 is essential for mitochondrial 16S rRNA processing in mammals.

Shengjie Zhang, Zi Dong, Yang Feng, Wei Guo, Chen Zhang, Yifan Shi, Zhiyun Zhao, Jiqiu Wang, Guang Ning, Guorui Huang.

Mitochondrial rRNAs play important roles in regulating mtDNA-encoded gene expression and energy metabolism subsequently. However, the proteins that regulate mitochondrial 16S rRNA processing remain poorly understood. Herein, we generated adipose-specific Wbscr16-/-mice and cells, both of which exhibited dramatic mitochondrial changes. Subsequently, WBSCR16 was identified as a 16S rRNA-binding protein essential for the cleavage of 16S rRNA-mt-tRNALeu, facilitating 16S rRNA processing and mitochondrial ribosome assembly. Additionally, WBSCR16 recruited RNase P subunit MRPP3 to nascent 16S rRNA and assisted in this specific cleavage. Furthermore, evidence showed that adipose-specific Wbscr16 ablation promotes energy wasting via lipid preference in brown adipose tissue, leading to excess energy expenditure and resistance to obesity. In contrast, overexpression of WBSCR16 upregulated 16S rRNA processing and induced a preference for glucose utilization in both transgenic mouse models and cultured cells. These findings suggest that WBSCR16 plays essential roles in mitochondrial 16S rRNA processing in mammals, and is the key mitochondrial protein to balance glucose and lipid metabolism.

DOI: https://doi.org/10.1093/nar/gkae1325
Cell Death Dis. 2025 Jan 25. 16(1): 40

Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.

Lohans Pedrera, Laura Prieto Clemente, Alina Dahlhaus, Sara Lotfipour Nasudivar, Sofya Tishina, Daniel Olmo González, Jenny Stroh, Fatma Isil Yapici, Randhwaj Pratap Singh, Nils Grotehans, Thomas Langer, Ana J García-Sáez, Silvia von Karstedt.

Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.

DOI: https://doi.org/10.1038/s41419-024-07312-2
Elife. 2025 Jan 29. pii: RP102852. [Epub ahead of print]13

PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.

Ling Cheng, Ian Meliala, Yidi Kong, Jingyuan Chen, Christopher G Proud, Mikael Björklund.

  Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1's role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.

Keywords:  PEBP1; cell biology; human; integrated stress response; mitochondrial dysfunction

DOI:  https://doi.org/10.7554/eLife.102852
J Gerontol A Biol Sci Med Sci. 2025 Jan 31. pii: glaf015. [Epub ahead of print]

Investigating the role of adipose tissue in mobility and aging: design and methods of the Adipose Tissue ancillary to the Study of Muscle, Mobility and Aging (SOMMA-AT).

Reichelle X Yeo, Theresa Mau, Zana M Ross, Nicholas P Edenhoffer, Jingfang Liu, Haley N Barnes, Li-Yung Lui, Joshua N Adkins, James A Sanford, Marcus M Seldin, Carlos H Viesi, Mingqi Zhou, Heather L Gregory, Frederico G S Toledo, Maja Stefanovic-Racic, Mary Lyles, Ashlee N Wood, Polly E Mattila, Elizabeth A Blakley, Iva Miljkovic, Peggy M Cawthon, Anne B Newman, Stephen B Kritchevsky, Steven R Cummings, Bret H Goodpaster, Jamie N Justice, Erin E Kershaw, Lauren M Sparks.

   BACKGROUND: Age-related changes in adipose tissue impact chronic medical diseases and mobility disability but mechanism remains poorly understood. The goal of this study is to define methods for phenotyping unique characteristics of adipose tissue from older adults.
METHODS: Older adults enrolled in Study of Muscle, Mobility and Aging selected for the adipose tissue ancillary (SOMMA-AT; N=210, 52.38% women, 76.12±4.37 years) were assessed for regional adiposity by whole-body magnetic resonance (AMRA) and underwent a needle-aspiration biopsy of abdominal subcutaneous adipose tissue (ASAT). ASAT biopsies were flash frozen, fixed, or processed for downstream applications and deposited at the biorepository. Biopsy yields, qualitative features, adipocyte sizes, and concentration of adipokines secreted in ASAT explant conditioned media were measured. Inter-measure Spearman correlations were determined.
RESULTS: Regional, but not total, adiposity differed by sex: women had greater ASAT mass (8.20±2.73kg, p<0.001) and biopsy yield (3.44±1.81g, p<0.001) than men (ASAT=5.95±2.30kg, biopsy=2.30±1.40g). ASAT mass correlated with leptin (r=0.54, p<0.001) and not resistin (p=0.248) and adiponectin (p=0.353). Adipocyte area correlated with ASAT mass (r=0.34, p<0.001), BMI (r=0.33, p<0.001), adiponectin (r=-0.22, p=0.005) and leptin (r=0.18, p=0.024) but not with resistin (p=0.490).
CONCLUSION: In addition to the detailed ASAT biopsy processing in this report, we found that adipocyte area correlated with ASAT mass, and both measures related to some key adipokines in the explant conditioned media. These results, methods, and biological repositories underscore the potential of this unique cohort to impact the understanding of aging adipose biology on disease, disability, and other aging tissues.

