bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–08–10
nineteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. ATP Synthase Abundance in Neuronal Extracellular Vesicles Reflects Changes in the Mitochondria of Parent Neurons.
  2. Retrospective observational study of the magnetic resonance imaging features of MPV17-related mitochondrial DNA depletion syndrome.
  3. The cytochrome oxidase defect in ISC-depleted yeast is caused by impaired iron-sulfur cluster maturation of the mitoribosome assembly factor Rsm22.
  4. Mitochondrial disease management through phytochemical interventions.
  5. Noninvasive Assessments of Mitochondrial Capacity in People with Mitochondrial Myopathies.
  6. Impaired mitochondria-initiated crosstalk with lysosomes reciprocally aggravates mitochondrial defect through LManVI.
  7. Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
  8. A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
  9. The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.
  10. Pioglitazone Ameliorates Mitochondrial Oxidative Stress and Inflammation via AMPK-Dependent Inhibition of Mitochondrial Fission in Leigh Syndrome.
  11. Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
  12. A novel founder mutation in the MFN2 gene associated with variable Charcot-Marie-Tooth type 2 phenotype in two families from Southern Italy.
  13. PML is crucial for neural stem cell differentiation, stress tolerance and mitochondrial integrity.
  14. Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations.
  15. Nicotinamide phosphoribosyltransferase in NAD+ metabolism: physiological and pathophysiological implications.
  16. Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue.
  17. Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.
  18. IP3-mediated Ca2+ transfer from ER to mitochondria stimulates ATP synthesis in primary hippocampal neurons.
  19. Preclinical evaluation of candidate "kill or cure" strategies to treat MFN2-related lipodystrophy.
  1. J Extracell Vesicles. 2025 Aug;14(8): e70140
    ATP Synthase Abundance in Neuronal Extracellular Vesicles Reflects Changes in the Mitochondria of Parent Neurons.
    Pamela J Yao, Carlos Nogueras-Ortiz, Krishna Ananthu Pucha, Dimitrios Kapogiannis.
      Mitochondrial proteins are found in extracellular vesicles (EVs) such as neuron-derived EVs (NEVs). Yet whether and how NEV-borne mitochondrial proteins relate to the state of mitochondria in the parent neurons is unclear. Studying the mitochondrial ATP synthase in primary hippocampal neurons and their released EVs, we discovered that the abundance of ATP synthase in NEVs echoes the catalytic activity level of ATP synthase in neurons. We also observed, unexpectedly, that within the neuron, the quantity of ATP synthase remains constant irrespective of the level of its activity. Using non-canonical amino acid tagging coupled with proximity ligation assay, we found that the amount of nascent ATP synthase is linearly correlated to its activity, which may contribute to maintaining the overall quantity of ATP synthase in the neuron stable. Furthermore, we identified a sub-population of mitochondria-derived vesicles (MDVs) that carry ATP synthase and are not targeted to lysosomal degradation. Our findings suggest a strategy used by neurons in regulating and fine-tuning mitochondrial ATP synthase through MDV and NEV generation. Further studies are needed to elucidate the relationship between ATP synthase-containing-NEVs and -MDVs.
    Keywords:  ATP synthase; extracellular vesicles; mitochondria; mitochondrial‐derived vesicles; mitovesicles; neurons
    DOI:  https://doi.org/10.1002/jev2.70140
  2. Pediatr Radiol. 2025 Aug 07.
    Retrospective observational study of the magnetic resonance imaging features of MPV17-related mitochondrial DNA depletion syndrome.
    Suzanne O'Hagan, Surita Meldau, Penelope Rose, Magriet Van Niekerk, Christelle Ackermann, Gillian Riordan, Ronald Van Toorn.
       BACKGROUND: MPV17-related mitochondrial deoxyribonucleic acid (DNA) maintenance defects present in most affected individuals as an early-onset encephalohepatopathic disease. Diagnosis requires comprehensive molecular genetic testing, which is often not available in resource-limited settings. Therefore, the role of imaging as a diagnostic tool necessitates further exploration. Herein, we present the largest known cohort of patients with genetically confirmed MPV17-related mitochondrial DNA depletion syndrome, highlighting in detail the neuroimaging findings.
