bims-mitmed 2025-04-27 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–04–27
thirty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.
Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases.
Interpreting the clinical significance of multiple large-scale mitochondrial DNA deletions (MLSMD) in skeletal muscle tissue in the diagnostic evaluation of primary mitochondrial disease.
Mitochondrial DNA signals driving immune responses: Why, How, Where?
Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.
TMBIM-2 links neuronal mitochondrial stress to systemic adaptation via calcium signaling.
Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.
Bergenin promotes mitochondrial biogenesis via the AMPK/SIRT1 axis in hepatocytes.
Krüppel-like factors in mitochondrial quality control.
A rare mitochondrial disease with infantile severe metabolic disturbances that improved spontaneously.
OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation.
Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy.
Palatal tremor as the clue sign of POLG-related syndrome.
PPARα regulates ER-lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes.
SIRT1-based therapy targets a gene program involved in mitochondrial turnover in a model of retinal neurodegeneration.
Prenatal FBXL4-Associated Mitochondrial DNA Depletion Syndrome-13: A New Case and Review of the Literature.
Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.
Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.
Integrated analysis of molecular atlases unveils modules driving developmental cell subtype specification in the human cortex.
CNS Mitochondria-Derived Vesicle in Blood: Potential Biomarkers for Brain Mitochondria Dysfunction.
The genetic landscape of sporadic adult-onset degenerative ataxia: a multi-modal genetic study of 377 consecutive patients from the longitudinal multi-centre SPORTAX cohort.
Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration.
Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.
Mitochondrial calpain-1 truncates ATP synthase beta subunit.
Autophagosomes anchor an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling.
NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway.
Mitochondrial Dysfunction and Reduced TCA Cycle Metabolite Levels in Inflammatory Bowel Disease Patients.
Metabolic origin and significance of 3-methylglutaryl CoA.
Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.

J Mol Biol. 2025 Apr 21. pii: S0022-2836(25)00227-X. [Epub ahead of print] 169161

Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.

Bishal Basak, Erika L F Holzbaur.

  Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis(ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.

Keywords:  PINK1; Parkin; autophagosomes; lysosomes; mitochondria; mitophagy; neurodegeneration

DOI:  https://doi.org/10.1016/j.jmb.2025.169161
Mitochondrion. 2025 Apr 17. pii: S1567-7249(25)00037-6. [Epub ahead of print]84 102040

Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases.

Isabel Amador-Martínez, Ana Karina Aranda-Rivera, Mauricio Raziel Martínez-Castañeda, José Pedraza-Chaverri.

  Mitochondria are essential organelles for cellular function and have become a broad field of study. In cardio-renal diseases, it has been established that mitochondrial dysfunction is a primary mechanism leading to these pathologies. Under stress, mitochondria can develop stress response mechanisms to maintain mitochondrial quality control (MQC) and functions. In contrast, the perturbation of these mechanisms has been associated with the pathogenesis of several diseases. Thus, targeting specific pathways within MQC could offer a therapeutic avenue for protecting mitochondrial integrity. However, the mechanisms related to MQC and mitochondrial stress signaling in the cardio-renal axis have been poorly explored. The primary limitations include the lack of reproducibility in the experimental models of cardio-renal disease, the incomplete knowledge of molecules that generate bidirectional damage, and the temporality of the study models. Therefore, we believe that integration of all of those limitations, along with recent advances in MQC mechanisms (i.e., mitophagy), stress signaling pathways (e.g., integrated stress response, mitochondrial unfolded protein response, and mitochondrial protein import), associated pharmacology, and targeted therapeutic approaches could reveal what the deregulation of these mechanisms is like and provide ideas for generating strategies that seek to avoid the progression of cardio-renal diseases.

Keywords:  Cardio-renal disease; Integrated stress response; Mitochondrial dysfunction; Mitochondrial import; Mitochondrial quality control; Mitochondrial unfolded protein response

DOI:  https://doi.org/10.1016/j.mito.2025.102040
Front Pharmacol. 2025 ;16 1507493

Interpreting the clinical significance of multiple large-scale mitochondrial DNA deletions (MLSMD) in skeletal muscle tissue in the diagnostic evaluation of primary mitochondrial disease.

Jing Wang, James T Peterson, Joaquim Diego D Santos, Ada J S Chan, Maria Alejandra Diaz-Miranda, Imon Rahaman, Jean Flickinger, Amy Goldstein, Emily Bogush, Elizabeth M McCormick, Colleen C Muraresku, Vernon E Anderson, Matthew C Dulik, Douglas C Wallace, Rui Xiao, Marni J Falk, Angela N Viaene, Zarazuela Zolkipli-Cunningham.

   Background and Objectives: Improved detection sensitivity from combined Long-Range PCR (LR-PCR), Next-Generation Sequencing (NGS), and droplet digital PCR (ddPCR) to identify multiple large-scale mtDNA deletions (MLSMD) and quantify deletion heteroplasmy have introduced clinical interpretation challenges. We sought to evaluate clinical, biochemical, and histopathological phenotypes of a large clinical cohort harboring MLSMD in muscle to better understand their significance across a range of clinical phenotypes.
Methods: A single-site retrospective study was performed of 212 diagnostic muscle biopsies obtained from patients referred for Primary Mitochondrial Disease (PMD) evaluation with muscle mitochondrial (mt)DNA sequencing performed at our institution, including electronic medical record (EMR) review of symptoms, biochemical results, and Mitochondrial Myopathy Composite Assessment Tool (MM-COAST) scores.
Results: MLSMD were identified in 50 of 212 (24%) diagnostic tissue biopsies, and were universally present. in subjects ≥50 years (n = 18/18). In 45 of 50 (90%) subjects with MLSMD, no definitive genetic etiology was identified, despite clinical whole exome sequencing (WES) and/or whole genome sequencing (WGS). MLSMD heteroplasmy levels quantified by ddPCR ranged from 0% to 33%, exceeding 10% heteroplasmy in 5/45 (11%). Subjects with MLSMD (n = 45) were more likely to demonstrate mitochondrial abnormalities on histopathology, upregulation (≥150% of control mean) of one or more electron transport chain (ETC) complex enzyme activities, and reduced citrate synthase indicative of mitochondrial depletion (<60% of control mean) relative to subjects without MLSMD (n = 155). As clinical phenotypes varied across the MLSMD cohort, Bernier diagnostic criteria major/minor symptoms were used to discriminate 13 of 45 subjects with "suspected" PMD having unrevealing WES/WGS results and 32 of 45 subjects scored as "less likely" to have PMD. Relative to the "less likely" cohort, a significantly higher frequency of biochemical and muscle histopathological abnormalities (ragged red and COX negative fibers) were observed in the "suspected" cohort, further supporting a higher index of suspicion for PMD, p < 0.05.
Discussion: MLSMD in skeletal muscle tissue were a common molecular finding (24%) in our cohort and consistently present in subjects ≥50 years. Among those with genetically undiagnosed MLSMD (n = 45), the "suspected" PMD subset (n = 13/45) represent a promising cohort for novel gene discoveries.