Keywords:  SOMMA; adipokines; adipose tissue; human aging

DOI:  https://doi.org/10.1093/gerona/glaf015
FASEB J. 2025 Jan 31. 39(2): e70350

Mitochondrial respiration in white adipose tissue is dependent on body mass index and tissue location in patients undergoing oncological or parietal digestive surgery.

Lisa Guerrier, Ophélie Bacoeur-Ouzillou, Julianne Touron, Sami Mezher, Lucie Cassagnes, Aurélie Vieille-Marchiset, Stéphanie Chanon, Bruno Pereira, Denis Pezet, Alexandre Pinel, Johan Gagnière, Corinne Malpuech-Brugère, Ruddy Richard.

  Adipose tissue (AT), is a major endocrine organ that plays a key role in health and disease. However, adipose dysfunctions, especially altered energy metabolism, have been under-investigated as white adipocytes have relatively low mitochondrial density. Nevertheless, recent studies suggest that mitochondria could play a major role in AT disorders and that AT mitochondrial activity could depend on adiposity level and location. This clinical study aimed to evaluate mitochondrial respiration and metabolism in human visceral (vAT) and subcutaneous (scAT) AT and their relationship with body mass index (BMI). This clinical study enrolled 67 patients (30 females/37 males) scheduled for digestive surgery without chemotherapy and parietal infection. BMI ranged from 15.4 to 51.9 kg·m-2 and body composition was estimated by computed tomographic images. Mitochondrial respiration was measured in situ in digitonin-permeabilized AT using high-resolution respirometry and a substrate/inhibitor titration approach. Protein levels of mitochondrial and lipid metabolism key elements were evaluated by Western blot. Maximal mitochondrial respiration correlated negatively with BMI (p < .01) and AT area (p < .001) regardless of the anatomical location. However, oxidative phosphorylation respiration was significantly higher in vAT (2.22 ± 0.15 pmol·sec-1·mg-1) than scAT (1.79 ± 0.17 pmol·sec-1·mg-1) (p < 0.001). In line with oxygraphy results, there were higher levels of mitochondrial respiratory chain complexes in low-BMI patients and vAT. Mitochondrial respiration decreased with increasing BMI in both scAT and vAT, without sex-associated difference. Mitochondrial respiration appeared to be higher in vAT than scAT. These differences were both qualitative and quantitative. Clinical Trials Registration IDNCT05417581.

Keywords:  body composition; body mass index; human; lipid metabolism; mitochondrial respiration; white adipose tissue

DOI:  https://doi.org/10.1096/fj.202402243R
Eur Heart J. 2025 Jan 28. pii: ehaf057. [Epub ahead of print]

Near-universal prevalence of central adiposity in heart failure with preserved ejection fraction: the PARAGON-HF trial.

Alexander Peikert, Muthiah Vaduganathan, Brian L Claggett, Ian J Kulac, Sheldon Litwin, Michael Zile, Akshay S Desai, Pardeep S Jhund, Jawad H Butt, Carolyn S P Lam, Felipe Martinez, Dirk J Van Veldhuisen, Faiez Zannad, Jean Rouleau, Martin Lefkowitz, John J V McMurray, Scott D Solomon, Milton Packer.