    OBJECTIVE: To establish novel features on magnetic resonance imaging (MRI) that characterise MPV17-related mitochondrial DNA depletion syndrome, in order to provide a non-invasive, accessible, and reproducible biomarker inquiry.
    MATERIALS AND METHODS: Retrospective, descriptive study based at a large tertiary level hospital. Eight patients with MPV17-related mitochondrial DNA depletion syndrome who had undergone brain MRI were identified between 2015 and 2023. Neuroimaging findings were captured and described in detail. Two board-certified radiologists with experience in paediatric neuroradiology reviewed all images by consensus.
    RESULTS: All patients were homozygous for the MPV17: c.106C>T variant. Age at brain MRI ranged from 11 days to 8 months. Seven out of the eight patients showed signal abnormalities in the reticulospinal tracts and/or reticular formation. Other neuroimaging findings included leukoencephalopathy, injury to extra-reticular white matter tracts and frequent basal ganglia involvement. Newly identified areas of involvement include the perirolandic cortices, hippocampi, optic pathways and olfactory nerves.
    CONCLUSION: Lesions in the reticular formation and reticulospinal tracts on brain MRI in a neonate or infant with hepatic dysfunction may represent a distinctive, albeit not specific, feature of MPV17-related mitochondrial DNA depletion syndrome.
    Keywords:  MPV17 mitochondrial DNA depletion syndrome; Mitochondrial DNA; Mitochondrial disease; Neuroimaging; Pediatric; Resource-limited settings; Reticular formation
    DOI:  https://doi.org/10.1007/s00247-025-06341-z
  3. FEBS Lett. 2025 Aug 06.
    The cytochrome oxidase defect in ISC-depleted yeast is caused by impaired iron-sulfur cluster maturation of the mitoribosome assembly factor Rsm22.
    Ulrich Mühlenhoff, Dominik Trauth, Weronika Śliwińska, Linda Boss, Roland Lill.
      Mitochondria contain the bacteria-inherited iron-sulfur cluster assembly (ISC) machinery to generate cellular iron-sulfur (Fe/S) proteins. Mutations in human ISC genes cause severe disorders with a broad clinical spectrum and are associated with strong defects in mitochondrial Fe/S proteins, including respiratory complexes I-III. For unknown reasons, complex IV (aka cytochrome c oxidase), a non-Fe/S, heme-containing enzyme, is severely affected. Using yeast as a model, we show that depletion of Rsm22, the counterpart of the human mitoribosome assembly factor METTL17, phenocopies the defects observed upon impairing late-acting ISC proteins, that is, diminished activities of mitoribosomal translation and respiratory complexes III and IV. Rsm22 binds Fe/S clusters in vivo, thereby satisfactorily explaining the defect of respiratory complex IV in ISC-deficient cells, because this complex contains three mitochondrial DNA-encoded subunits. Impact statement Defects in mitochondrial Fe/S protein biogenesis also impact respiratory complex IV (COX), even though it lacks Fe/S clusters. Here, we show that the mitoribosome assembly factor Rsm22 binds Fe/S clusters in vivo. Rsm22 maturation defects impair mitoribosomal protein translation including COX subunits, explaining the COX defects in Fe/S cluster-deficient cells.
    Keywords:  biogenesis; cytochromes; iron–sulfur protein; mitochondrial DNA; mitochondrial ribosomes; respiratory chain complexes; translation
    DOI:  https://doi.org/10.1002/1873-3468.70129
  4. Mol Cell Biochem. 2025 Aug 03.
    Mitochondrial disease management through phytochemical interventions.
    R Prabhu Ramya, K B Megha, S Reshma, M J Ajai Krishnan, S Amir, Rashmi Sharma, P V Mohanan.