Keywords:  electron transport chain (ETC) enzymatic activity; mitochondrial DNA (mtDNA); multiple large-scale mitochondrial DNA deletions (MLSMD); primary mitochondrial disease (PMD); ragged blue fibers (RBF); ragged red fibers (RRF)

DOI:  https://doi.org/10.3389/fphar.2025.1507493
Cell Commun Signal. 2025 Apr 22. 23(1): 192

Mitochondrial DNA signals driving immune responses: Why, How, Where?

Luca Giordano, Sarah A Ware, Claudia J Lagranha, Brett A Kaufman.

  There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.

Keywords:  Circulating cell-free DNA; DNA-sensing receptors; Inflammation; Innate immunity; Mitochondria; Mitochondrial DNA

DOI:  https://doi.org/10.1186/s12964-025-02042-0
Nat Cell Biol. 2025 Apr 21.

Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.

Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P Praharaj, Stewart Morley, Bookyong Ko, Mona H Soflaee, Harrison J Tom, Harrison Brown, Hieu S Vu, Shih-Chia Tso, Chad A Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K Allen, Gerta Hoxhaj.

Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.

DOI: https://doi.org/10.1038/s41556-025-01655-4
J Inherit Metab Dis. 2025 May;48(3): e70029

YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.

Anthi Demetriadou, Olga Grafakou, Theodoros Georgiou, Daniela Burska, Anna Malekkou, Jana Krizova, Efstathia Paramera, Gavriella Mavrikiou, Maria Dionysiou, Athina Theodosiou, Carolina Sismani, Violetta Anastasiadou, Ioannis Ioannou, Evangelos Papakonstantinou, Hana Hansikova, Anthi Drousiotou, Petros P Petrou.

  3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient-derived fibroblasts. Furthermore, our results indicate that YME1L1L667V is associated with attenuated activity of rate-limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build-up of 3-methylglutaconic and 3-methylglutaric acid due to the diversion of acetyl-CoA, not efficiently processed in the Krebs cycle, towards the formation of 3-methylglutaconyl-CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3-MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.

Keywords:  3‐methylglutaconic aciduria; YME1L1; inherited metabolic disorders; mitochondrial disorders; mitochondrial dysfunction; mitochondrial fragmentation

DOI:  https://doi.org/10.1002/jimd.70029
J Cell Biol. 2025 May 05. pii: e202503004. [Epub ahead of print]224(5):

TMBIM-2 links neuronal mitochondrial stress to systemic adaptation via calcium signaling.

Yu Sun, Terytty Yang Li.

Mitochondrial function is critical for neuronal activity and systemic metabolic adaptation. In this issue, Li et al. (https://doi.org/10.1083/jcb.202408050) identify TMBIM-2 as a key regulator of calcium dynamics, coordinating the neuronal-to-intestinal mitochondrial unfolded protein response (UPRmt), pathogen-induced aversive learning, and aging.

DOI: https://doi.org/10.1083/jcb.202503004
Sci Rep. 2025 Apr 21. 15(1): 13811

Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.

Emi Matsumoto, Taeko Sasaki, Tetsuya Higashiyama, Narie Sasaki.

  Mitochondrial DNA (mtDNA) is organized with proteins into mitochondrial nucleoid (mt-nucleoid). The mt-nucleoid is a unit for the maintenance and function of mtDNA. The regulator of chromosome condensation 1-like protein (RCC1L) performs various functions in mitochondria, including translation, but its involvement in regulating mt-nucleoid maintenance is unknown. Herein, we found that human RCC1L was required to maintain mt-nucleoids and mtDNA. Human RCC1L has three splicing isoforms: RCC1LV1, RCC1LV2, and RCC1LV3. Knockout (KO) cells lacking all RCC1L isoforms, which were lethal without pyruvate and uridine, exhibited a decrease in mt-nucleoids and mtDNA, along with swollen and fragmented mitochondria. Among the three RCC1L isoforms, only RCC1LV1 recovered all phenotypes observed in RCC1L KO cells. As the treatment of wild-type cells with chloramphenicol, a mitochondrial translation inhibitor, did not lead to the decrease in mt-nucleoids accompanied by mtDNA depletion, the decrease in mt-nucleoids and mtDNA in RCC1L KO cells was not solely attributed to impaired mitochondrial translation. Using conditional RCC1L KO cells, we observed a rapid decrease in mt-nucleoids and mtDNA during a specific period following RCC1L loss. Our findings indicate that RCC1L regulates the maintenance of mt-nucleoids and mtDNA besides its role in mitochondrial translational regulation.

Keywords:  Mitochondrial DNA; Mitochondrial nucleoid; RCC1L

DOI:  https://doi.org/10.1038/s41598-025-98397-y
J Med Invest. 2025 ;72(1.2): 66-75

Bergenin promotes mitochondrial biogenesis via the AMPK/SIRT1 axis in hepatocytes.