   BACKGROUND AND AIMS: An expansion of fat mass is an integral feature of patients with heart failure and preserved ejection fraction (HFpEF). While body mass index (BMI) is the most common anthropometric measure, a measure of central adiposity-the waist-to-height ratio (WHtR)-focuses on body fat content and distribution; is not distorted by bone or muscle mass, sex, or ethnicity; and may be particularly relevant in HFpEF.
METHODS: The PARAGON-HF trial randomized 4796 patients with heart failure and ejection fraction ≥45% to valsartan or sacubitril/valsartan. The current work characterizes the association of BMI and WHtR with clinical features, outcomes, and the response to neprilysin inhibition.
RESULTS: About half (49%) of the participants were considered obese by BMI (≥30 kg/m2), but nearly every patient (96%) had central adiposity (WHtR ≥0.5). Among patients who were not obese (BMI <30 kg/m2), 860 (37%) had marked central adiposity (WHtR ≥0.6). Higher BMI and WHtR were both associated with higher risk of total heart failure hospitalizations, but as compared with BMI, WHtR was linearly associated with heart failure outcomes and identified a higher proportion of patients who had a particularly elevated risk (i.e., 30% or greater). An obesity-survival paradox (i.e., improved outcomes in those with greater adiposity) was apparent with BMI in unadjusted analyses, but it was not observed with WHtR. Although neprilysin inhibition appeared to have greater effects on heart failure outcomes in patients with higher BMI and WHtR, analyses of interaction with obesity metrics did not show significant heterogeneity across the range of values for adiposity.
CONCLUSIONS: In PARAGON-HF, in contrast with BMI, nearly every patient with HFpEF had central adiposity (as assessed by WHtR), and the risks of adverse heart failure events were more robustly related to WHtR. These data challenge the current reliance on BMI as an appropriate metric of adiposity, and they suggest that-rather than obesity-related HFpEF being regarded as a select HFpEF subgroup-central adiposity is a ubiquitous feature of HFpEF.

Keywords:  angiotensin receptor–neprilysin inhibitor; body mass index; heart failure with preserved ejection fraction; obesity; waist-to-height ratio

DOI:  https://doi.org/10.1093/eurheartj/ehaf057
J Clin Endocrinol Metab. 2025 Jan 28. pii: dgaf043. [Epub ahead of print]

Utility of the C-peptide/insulin molar ratio for distinguishing type A insulin resistance syndrome from type 2 diabetes.

Seiji Nishikage, Yushi Hirota, Tomofumi Takayoshi, Kai Yoshimura, Takehito Takeuchi, Tetsushi Hamaguchi, Mariko Ueda, Akane Yamamoto, Kazuhiko Sakaguchi, Wataru Ogawa.

   OBJECTIVE: Type A insulin resistance syndrome (IRS), characterized by impaired insulin receptor function due to variants of the insulin receptor gene, manifests as severe insulin-resistant diabetes. Differentiation of type A IRS from type 2 diabetes on the basis of hyperinsulinemia can be challenging. Given the association between insulin receptor dysfunction and reduced insulin clearance, we evaluated the potential of the circulating C-peptide reactivity (CPR)/immunoreactive insulin (IRI) molar ratio, a marker of insulin clearance, for distinguishing type A IRS from type 2 diabetes.
METHODS: We retrospectively analyzed CPR and IRI levels measured during a 75-g oral glucose tolerance test (OGTT) in 18 individuals with type A IRS and 126 with type 2 diabetes. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic performance of the CPR/IRI molar ratio and IRI levels.
RESULTS: IRI levels were significantly higher and the CPR/IRI molar ratio significantly lower in individuals with type A IRS compared with those with type 2 diabetes. The area under the ROC curve for the CPR/IRI molar ratio at baseline, 1 hour, and 2 hours after OGTT initiation was 0.997 (sensitivity 100%, specificity 99.2%), 0.999 (sensitivity 100%, specificity 97.6%), and 0.997 (sensitivity 100%, specificity 95.1%), respectively. The CPR/IRI molar ratio demonstrated robust diagnostic performance regardless of body mass index or hyperinsulinemia severity.
CONCLUSIONS: The CPR/IRI molar ratio, both at baseline and during OGTT, exhibited higher sensitivity and specificity than IRI levels alone for distinguishing type A IRS from type 2 diabetes. This ratio may serve as a reliable clinical marker for early and accurate diagnosis of type A IRS.

Keywords:  C-peptide reactivity; Diagnostic marker; Hyperinsulinemia; Immunoreactive insulin; Insulin resistance syndrome; Oral glucose tolerance test

DOI:  https://doi.org/10.1210/clinem/dgaf043
Life Metab. 2025 Feb;4(1): loae035

CIDEC/FSP27 exacerbates obesity-related abdominal aortic aneurysm by promoting perivascular adipose tissue inflammation.