      Mitochondrial diseases are a diverse group of disorders caused by dysfunction in mitochondria, the energy-generating organelles of cells. These disorders result from mutations in either nuclear or mitochondrial DNA and can be classified as primary (genetic origin) or secondary (environmentally induced). Due to their systemic impact, mitochondrial dysfunction leads to a wide range of clinical symptoms varying from tissue type and patient age. This review aims to provide a comprehensive overview of mitochondrial diseases, focusing on their classification, pathophysiology, diagnostic challenges and emerging therapeutic strategies. Current diagnostic approaches face limitations due to the complexity and heterogeneity of mitochondrial disorders. Recent evidence highlights the potential of phytochemicals such as polyphenols, flavonoids, alkaloids and terpenoids in modulating mitochondrial function. These natural compounds can enhance mitochondrial biogenesis, reduce oxidative stress and improve cellular energy metabolism. Phytochemicals represent a promising therapeutic avenue for mitigating mitochondrial dysfunction. However, further research is needed to validate their efficacy and develop standardized treatment protocols. An improved understanding of the molecular mechanisms involved in mitochondrial pathology will aid in developing more targeted diagnostic and therapeutic strategies.
    Keywords:  Mitochondrial biogenesis; Mitochondrial diseases; Oxidative stress; Phytochemicals; Therapeutic strategies
    DOI:  https://doi.org/10.1007/s11010-025-05360-6
  5. Muscles. 2024 Nov 26. 3(4): 393-403
    Noninvasive Assessments of Mitochondrial Capacity in People with Mitochondrial Myopathies.
    Kevin K McCully, Hannah M Bossie, Fran D Kendall.
      People affected by mitochondrial myopathies (MITOs) are thought to have impaired skeletal muscle oxygenation. The aims of this study were to measure skeletal muscle mitochondrial capacity in MITO participants and able-bodied (AB) participants and evaluate the influence of muscle-specific endurance training in one MITO participant. Participants (n = 7) with mitochondrial disease and controls (n = 9) were tested (ages 18-54 years). Mitochondrial capacity (mVO2max) was measured using the rate constant of recovery of oxygen consumption (mVO2) after exercise in the forearm flexor muscles with near-infrared spectroscopy (NIRS). One MITO participant was tested before and after performing 18 forearm exercise sessions in 30 days. There were no differences between MITO and AB participants in mVO2max (MITO: 1.4 ± 0.1 min-1; AB: 1.5 ± 0.3 min-1; p = 0.29), resting mVO2 (MITO: -0.4 ± 0.2%/min; AB: -0.3 ± 0.1%/min; p = 0.23), or initial post exercise oxygen consumption rates (MITO: 4.3 ± 1.2%/min; AB: 4.4 ± 1.4%/min; p = 0.9). Exercise oxygen desaturation was greater in MITO (39.8 ± 9.7% range) than in AB (28 ± 8.8% range) participants, p = 0.02. The MITO participant who trained increased her mitochondrial capacity (58%) and muscle-specific endurance (24%) and had reduced symptoms of muscle fatigue. We found no evidence supporting in vivo impairment of forearm muscle mVO2max in genetically confirmed MITO participants. This is consistent with studies that report increased mitochondrial content, which offsets the decrease in mitochondrial function. Positive muscle adaptations to endurance training appear to be possible in people with MITOs. Characterization of study populations will be important when interpreting the relationship between in vivo mitochondrial capacity and mitochondrial disease.
    Keywords:  Kearns–Sayre syndrome; MELAS; NIRS; near-infrared spectroscopy; skeletal muscle
    DOI:  https://doi.org/10.3390/muscles3040033
  6. Nat Commun. 2025 Aug 07. 16(1): 7304
    Impaired mitochondria-initiated crosstalk with lysosomes reciprocally aggravates mitochondrial defect through LManVI.
    Shengnan Li, Zhaoliang Shan, Guochun Zhao, Yuwei Li, Minghui Du, Xiuxiu Ti, Yuxue Gao, Wenting Li, Hui Zuo, Yan Wang, Qing Zhang.