Yuki Nagara, Kentaro Tsuji, Yuki Kamei, Mitsugu Akagawa.

  Aging and obesity trigger liver mitochondrial decline, impairing liver function and energy metabolism. Effective hepatic mitochondrial biogenesis helps maintain and restore hepatocyte function. The effects of bergenin, a polyphenol with various pharmacological effects, on hepatic mitochondrial biogenesis remain unclear. Therefore, we aimed to determine its effects on mitochondrial biogenesis in hepatocytes. We measured mitochondrial content in human HepG2 hepatocytes using MitoTracker Green FM ; intracellular ATP content using an ATP assay kit ; and mitochondrial DNA (mtDNA) using the ratio of mtDNA to nuclear DNA by qPCR. Protein levels were analyzed using immunoblotting. Nuclear translocation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was assessed by immunofluorescence staining and immunoblotting. In human HepG2 hepatocytes, bergenin increased mitochondrial content, elevated mitochondrial DNA and constituent proteins, and enhanced intracellular ATP levels and PGC-1α nuclear translocation, possibly promoting mitochondrial biosynthesis. SIRT1 expression was induced in bergenin-treated cells and may be responsible for bergenin-inducible mitochondrial biogenesis, which was abolished by the SIRT1 inhibitor EX-527. Furthermore, bergenin activated AMP-activated protein kinase (AMPK). Compound C, an AMPK inhibitor, abolished bergenin-induced SIRT1 expression and mitochondrial biogenesis. Overall, bergenin activates hepatic mitochondrial biogenesis through the AMPK / SIRT1 axis, which could help to prevent and ameliorate serious aging- and obesity-related liver diseases. J. Med. Invest. 72 : 66-75, February, 2025.

Keywords:  bergenin; biogenesis; hepatocytes; mitochondria

DOI:  https://doi.org/10.2152/jmi.72.66
Front Physiol. 2025 ;16 1554877

Krüppel-like factors in mitochondrial quality control.

M Y Zhang, H Zhang, Y M Yao, D W Yang.

  Krüppel-like factors (KLFs) are a group of transcription factors characterized by conserved zinc finger domains in the C-terminus, which are critically involved in basic cellular processes, including growth, differentiation, apoptosis, and angiogenesis, and play important roles in many pathophysiological responses. Mitochondrial homeostasis relies on a coordinated mitochondrial quality control system, which maintains the number and morphological stability and coordinates mitochondrial physiological functions through renewal and self-clearance. In this paper, we review the current advances of KLFs in mitochondrial quality control (MQC), including the potential roles and regulatory mechanisms in mitochondrial biogenesis, mitochondrial fusion/fission, mitophagy and mitochondrial unfolded protein response. We also introduce the specific pharmacological modulation of KLFs, expecting to transforming basic research achievements and providing the possibility of targeted therapy for KLFs.

Keywords:  Krüppel-like factors; mitochondrial biogenesis; mitochondrial fusion/fission; mitochondrial quality control; mitochondrial unfolded protein response; mitophagy

DOI:  https://doi.org/10.3389/fphys.2025.1554877
Pediatr Int. 2025 Jan-Dec;67(1):67(1): e70052

A rare mitochondrial disease with infantile severe metabolic disturbances that improved spontaneously.

Mikiko Koizumi, Tae Ikeda, Tomokazu Kimizu, Yasushi Okazaki, Kei Murayama, Yuri Etani.



Keywords:  mitochondrial disease; reversible infantile respiratory chain deficiency

DOI:  https://doi.org/10.1111/ped.70052
J Transl Med. 2025 Apr 24. 23(1): 471

OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation.

Kexuan Zhang, Wenqing Zhang, Lin Zhang, Xiaorong Hou, Runyi Tian, Zhengmao Hu, Lili Yin, Zhonghua Hu.

   BACKGROUND: Autosomal dominant optic atrophy (ADOA), a leading common inherited optic neuropathy, arises from progressive retinal ganglion cell degeneration, often linked to OPA1 mutations. OPA1, a mitochondrial GTPase, regulates mitochondrial fusion, crista structure, and apoptosis. While GTPase-related dysfunction is well-studied, the role of other OPA1 domains in ADOA pathology remains unclear.
METHODS: To investigate ADOA-linked OPA1 mutations, we assessed mitochondrial morphology, membrane potential, cytochrome c release, and cell viability in primary cortical neurons and N2a cells expressing OPA1 wild-type or mutant constructs. RNA sequencing and structural predictions (SWISS-MODEL) provided insights into molecular pathways and structural impacts.
RESULTS: Two ADOA-associated mutations were characterized: V465F (GTPase β-fold) and V560F (BSE α-helix). Both mutations impaired mitochondrial fusion and cell survival under apoptotic stimuli. Notably, the BSE-located V560F mutation caused greater deficits in membrane potential maintenance, earlier apoptosis, and distinct molecular pathway changes compared to V465F.
CONCLUSIONS: This study highlights the domain-specific impacts of OPA1 mutations on mitochondrial function and ADOA pathology, revealing unique roles of the BSE domain in apoptosis regulation and mitochondrial integrity. These findings provide insights into ADOA mechanisms and potential therapeutic targets.

Keywords:  Apoptosis; Autosomal dominant optic atrophy (ADOA); Bundle signaling element (BSE); GTPase activity; Mitochondrial dynamics; OPA1 mutations

DOI:  https://doi.org/10.1186/s12967-025-06471-w
Acta Neuropathol Commun. 2025 Apr 24. 13(1): 83

Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy.

Veronica Riccardi, Carlo Fiore Viscomi, Marco Sandri, Angelo D'Alessandro, Monika Dzieciatkowska, Daniel Stephenson, Enrica Federti, Andreas Hermann, Leonardo Salviati, Angela Siciliano, Immacolata Andolfo, Seth L Alper, Jacopo Ceolan, Achille Iolascon, Gaetano Vattemi, Adrian Danek, Ruth H Walker, Alexander Mensch, Markus Otto, Marcus Deschauer, Moritz Armbrust, Cristiane Beninca', Valentina Salari, Paolo Fabene, Kevin Peikert, Lucia De Franceschi.