Qing Zhu, Da Luo, Yining Li, Liyang Yu, Zixuan Zhang, Feng Ouyang, Liangkui Li, Manxi Lu, Changyong Hu, Yinuo Dong, Chengxin Ma, Yan Liang, Tong-Jin Zhao, Feng-Jung Chen, Peng Li, Tian-Shu Yang.

  Abdominal aortic aneurysm (AAA) is strongly correlated with obesity, partially due to the abnormal expansion of abdominal perivascular adipose tissue (PVAT). Cell death-inducing DNA fragmentation factor-like effector C (CIDEC), also known as fat-specific protein 27 (FSP27) in rodents, is specifically expressed in adipose tissue where it mediates lipid droplet fusion and adipose tissue expansion. Whether and how CIDEC/FSP27 plays a role in AAA pathology remains elusive. Here, we show that FSP27 exacerbates obesity and angiotensin Ⅱ (Ang Ⅱ)-induced AAA progression. FSP27 deficiency in mice inhibited high-fat diet-induced PVAT expansion and inflammation. Both global and adipose tissue-specific FSP27 ablation significantly decreased obesity-related AAA incidence. Deficiency of FSP27 in adipocytes abrogated matrix metalloproteinase-12 (MMP12) expression in aortic tissues. Infiltrated macrophages, which partially colocalize with MMP12, were significantly decreased in the FSP27-deficient aorta. Mechanistically, knockdown of Fsp27 in 3T3-L1 adipocytes inhibited C-C motif chemokine ligand 2 (CCL2) expression and secretion through a c-Jun N-terminal kinase (JNK)-dependent pathway, thereby leading to reduced induction of macrophage migration, while Cidec overexpression rescued this effect. Overall, our study demonstrates that CIDEC/FSP27 in adipose tissue contributes to obesity-related AAA formation, at least in part, by enhancing PVAT inflammation and macrophage infiltration, thus shedding light on its significance as a key regulator in the context of obesity-related AAA.

Keywords:  AAA; CCL2; Cidec; PVAT; inflammation

DOI:  https://doi.org/10.1093/lifemeta/loae035
Lancet Diabetes Endocrinol. 2025 Jan 24. pii: S2213-8587(24)00363-2. [Epub ahead of print]

Estimating direct tissue effects versus weight loss effects of incretin-based drugs for obesity on various chronic conditions.

Naveed Sattar, Matthew M Y Lee.

The extent to which newer, incretin-based drugs for obesity improve disease outcomes via weight loss versus the direct effects of these drugs is the subject of intense interest. Although reductions in major adverse cardiovascular events appear to be predominantly driven by the direct tissue effects of such drugs, the associated weight loss effects must be relevant to the benefits observed in other major outcomes, albeit to differing extents. In this Personal View, we draw on evidence to support that weight loss is at least partly responsible (albeit to differing extents) for the reported benefits of incretin-based drugs for obesity in people living with heart failure with preserved ejection fraction, hypertension, chronic kidney disease, and type 2 diabetes. Concurrently, we propose that drug-induced weight loss is largely responsible for the reported improvements in osteoarthritis, obstructive sleep apnoea, and metabolic dysfunction-associated steatohepatitis outcomes. However, more evidence is needed to solidify these observations, including, when possible, trials comparing the effects of incretin-based drugs for obesity with calorie-reduced diets on both outcomes and mechanistic pathways. Such evidence has implications for public health and the design of future trials of novel drugs for obesity.

DOI: https://doi.org/10.1016/S2213-8587(24)00363-2
N Engl J Med. 2025 Jan 30. 392(5): 505-506

Toward a New SUMMIT in Heart Failure with Preserved Ejection Fraction.

G Michael Felker.

DOI: https://doi.org/10.1056/NEJMe2415551
Nat Commun. 2025 Jan 24. 16(1): 978

SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.

Izabella A Pena, Jeffrey S Shi, Sarah M Chang, Jason Yang, Samuel Block, Charles H Adelmann, Heather R Keys, Preston Ge, Shveta Bathla, Isabella H Witham, Grzegorz Sienski, Angus C Nairn, David M Sabatini, Caroline A Lewis, Nora Kory, Matthew G Vander Heiden, Myriam Heiman.

Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5'-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5'-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5'-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5'-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia.

DOI: https://doi.org/10.1038/s41467-025-56130-3