      Mitochondria coordinate with lysosomes to maintain cellular homeomstasis. However, in mitochondrial defect condition, how they communicate is less clear. Here, utilizing dMterf4 RNAi fly model, we find that expression of lysosomal alpha-mannosidase VI (LManVI) is significantly downregulated. Mechanistically, we show that dMterf4 RNAi-triggered mitochondrial defect mediates downregulation of lysosomal LManVI through Med8/Tfb4-E(z)/pho axis, causing impairment of lysosomal function. Reciprocally, downregulation of lysosomal LManVI further decreases many mitochondrial genes expression through downregulation of transcriptional coactivator PGC-1, leading to aggravating the dMterf4 RNAi-mediated mitochondrial defect, suggesting that mitochondrial defect can crosstalk with lysosomes to make mitochondrial status worse in a positive feedback way. Finally, we demarcate that this interaction between mitochondria and lysosomes may be conserved in mammalian cells. Therefore, our findings unveil a communication mechanism between mitochondria and lysosomes in mitochondrial defect case, which provides insights about the treatments of related mitochondrial and lysosomal diseases through modulation of the mitochondria-lysosomes axis.
    DOI:  https://doi.org/10.1038/s41467-025-62147-5
  7. bioRxiv. 2025 Jul 21. pii: 2025.07.17.665416. [Epub ahead of print]
    Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
    Leena Kadam, Kaylee Chan, Ethan Tawater, Leslie Myatt.
       Introduction: The placenta is exposed to an altered metabolic environment in obesity and gestational diabetes (GDM) leading to disruption in placental function. Mitochondria are critical for energy production and cellular adaptation to stress. We previously reported reduced trophoblast mitochondrial respiration in GDM. Here we examine changes in mitochondrial structure dynamics, quality and protein homeostasis as well as clearance in both obese and GDM placentas of male and female fetuses. As obesity significantly increases the risk for GDM, our goal is to determine the distinct effects of each on placental mitochondria.
    Methods: We collected placental villous tissue following elective cesarean section at term from lean (LN, pre-pregnancy BMI 18.5-24.9), obese (OB, BMI>30) or obese with type A2 GDM women. Expression of proteins involved in mitochondrial biogenesis, structure dynamics, quality control and clearance were assessed by Western blotting. Significant changes between groups were determined in fetal sex-dependent and independent manner.
    Results: Only placentas from obese women showed increase in proteins regulating mitochondrial biogenesis (PGC-1α and SIRT1). We report fetal sex-specific changes in mitochondrial fusion but an overall decline in fission in OB and GDM placentas. Both maternal obesity and GDM affected proteins involved in maintaining mitochondrial protein quality and genome stability. This was accompanied by a reduction in mitochondrial complexes, suggesting impaired mitochondrial function. Obesity led to partial activation of mitophagy pathways (e.g., increased PINK1 without PARKIN activation), GDM placentas failed to mount this response.
    Discussion: Obesity and GDM affect placental mitochondria through distinct complex sex-specific mechanisms that may contribute to altered mitochondrial function.
    DOI:  https://doi.org/10.1101/2025.07.17.665416
  8. BMJ Case Rep. 2025 Aug 08. pii: bcr0720080504. [Epub ahead of print]2009
    A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
    An I Jonckheere, Marije Hogeveen, Leo Nijtmans, Mariel van den Brand, Antoon Janssen, Heleen Diepstra, Frans van den Brandt, Bert van den Heuvel, Frans Hol, Tom Hofste, Livia Kapusta, U Dillmann, M Shamdeen, J Smeitink, J Smeitink, Richard Rodenburg.
      To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing.A homoplasmic nonsense mutation m.8529G→A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNAWe describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.
    DOI:  https://doi.org/10.1136/bcr.07.2008.0504
  9. Annu Rev Cell Dev Biol. 2025 Aug 06.
    The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.
    Nazma Malik, Reuben J Shaw.
      Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of eukaryotes to the mitochondria as the central source of ATP to hundreds of other metabolites required for cellular homeostasis, survival, and proliferation, cells had to evolve sensors to detect even modest changes in mitochondrial function in order to safeguard cellular integrity and prevent energetic catastrophe. Homologs of AMP-activated protein kinase (AMPK) are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. Here we explore advances in how AMPK modulates core processes underpinning the mitochondrial life cycle and how it serves to restore mitochondrial health in parallel with other beneficial metabolic adaptations.
    DOI:  https://doi.org/10.1146/annurev-cellbio-120420-094431
  10. Cell Prolif. 2025 Aug 06. e70109
    Pioglitazone Ameliorates Mitochondrial Oxidative Stress and Inflammation via AMPK-Dependent Inhibition of Mitochondrial Fission in Leigh Syndrome.
    Jie Luo, Ling Chen, Xiaoxian Zhang, Qiang Su, Xiaoya Zhou, Qizhou Lian.
      Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. However, there is currently no effective treatment. Here, we demonstrate that pioglitazone significantly mitigates mitochondrial reactive oxygen species (ROS) generation, lowers cyclooxygenase-2 (COX-2) mRNA levels, and rescues aberrant mitochondrial dynamics in vitro (increasing Opa-1 expression while decreasing Drp-1 expression). Furthermore, similar effects were observed with the selective Drp-1 inhibitor mdivi-1, suggesting that inhibiting mitochondrial fission mediates the therapeutic effects of pioglitazone. Pioglitazone administration activated AMPK phosphorylation, but these effects, along with pioglitazone's ability to reverse oxidative stress, inflammation, and mitochondrial fission, were abolished by the AMPK inhibitor compound C. In vivo, pioglitazone alleviated motor dysfunction, prolonged lifespan, and promoted weight gain in Ndufs4 KO mice. This was accompanied by enhanced mitochondrial fusion and increased levels of mitochondrial complex subunits. Consistently, pioglitazone attenuated neuroinflammation and oxidative stress in vivo. Collectively, our findings indicate that pioglitazone alleviates mitochondrial oxidative stress and inflammation through an AMPK-dependent inhibition of Drp-1-mediated mitochondrial fission. Therefore, suppression of mitochondrial fission may represent a novel therapeutic strategy for Leigh syndrome (LS).
    DOI:  https://doi.org/10.1111/cpr.70109
  11. Nat Commun. 2025 Aug 04. 16(1): 7174
    Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
    Ioannis Segos, Jens Van Eeckhoven, Simon Berger, Nikhil Mishra, Eric J Lambie, Barbara Conradt.
      The unequal segregation of organelles has been proposed to be an intrinsic mechanism that contributes to cell fate divergence during asymmetric cell division; however, in vivo evidence is sparse. Using super-resolution microscopy, we analysed the segregation of organelles during the division of the neuroblast QL.p in C. elegans larvae. QL.p divides to generate a daughter that survives, QL.pa, and a daughter that dies, QL.pp. We found that mitochondria segregate unequally by density and morphology and that this is dependent on mitochondrial dynamics. Furthermore, we found that mitochondrial density in QL.pp correlates with the time it takes QL.pp to die. We propose that low mitochondrial density in QL.pp promotes the cell death fate and ensures that QL.pp dies in a highly reproducible and timely manner. Our results provide in vivo evidence that the unequal segregation of mitochondria can contribute to cell fate divergence during asymmetric cell division in a developing animal.
    DOI:  https://doi.org/10.1038/s41467-025-62484-5
  12. BMJ Case Rep. 2025 Aug 08. pii: bcr0820080652. [Epub ahead of print]2009
    A novel founder mutation in the MFN2 gene associated with variable Charcot-Marie-Tooth type 2 phenotype in two families from Southern Italy.
    Maria Muglia, Giovanni Vazza, Alessandra Patitucci, Micaela Milani, Davide Pareyson, Franco Taroni, Aldo Quattrone, Maria Luisa Mostacciuolo.
      Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy. CMT falls into two main forms: the demyelinating CMT type 1 with decreased nerve conduction velocities and the axonal CMT type 2. CMT2 is further subtyped by linkage analysis into >10 loci, with eight genes identified.Recently, mutations in the mitochondrial fusion protein 2 (MFN2) gene were reported in families with CMT2A1 and additional mutations have been detected in other studies, bringing to 42 the total number of different MFN2 mutations described thus far.2-4In the current study, we report a novel MFN2 mutation shared by two apparently unrelated CMT2 families originating from the same area in Southern Italy.
    DOI:  https://doi.org/10.1136/bcr.08.2008.0652
  13. Stem Cell Reports. 2025 Jul 29. pii: S2213-6711(25)00202-4. [Epub ahead of print] 102598
    PML is crucial for neural stem cell differentiation, stress tolerance and mitochondrial integrity.
    Syrago Spanou, Takis Makatounakis, Elena Deligianni, Sofia Papanikolaou, Martina Samiotaki, Fabien Moretto, Christoforos Nikolaou, Joseph Papamatheakis, Androniki Kretsovali.
      The tumor suppressor promyelocytic leukemia protein (PML) has important roles in brain development; however, the molecular and cellular pathways regulated by PML in neuronal cells remain largely unknown. To address this issue, we analyzed gene expression changes caused by loss of PML in neural stem cells. Our findings revealed that PML-deficient cells exhibited increased mTOR (mammalian target of rapamycin) pathway activation and protein translation, as well as impaired autophagy and proteasome activity, resulting in increased formation of aggregates and stress-induced death. Loss of PML disrupted mitochondrial integrity, leading to impaired respiration, membrane potential, morphology, and production of increased reactive oxygen species. These mitochondrial defects were caused by diminished PGC-1α expression and PPARγ (peroxisome proliferator-activated receptor gamma) signaling and could be reversed using a PPAR agonist. Together, our results indicate that PML is a critical regulator of neuronal survival and protection from stress. We propose that enhancing PML expression may offer therapeutic benefits in neurological disorders.
    Keywords:  PGC-1α; PML; PPARγ; eNSC; embryonic neural stem cell; mitochondria metabolism; peroxisome proliferator-activated receptor gamma; peroxisome proliferator-activated receptor gamma coactivator 1-alpha; promyelocytic leukemia protein; proteomics; transcriptomics
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102598
  14. Sci Adv. 2025 Aug 08. 11(32): eadw4954
    Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations.
    Barbara Arbeithuber, Kate Anthony, Bonnie Higgins, Peter Oppelt, Omar Shebl, Irene Tiemann-Boege, Francesca Chiaromonte, Thomas Ebner, Kateryna D Makova.
      Mitochondria, cellular powerhouses, harbor DNA [mitochondrial DNA (mtDNA)] inherited from the mothers. mtDNA mutations can cause diseases, yet whether they increase with age in human oocytes remains understudied. Here, using highly accurate duplex sequencing, we detected de novo mutations in single oocytes, blood, and saliva in women 20 to 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies were less prevalent in coding than noncoding regions, whereas mutations with low allele frequencies were more uniformly distributed along the mtDNA, suggesting frequency-dependent purifying selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations with aging and having functional consequences. These findings are particularly timely as humans tend to reproduce later in life.
    DOI:  https://doi.org/10.1126/sciadv.adw4954
  15. Cell Death Discov. 2025 Aug 08. 11(1): 371
    Nicotinamide phosphoribosyltransferase in NAD+ metabolism: physiological and pathophysiological implications.
    Weijia Zhang, Haoyu Ren, Wangwang Chen, Bo Hu, Chao Feng, Peishan Li, Yufang Shi, Jiankai Fang.