  VPS13A disease (chorea-acanthocytosis), is an ultra-rare autosomal recessive neurodegenerative disorder caused by mutations of the VPS13A gene encoding Vps13A. Increased serum levels of the muscle isoform of creatine kinase associated with often asymptomatic muscle pathology are among the poorly understood early clinical manifestations of VPS13A disease. Here, we carried out an integrated analysis of skeletal muscle from Vps13a-/- mice and from VPS13A disease patient muscle biopsies. The absence of Vps13A impaired autophagy, resulting in pathologic metabolic remodeling characterized by cellular energy depletion, increased protein/lipid oxidation and a hyperactivated unfolded protein response. This was associated with defects in myofibril stability and the myofibrillar regulatory proteome, with accumulation of the myocyte senescence marker, NCAM1. In Vps13a-/- mice, the impairment of autophagy was further supported by the lacking effect of starvation alone or in combination with colchicine on autophagy markers. As a proof of concept, we showed that rapamycin treatment rescued the accumulation of terminal phase autophagy markers LAMP1 and p62 as well as NCAM1, supporting a connection between impaired autophagy and accelerated aging in the absence of VPS13A. The premature senescence was also corroborated by local activation of pro-inflammatory NF-kB-related pathways in both Vps13a-/- mice and patients with VPS13A disease. Our data link for the first time impaired autophagy and inflammaging with muscle dysfunction in the absence of VPS13A. The biological relevance of our mouse findings, supported by human muscle biopsy data, shed new light on the role of VPS13A in muscle homeostasis.

Keywords:  Autophagy; Energy; Inflammaging; Metabolome; NF-kB

DOI:  https://doi.org/10.1186/s40478-025-01997-y
Neurol Sci. 2025 Apr 21.

Palatal tremor as the clue sign of POLG-related syndrome.

Sara Satolli, Andrea Mignarri, Filippo Maria Santorelli.

  We present the case of a man who complained of clinical features of a mitochondrial ataxia. He ultimately harbored a homozygous variant in the POLG gene. The patient also showed evidence of palatal tremor, a possible clue for POLG-related condition.

Keywords:  Ataxia; POLG; Palatal; Tremor

DOI:  https://doi.org/10.1007/s10072-025-08178-8
Proc Natl Acad Sci U S A. 2025 Apr 29. 122(17): e2426338122

PPARα regulates ER-lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes.

Lauren F Uchiyama, Alexander Nguyen, Kevin Qian, Liujuan Cui, Khoi T Pham, Xu Xiao, Yajing Gao, Yuta Shimanaka, Marcus J Tol, Laurent Vergnes, Karen Reue, Peter Tontonoz.

  Ketogenesis requires fatty acid flux from intracellular (lipid droplets) and extrahepatic (adipose tissue) lipid stores to hepatocyte mitochondria. However, whether interorganelle contact sites regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3β (CLSTN3β), an endoplasmic reticulum-lipid droplet contact site protein, in the control of lipid utilization in adipose tissue. Here, we show that Clstn3b expression is induced in the liver by the nuclear receptor PPARα in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of CLSTN3β in mice impairs ketogenesis independent of changes in PPARα activation. Conversely, hepatic overexpression of CLSTN3β promotes ketogenesis in mice. Mechanistically, CLSTN3β affects LD-mitochondria crosstalk, as evidenced by changes in fatty acid oxidation, lipid-dependent mitochondrial respiration, and the mitochondrial integrated stress response. These findings define a function for CLSTN3β-dependent membrane contacts in hepatic lipid utilization and ketogenesis.

Keywords:  hepatocyte; ketogenesis; ketogenic diet; lipid metabolism

DOI:  https://doi.org/10.1073/pnas.2426338122
Sci Rep. 2025 Apr 19. 15(1): 13585

SIRT1-based therapy targets a gene program involved in mitochondrial turnover in a model of retinal neurodegeneration.

Brahim Chaqour, Jacob B Rossman, Miranda Meng, Kimberly E Dine, Ahmara G Ross, Kenneth S Shindler.

  Neurodegenerative diseases of the eye such as optic neuritis (ON) are hallmarked by retinal ganglion cell (RGC) loss and optic nerve degeneration leading to irreversible blindness. Therapeutic interventions enhancing expression or activity of SIRT1, an NAD+-dependent deacetylase, support, at least in part, survival of RGCs in the face of injury. Herein, we used mice with experimental autoimmune encephalomyelitis (EAE) which recapitulates axonal and neuronal damages characteristic of ON to identify gene regulatory networks affected by constitutive ubiquitous Sirt1 expression in SIRT1 knock-in mice and wild-type mice upon targeted adeno-associated virus (AAV)-mediated SIRT1 expression in RGCs. RNA seq data analysis showed that the most upregulated genes in EAE mouse retinas include those involved in inflammation, immune response, apoptosis, and mitochondrial turnover. The latter includes genes regulating mitophagy (e.g., Atg4), mitochondrial transport (e.g., Ipo- 6, Xpo- 6), and mitochondrial localization (e.g., Chrna4, Scn9a). The constitutive or RGC-targeted SIRT1 overexpression in EAE mice upregulated the expression of non-mitochondrial genes such as Ecel1 and downregulated the expression of mitophagy genes (e.g., Atg2b, Arifip1) which were upregulated by EAE alone. Thus, SIRT1 induces neuroprotection by, at least in part, balancing mitochondrial biogenesis and mitophagy and/or enhancing mitochondrial self-repair to preserve the bioenergetic capacity of RGCs.

Keywords:  Experimental autoimmune encephalomyelitis; Optic neuritis; SIRT1

DOI:  https://doi.org/10.1038/s41598-025-97456-8
Prenat Diagn. 2025 Apr 19.

Prenatal FBXL4-Associated Mitochondrial DNA Depletion Syndrome-13: A New Case and Review of the Literature.

Andrea Ros, Ivan Hurtado, Élida Vázquez-Méndez, Laura Monlleó-Neila, Montserrat Pauta, M Mar Rovira-Remisa, Belen García, Barbara Masotto, Carmina Comas, Ignacio Blanco, Aneta Zientalska.

OBJECTIVE: Mitochondrial DNA depletion syndrome-13 associated with FBXL4 (MTDPS13) is an autosomal recessive disorder characterized by encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. This report aims to provide a comprehensive analysis of a new prenatal-onset case of MTDPS13 and to review previously documented cases.
METHOD: We report a prenatal-onset case of MTDPS13 and review the three previously published cases.
RESULTS: The fetus initially presented with abnormal ultrasound findings at 20 weeks of gestation, including a mega cisterna magna, hypoplasia of the cerebellar vermis, and large bilateral choroid plexus cysts. At 23 weeks of gestation, fetal magnetic resonance imaging (MRI) confirmed the ultrasound findings and revealed small periventricular cystic areas suggestive of cavitations in the ganglionic eminences. At 31 weeks, MRI identified vermian hypoplasia with an increased retrocerebellar space, elevated tentorial insertion, and unilateral ventriculomegaly. Later in pregnancy, exome sequencing identified the homozygous pathogenic variant NM_012160.4:c.141del in the FBXL4 gene, thereby confirming the diagnosis of MTDPS13.
CONCLUSION: This case illustrates the prenatal onset of MTDPS13, with central nervous system abnormalities apparent from the second trimester. Only three similar cases have been reported, all in males, presenting at least one truncating variant in FBXL4 gene. The literature and our case highlight that the prenatal clinical manifestations can include ventriculomegaly, periventricular cysts, mega cisterna magna, cerebellar vermis hypoplasia, and cardiac anomalies.

DOI: https://doi.org/10.1002/pd.6794
Cell Metab. 2025 Apr 18. pii: S1550-4131(25)00211-6. [Epub ahead of print]

Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.

Yuki Tatekoshi, Amir Mahmoodzadeh, Jason S Shapiro, Mingyang Liu, George M Bianco, Ayumi Tatekoshi, Spencer Duncan Camp, Adam De Jesus, Navid Koleini, Santiago De La Torre, J Andrew Wasserstrom, Wolfgang H Dillmann, Benjamin R Thomson, Kenneth C Bedi, Kenneth B Margulies, Samuel E Weinberg, Hossein Ardehali.

  Heart failure with preserved ejection fraction (HFpEF) is a common cause of morbidity and mortality worldwide, but its pathophysiology remains unclear. Here, we report a mouse model of HFpEF and show that hexokinase (HK)-1 mitochondrial binding in endothelial cells (ECs) is critical for protein O-GlcNAcylation and the development of HFpEF. We demonstrate increased mitochondrial dislocation of HK1 within ECs in HFpEF mice. Mice with deletion of the mitochondrial-binding domain of HK1 spontaneously develop HFpEF and display impaired angiogenesis. Spatial proximity of dislocated HK1 and O-linked N-acetylglucosamine transferase (OGT) causes increased OGT activity, shifting the balance of the hexosamine biosynthetic pathway intermediates into the O-GlcNAcylation machinery. EC-specific overexpression of O-GlcNAcase and an OGT inhibitor reverse angiogenic defects and the HFpEF phenotype, highlighting the importance of protein O-GlcNAcylation in the development of HFpEF. Our study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation, and provides a potential therapy for HFpEF.

Keywords:  HFpEF; O-GlcNAcylation; endothelial cell; hexokinase 1; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.04.001
Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00380-8. [Epub ahead of print]44(5): 115609

Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.

Netherlands Brain Bank

  Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their hematopoietic stem cell (HSC) derivation, monocyte-derived microglia (MoMg) are unlike yolk-sac-derived cells, targets of clonal hematopoiesis (CH). Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human CH variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can cause brain pathology.

Keywords:  ARCH; CH; CHIP; CP: Immunology; CP: Neuroscience; DNMT3A R882H; HSC; brain macrophages; clonal hematopoiesis; microglia; monocytes

DOI:  https://doi.org/10.1016/j.celrep.2025.115609
Nat Neurosci. 2025 Apr 21.

Integrated analysis of molecular atlases unveils modules driving developmental cell subtype specification in the human cortex.

Patricia R Nano, Elisa Fazzari, Daria Azizad, Antoni Martija, Claudia V Nguyen, Sean Wang, Vanna Giang, Ryan L Kan, Juyoun Yoo, Brittney Wick, Maximilian Haeussler, Aparna Bhaduri.

Human brain development requires generating diverse cell types, a process explored by single-cell transcriptomics. Through parallel meta-analyses of the human cortex in development (seven datasets) and adulthood (16 datasets), we generated over 500 gene co-expression networks that can describe mechanisms of cortical development, centering on peak stages of neurogenesis. These meta-modules show dynamic cell subtype specificities throughout cortical development, with several developmental meta-modules displaying spatiotemporal expression patterns that allude to potential roles in cell fate specification. We validated the expression of these modules in primary human cortical tissues. These include meta-module 20, a module elevated in FEZF2+ deep layer neurons that includes TSHZ3, a transcription factor associated with neurodevelopmental disorders. Human cortical chimeroid experiments validated that both FEZF2 and TSHZ3 are required to drive module 20 activity and deep layer neuron specification but through distinct modalities. These studies demonstrate how meta-atlases can engender further mechanistic analyses of cortical fate specification.

DOI: https://doi.org/10.1038/s41593-025-01933-2
Ann Clin Transl Neurol. 2025 Apr 25.

CNS Mitochondria-Derived Vesicle in Blood: Potential Biomarkers for Brain Mitochondria Dysfunction.