      Nicotinamide adenine dinucleotide (NAD⁺) is a critical coenzyme involved in cellular metabolism, energy balance, and various physiological processes. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in NAD⁺ synthesis, regulating the NAD⁺ regeneration pathway. This review summarizes the multiple roles of NAMPT in both physiological and pathological states, particularly in cellular stress, aging, metabolic disorders, and cancer. We first describe the central role of NAMPT in NAD⁺ synthesis and explore how NAD⁺ levels are regulated through NAMPT to control cellular functions and metabolic adaptation. Second, we analyze the pathological roles of NAMPT in aging and related diseases, highlighting how NAD⁺ depletion leads to mitochondrial dysfunction, DNA damage, and immune system dysregulation. Notably, NAMPT exacerbates cancer immune evasion mechanisms by influencing immune cell functions and the metabolic environment of tumors. We also discuss the potential of NAMPT as a therapeutic target, particularly through NAD⁺ precursor supplementation or the use of NAMPT activators and inhibitors to modulate NAD⁺ metabolism in aging, metabolic diseases, and cancer. Future research should focus on exploring the functional differences of NAMPT in various tissues and its therapeutic potential in disease treatment.
    DOI:  https://doi.org/10.1038/s41420-025-02672-w
  16. Mol Metab. 2025 Aug 01. pii: S2212-8778(25)00134-6. [Epub ahead of print] 102227
    Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue.
    Dorota Kaminska, Calvin Pan, Laurent Vergnes, Ashlyn Ro, Gurugowtham Ulaganathan, Aldons J Lusis.
       OBJECTIVE: Sex differences in adipose tissue impact metabolic health, but the underlying molecular mechanisms remain unclear. We previously identified a female-specific chr17 trans-eQTL hotspot regulating mitochondrial gene expression in gonadal white adipose tissue (gWAT). Here, we tested whether iWAT contributes comparably to sex differences in mitochondrial function and futile cycling.
    METHODS: We analyzed iWAT and gWAT from male and female mice across 58 genetically diverse Hybrid Mouse Diversity Panel (HMDP) strains fed a high-fat, high-sucrose diet. We assessed mitochondrial DNA (mtDNA), oxidative phosphorylation (OXPHOS) and futile cycle gene expression, performed genetic mapping, and measured respiration.
    RESULTS: In gWAT, females showed higher mtDNA, OXPHOS expression, and a female-specific chr17 trans-eQTL, correlating with metabolic traits. In contrast, iWAT lacked this hotspot and showed higher mtDNA, OXPHOS expression, and respiration in males. Lipid cycling genes (Lipe, Mgll, Pnpla2) were elevated in male iWAT, while Mpc1, Mpc2, and Pck1 were enriched in female gWAT. Ucp1 was higher in female gWAT but not sex-biased in iWAT. Alpl (TNAP), key creatine cycling gene, was upregulated in females in both depots, particularly in iWAT.
    CONCLUSIONS: Female gWAT shows genetically driven mitochondrial regulation linked to metabolic protection, whereas male iWAT has higher mitochondrial content, OXPHOS expression, and respiration. Elevated lipolytic enzymes in male iWAT suggest greater FFA release, while higher pyruvate import and glyceroneogenesis genes in female gWAT favor FFA recycling. Alpl upregulation in females indicates sex-biased UCP1-independent thermogenesis. These depot- and sex-specific signatures reflect distinct metabolic strategies and highlight the need to consider both in adipose research.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102227
  17. Nat Neurosci. 2025 Aug 06.
    Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.
    Eizo Marutani, Maria Miranda, Timothy J Durham, Sharon H Kim, Dreson L Russell, Presli P Wiesenthal, Paul Lichtenegger, Marissa A Menard, Charlotte F Brzozowski, Haobo Li, Gary Ruvkun, Joshua D Meisel, Laura Volpicelli-Daley, Vamsi K Mootha, Fumito Ichinose.
      Parkinson's disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes.
    DOI:  https://doi.org/10.1038/s41593-025-02010-4
  18. Neuropharmacology. 2025 Aug 06. pii: S0028-3908(25)00334-X. [Epub ahead of print] 110626
    IP3-mediated Ca2+ transfer from ER to mitochondria stimulates ATP synthesis in primary hippocampal neurons.
    Ankit Dhoundiyal, Vanessa Goeschl, Stefan Boehm, Helmut Kubista, Matej Hotka.