Qi Liu, Wentao Chen, Yahong Wu, Zhen Guo, Jun Chen, Chen Tian, Pan Wang, Shaopeng Zeng, Bin Xu, Jing Duan, Shilong Han, Xiao Xiong, Jing Zhang.

   OBJECTIVE: Mitochondrial dysfunction is a hallmark of neurodegenerative diseases like Alzheimer's (AD) and Parkinson's (PD). Our goal was to develop practical, noninvasive methods to assess mitochondrial status through the detection of mitochondria-derived vesicles (MDVs).
METHODS: We explored blood-borne MDVs, a recently identified class of extracellular vesicles, as potential biomarkers for CNS mitochondrial status.
RESULTS: The study identified MDVs from neurons, astrocytes, and oligodendrocytes specifically in human plasma. A novel nanoflow cytometry was developed to evaluate the level of neuron-, astrocyte-, and oligodendrocyte-derived MDVs in plasma in AD and PD patients. Importantly, analyses of discovery and validation cohorts revealed significantly lower brain cell-specific MDVs in AD and PD patients compared to healthy controls.
INTERPRETATION: This study suggests that blood MDVs could serve as noninvasive biomarkers for mitochondrial dysfunction in AD, PD, and beyond, potentially aiding in monitoring mitochondrial-focused therapies for neurological disorders.

Keywords:  Alzheimer's diseases; Parkinson's diseases; mitochondrial dysfunction; mitochondria‐derived vesicles

DOI:  https://doi.org/10.1002/acn3.70060
EBioMedicine. 2025 Apr 23. pii: S2352-3964(25)00159-8. [Epub ahead of print]115 105715

The genetic landscape of sporadic adult-onset degenerative ataxia: a multi-modal genetic study of 377 consecutive patients from the longitudinal multi-centre SPORTAX cohort.

SPORTAX consortium

   BACKGROUND: While most sporadic adult-onset neurodegenerative diseases have only a minor monogenic component, given several recently identified late adult-onset ataxia genes, the genetic burden may be substantial in sporadic adult-onset ataxias. We report systematic mapping of the genetic landscape of sporadic adult-onset ataxia in a well-characterised, multi-centre cohort, combining several multi-modal genetic screening techniques, plus longitudinal natural history data.
METHODS: Systematic clinico-genetic analysis of a prospective longitudinal multi-centre cohort of 377 consecutive patients with sporadic adult-onset ataxia (SPORTAX cohort), including clinically defined sporadic adult-onset ataxia of unknown aetiology (SAOA) (n = 229) and 'clinically probable multiple system atrophy of cerebellar type' (MSA-Ccp) (n = 148). Combined GAA-FGF14 (SCA27B) and RFC1 repeat expansion screening with next-generation sequencing (NGS) was complemented by natural history and plasma neurofilament light chain analysis in key subgroups.
FINDINGS: 85 out of 377 (22.5%) patients with sporadic adult-onset ataxia carried a pathogenic or likely pathogenic variant, thereof 67/229 (29.3%) patients with SAOA and 18/148 (12.2%) patients meeting the MSA-Ccp criteria. This included: 45/377 (11.9%) patients with GAA-FGF14≥250 repeat expansions (nine with MSA-Ccp), 17/377 (4.5%) patients with RFC1 repeat expansions (three with MSA-Ccp), and 24/377 (6.4%) patients with single nucleotide variants (SNVs) identified by NGS (six with MSA-Ccp). Five patients (1.3%) were found to have two relevant genetic variants simultaneously (dual diagnosis).
INTERPRETATION: In this cohort of sporadic adult-onset ataxia, a cohort less likely to have a monogenic cause, a substantial burden of monogenic variants was identified, particularly GAA-FGF14 and RFC1 repeat expansions. This included a substantial share of patients meeting the MSA-Ccp criteria, suggesting a reduced specificity of this clinical diagnosis and potential co-occurrence of MSA-C plus a second, independent genetic condition. These findings have important implications for the genetic work-up and counselling of patients with sporadic ataxia, even when presenting with MSA-like features. With targeted treatments for genetic ataxias now on the horizon, these findings highlight their potential utility for these patients.
FUNDING: This work was supported by the Clinician Scientist programme "PRECISE.net" funded by the Else Kröner-Fresenius-Stiftung (to DM, AT, CW, OR, and MS), by the Deutsche Forschungsgemeinschaft (as part of the PROSPAX project), and by the Canadian Institutes of Health Research and the Fondation Groupe Monaco. Support was also provided by Humboldt Research Fellowship for Postdocs and the Hertie-Network of Excellence in Clinical Neuroscience and a Fellowship award from the Canadian Institutes of Health Research.

Keywords:  Adult-onset ataxia; CANVAS; Disease trajectories; Genetic testing; Genomics; Multiple system atrophy; Prospective cohort; SCA27B; Sporadic ataxia

DOI:  https://doi.org/10.1016/j.ebiom.2025.105715
Cell Mol Neurobiol. 2025 Apr 21. 45(1): 38

Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration.

Donghui Na, Zechen Zhang, Meng Meng, Meiyu Li, Junyan Gao, Jiming Kong, Guohui Zhang, Ying Guo.

  Aging is characterized by a gradual decline in physiological functions, with brain aging being a major risk factor for numerous neurodegenerative diseases. Given the brain's high energy demands, maintaining an adequate ATP supply is crucial for its proper function. However, with advancing age, mitochondria dysfunction and a deteriorating energy metabolism lead to reduced overall energy production and impaired mitochondrial quality control (MQC). As a result, promoting healthy aging has become a key focus in contemporary research. This review examines the relationship between energy metabolism and brain aging, highlighting the connection between MQC and energy metabolism, and proposes strategies to delay brain aging by targeting energy metabolism.

Keywords:  Brain aging; Energy metabolism; Mitochondrial quality control; Neurons

DOI:  https://doi.org/10.1007/s10571-025-01555-z
PLoS Genet. 2025 Apr 25. 21(4): e1011678

Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.