      During electrical activity, Ca2+ enhances mitochondrial ATP production, helping to replenish the energy consumed during this process. Most Ca2+ enters the cell via ligand- or voltage-gated channels on the neuronal membrane, where it stimulates the release of additional Ca2+ from the endoplasmic reticulum (ER). Although the influence of cytosolic Ca2+ on neuronal metabolism has been widely investigated, relatively few studies have explored the contribution of ER Ca2+ release in this context. Therefore, we investigated how activity-driven Ca2+ crosstalk between the ER and mitochondria influences the regulation of mitochondrial ATP production. We show that in primary hippocampal neurons derived from rat pups of either sex, depletion of ER Ca2+ led to a reduction in mitochondrial Ca2+ levels during both resting and stimulated states, while exerting only a minimal impact on cytosolic Ca2+ levels. Additionally, impaired ER-mitochondria Ca2+ transfer led to a reduction in mitochondrial ATP production. Similar effects were observed when inositol-3-phosphate receptors (IP3Rs), but not ryanodine receptors (RyRs), were pharmacologically inhibited. Together, our findings show that, in hippocampal neurons, Ca2+ is transferred from the ER to mitochondria through IP3 receptors, and this Ca2+ crosstalk in turn enhances mitochondrial ATP production in response to neuronal activity.
    Keywords:  ATP; ER calcium; IP(3)Rs; RyRs; mitochondria; neuronal metabolism
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110626
  19. Mol Med. 2025 Aug 04. 31(1): 273
    Preclinical evaluation of candidate "kill or cure" strategies to treat MFN2-related lipodystrophy.
    Ineke Luijten, Xiong Weng, Ula Kibildyte, Jana Buchan, Ami Onishi, Jake Mann, Eleanor McKay, David Savage, Robert K Semple.
       BACKGROUND: The mitofusin 2 (MFN2) R707W mutation causes debilitating human lipodystrophy featuring lower body adipose loss, upper body adipose hyperplasia, and dyslipidaemic insulin resistance. Mechanical complications include airway compromise due to head and neck adipose overgrowth. This condition, sometimes called Multiple Symmetrical Lipomatosis (MSL), is also seen in sporadic form strongly associated with excess ethanol consumption. Mitigating the cellular pathology, or, conversely, exacerbating it, inducing selective death of affected adipocytes, are potential therapeutic strategies.
    METHODS: Candidate exacerbating and mitigating approaches to MFN2-MSL were tested in human MFN2R707W/R707W fibroblasts, and in Mfn2R707W/R707W mice and derived preadipocytes. Cell survival, mitochondrial network morphology and integrated stress response markers were assessed in cells, and body composition and metabolic indices in mice.
    RESULTS: Forcing galactose metabolism in human MFN2R707W/R707W dermal fibroblasts did not replicate the overt adipose mitochondrial phenotype. 50mmol ethanol had little effect on Mfn2R707W/R707W white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in Mfn2R707W/R707W brown preadipocytes. 20% EtOH consumption increased brown adipose tissue in female Mfn2R707W/R707W mice, and serum lactate in males. Rapamycin - a candidate mitigating treatment - increased size and mitolysosome content of WT preadipocytes, and to a lesser degree of Mfn2R707W/R707W preadipocytes. In male Mfn2R707W/R707W mice, rapamycin reduced weight gain, brown adipose mass, and increased serum Fgf21. Finally, a panel of mitochondrial stressors solicited no selective death or ISR in Mfn2R707W/R707W preadipocytes.
    CONCLUSIONS: Ethanol mildly exacerbates murine MFN2-related MSL, while rapamycin is tolerated. MFN2-related MSL may not be solely attributable to compromised oxidative phosphorylation.
    Keywords:  Alcohol; Lipodystrophy; MFN2; Mitofusin; Multiple symmetrical lipomatosis; Rapamycin; Sirolimus
    DOI:  https://doi.org/10.1186/s10020-025-01314-2
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