Xiaomeng Yang, Ruichen Wei, Fanfan Meng, Dianchen Liu, Xuan Gong, Gary Ruvkun, Wei Wei.

Mitochondrial fission and fusion are tightly regulated to specify mitochondrial abundance, localization, and arrangement during cell division as well as in the diverse differentiated cell types and physiological states. However, the regulatory pathways for such mitochondrial dynamics are less explored than the mitochondrial fission and fusion components. Here we report a large-scale screen for genes that regulate mitochondrial fission. Mitochondrial fission defects cause a characteristic uneven fluorescent pattern in embryos carrying mitochondrial stress reporter genes. Using this uneven activation, we performed RNAi screens that identified 3 kinase genes from a ~ 500-kinase library and another 11 genes from 3,300 random genes that function in mitochondrial fission. Many of these identified genes play roles in chromosome segregation. We found that chromosome missegregation and genome instability lead to dysregulation of mitochondrial fission, possibly independent of DRP-1. ATL-1, the C. elegans ATR orthologue, plays a potentially protective role in alleviating the mitochondrial fission defect caused by chromosome missegregation. This establishes a screening paradigm for identifying mitochondrial fission regulators, which reveals the potential role of ATR in surveilling mitochondrial fission to mitigate dysregulation caused by improper chromosome segregation.

DOI: https://doi.org/10.1371/journal.pgen.1011678
Biochem Biophys Res Commun. 2025 Apr 16. pii: S0006-291X(25)00543-1. [Epub ahead of print]765 151829

Mitochondrial calpain-1 truncates ATP synthase beta subunit.

Yusaku Chukai, Nanami Furukawa, On Kosegawa, Lanlan Bai, Eriko Sugano, Tomokazu Fukuda, Hiroshi Tomita, Taku Ozaki.

  Calpains cleave proteins in a calcium concentration-dependent manner, modulating their intracellular functions. Calpain-1, a member of the calpain family, is localized in the cytosol and mitochondria. Mitochondrial calpain-1 induces mitochondrial dysfunction and apoptosis by cleaving its substrate. Thus, identifying the substrate of calpain-1 is essential to understand its function. However, little is known about the substrates of mitochondrial calpain-1. To address this issue, we screened mitochondrial proteins using bioinformatics approaches and two-dimensional gel electrophoresis. We identified ATP5B as a potential substrate of mitochondrial calpain-1. Calpeptin, a pan-calpain inhibitor, and Tat-μCL, a mitochondrial calpain-1 specific inhibitor, prevented the truncation of ATP5B during in vitro Ca2+ incubation. Using recombinant human calpain-1 and ATP5B proteins, we demonstrated that calpain-1 directly cleaved ATP5B, generating a fragment of ATP5B. Based on the predicted cleavage sites in ATP5B, this cleavage may disrupt its interaction with ATP5A1, leading to mitochondrial dysfunction in ATP production. This study identified ATP5B as a novel substrate of mitochondrial calpain-1. The results provide new insights into mitochondrial dysfunction.

Keywords:  ATP5B; Calpain-1; Mitochondria

DOI:  https://doi.org/10.1016/j.bbrc.2025.151829
EMBO J. 2025 Apr 22.

Autophagosomes anchor an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling.

Ashley Segura-Roman, Y Rose Citron, Myungsun Shin, Nicole Sindoni, Alex Maya-Romero, Simon Rapp, Claire Goul, Joseph D Mancias, Roberto Zoncu.

  Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (Cα) and regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). By binding to an AKAP11 scaffold, PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis. Mutations in AKAP11 promote schizophrenia and bipolar disorders (SZ-BP) through unknown mechanisms. Here, through proteomic-based analyses of immunopurified lysosomes, we identify the Cα-RIα-AKAP11 holocomplex as a prominent autophagy-associated protein-kinase complex. AKAP11 scaffolds Cα-RIα interaction with the autophagic machinery via its LC3-interacting region (LIR), enabling both PKA regulation by upstream signals, and its autophagy-dependent degradation. We identify Ser83 on the RIα linker-hinge region as an AKAP11-dependent phospho-residue that modulates RIα-Cα binding to the autophagosome and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters downstream phosphorylation events, supporting an autophagy-dependent checkpoint for PKA signaling. Ablating AKAP11 in induced pluripotent stem cell-derived neurons reveals dysregulation of multiple pathways for neuronal homeostasis. Thus, the autophagosome is a platform that modulates PKA signaling, providing a possible mechanistic link to SZ/BP pathophysiology.

Keywords:  AKAP11; Autophagy; Phosphoproteomics; Protein kinase A; Signaling

DOI:  https://doi.org/10.1038/s44318-025-00436-x
Front Pharmacol. 2025 ;16 1545585

NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway.

Yuxian Lin, Yajing Wang, Xinxin Yang, Ziwei Ding, Mingye Hu, Xianfeng Huang, Qichun Zhang, Yingcong Yu.

   Background: Age-related decline in nicotinamide adenine dinucleotide (NAD+)-a central regulator of cellular metabolism, DNA repair, and immune homeostasis-is strongly associated with physiological dysfunction. Nicotinamide mononucleotide (NMN), a potent NAD+ precursor, shows promise in counteracting aging-related pathologies, particularly neurodegenerative decline.
Methods: An aging model was established in mice through 8-week D-galactose (D-gal) exposure, followed by NMN oral supplementation. Behavioral outcomes (open field test, Morris water maze) were analyzed alongside oxidative stress markers (SOD, CAT, AGEs), inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10), and neurotransmitters (LC-MS/MS). Apoptotic activity (TUNEL, p16/p21), mitochondrial regulators (Sirt1, p-AMPK, PGC-1α), and intestinal barrier integrity (HE/AB-PAS staining) were evaluated. Sirt1 dependency was confirmed using inhibitor Ex527.
Results: NMN restored locomotor activity and spatial memory in D-gal mice without altering body weight. Mechanistically, NMN synergistically attenuated oxidative stress and systemic inflammation, elevating antioxidant enzymes (SOD, CAT) and IL-10 while suppressing pro-inflammatory cytokines (TNF-α, IL-6) and AGEs. Cortical/hippocampal analyses revealed reduced apoptosis (TUNEL+ cells) and senescence markers (p16, p21), with enhanced mitochondrial function via Sirt1/AMPK/PGC-1α activation (Sirt1, p-AMPK). NMN concurrently preserved intestinal mucosal architecture, mitigating D-gal-induced barrier disruption. Crucially, all benefits were abolished by Sirt1 inhibition, confirming pathway specificity.
Conclusion: Our findings establish NMN as a multifaceted therapeutic agent that preserves neurocognitive function and intestinal homeostasis in aging models by orchestrating antioxidative, anti-inflammatory, and antiapoptotic responses through Sirt1/AMPK/PGC-1α activation. This work provides translational insights into NAD+-boosting strategies for age-related disorders.

Keywords:  NMN; SIRT1; aging; intestinal barrier; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.3389/fphar.2025.1545585
J Inflamm Res. 2025 ;18 5205-5216

Mitochondrial Dysfunction and Reduced TCA Cycle Metabolite Levels in Inflammatory Bowel Disease Patients.

Ewa Dudzińska, Agnieszka Madro, Ann Katrin Sauer, Andreas M Grabrucker, Aneta Strachecka.

   Introduction: Inflammatory bowel disease (IBD) mainly includes ulcerative colitis (UC) and Crohn's disease (CD). These diseases are classified as chronic and recurrent inflammatory diseases affecting the digestive tract. An energy deficiency in intestinal cells is believed to be associated with IBD pathology.
Methods: Our study investigated the bioenergetic functionality of mitochondria using the plasma of patients with CD and UC by determining the concentration of intermediates of the tricarboxylic acid cycle (TCA), such as acetyl coenzyme A, succinate, fumarate, α-ketoglutarate, NADH2, IDH2, Cytochrome C Oxidase, Cytochrome C Reductase, and ATP.
Results: Our results show an imbalance in mitochondrial homeostasis and bioenergetics, demonstrated by reduced activity of respiratory complexes and reduced production of TCA intermediates in the plasma of patients with CD and UC. In the group of patients with CD, treatment with corticosteroids had a significant positive effect, as significantly higher IDH2 and succinate levels were found. Correlation analyses of mitochondrial functionality biomarkers with other blood markers revealed a significant relationship between CRP and ATP levels, with higher CRP significantly linked to lower ATP and a similar trend for succinate levels. Using the disease activity scale, we show that biomarkers such as IDH2, α-ketoglutarate, and succinate levels are significantly lower in patients with higher disease activity.
Conclusion: We conclude that reduced metabolites and respiratory complexes associated with the TCA indicate mitochondrial bioenergetic failure in IBD patients. Besides, Krebs cycle metabolites can be a good marker of predisposition to the disease and the course of IBD. They can be easily determined in a blood sample taken from the patient. Pharmacological protection of mitochondria in individuals predisposed to IBD development and compensation for the changed function of mitochondria in persons with the developed disease may become a new approach to personalized therapies focused on restoring the proper activity of mitochondrial enzymes.

Keywords:  Krebs cycle; inflammatory bowel disease; respiratory complexes

DOI:  https://doi.org/10.2147/JIR.S487349
Clin Chim Acta. 2025 Apr 17. pii: S0009-8981(25)00199-8. [Epub ahead of print] 120320

Metabolic origin and significance of 3-methylglutaryl CoA.

Elizabeth A Jennings, Zane H Abi-Rached, Robert O Ryan.

  3-Methylglutaryl (3MG) CoA is not part of any biochemical pathway, yet its byproducts, 3MG carnitine and 3MG acid, are disease biomarkers. Both compounds are excreted in HMG CoA lyase deficiency, while 3MG aciduria occurs in inborn errors of metabolism (IEM) associated with compromised mitochondrial energy metabolism. In one such disorder (i.e., TMEM70 deficiency), 3MG carnitine is also present. Moreover, in a number of chronic and acute maladies, elevated levels of 3MG carnitine are present. The precursor of 3MG CoA istrans-3-methylglutaconyl (3MGC) CoA. Whentrans-3MGC CoA levels rise, a portion of this metabolite pool is reduced to 3MG CoA, potentially via a side reaction involving glutaryl CoA dehydrogenase (GCDH), which normally catalyzes the oxidative decarboxylation of glutaryl CoA to crotonyl CoA and CO2. This reaction occurs via a two-step process wherein glutaryl CoA is initially oxidized to glutaconyl CoA, coupled to reduction of the enzyme's FAD prosthetic group. Enzyme-bound glutaconyl CoA is then decarboxylated to the reaction product, crotonyl CoA. Before GCDH can accept another glutaryl CoA the flavin prosthetic group must be oxidized to FAD by donating electrons to electron transferring flavoprotein (ETF). However, genetic- or disease-induced defects in electron transport chain function can impede this reaction. We propose thattrans-3MGC CoA is a substrate for reduced GCDH and, when glutaryl CoA andtrans-3MGC CoA are present, GCDH is able to bypass ETF and cycle between oxidized and reduced states, producing crotonyl CoA and CO2from glutaryl CoA, and 3MG CoA fromtrans-3MGC CoA.

Keywords:  3-methylglutaric acid; 3-methylglutaryl carnitine; Biomarker; Glutaryl CoA dehydrogenase; Mitochondria

DOI:  https://doi.org/10.1016/j.cca.2025.120320
Sci Adv. 2025 Apr 25. 11(17): eadq6077

Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.

Laurent Guillaud, Anna Garanzini, Sarah Zakhia, Sandra De la Fuente, Dimitar Dimitrov, Susan Boerner, Marco Terenzio.

Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.

DOI: https://doi.org/10.1126/sciadv.adq6077