bims-mitmed 2025-10-05 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–10–05
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Interconnectivity of mitochondrial protein biogenesis and quality control.
A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation.
Targeting mitochondrial Kv1.3 enables precise autoreactive T cell therapy for multiple sclerosis.
Establishment of human Leber's hereditary optic neuropathy model using iPSC-derived retinal organoids.
Developmental regulation of fetal mitochondrial respiratory function towards term: the role of glucocorticoid and thyroid hormones.
Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.
Imaging of mitochondrial matrix pH dynamics reveals a functional interaction between the ADP/ATP carrier and ATP synthase to regulate H+ distribution.
A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.
Successful treatment of congenital sideroblastic anemia with low-dose decitabine in a patient with NDUFB11 gene mutation (c.276_278del): A case report.
Biallelic variants in BCAT1 impair mitochondrial function and are associated with a candidate neurometabolic disorder.
COXFA4L3 enhances mitochondrial complex IV function to boost ATP synthesis and drive sperm motility.
Identification of novel NDUFA3 variants in a patient with mitochondrial disorders.
DDHD2 provides a flux of saturated fatty acids for neuronal energy and function.
Selective inhibition of mitochondrial Kv1.3 prevents and alleviates multiple sclerosis in vivo.
Mitochondrial fission process 1 protein: a comprehensive review of its core roles in mitochondrial dynamics, disease, and therapeutic targets.
A zebrafish model of nicotinamide adenine dinucleotide (NAD+) deficiency-derived congenital disorders.
Metabolomic landscape of fetal organ development during late gestation in mice.
AMPK activation mitigates α-synuclein pathology and dopaminergic degeneration in cellular and mouse models of Parkinson's disease.
Case Report: Biallelic variants in MRPS36, encoding a component of the 2-oxoglutarate dehydrogenase complex, cause leigh syndrome.
Dysphagia linked to clinical phenotype and disease progression in spinocerebellar ataxia type 3.

Trends Biochem Sci. 2025 Oct 02. pii: S0968-0004(25)00222-1. [Epub ahead of print]

Interconnectivity of mitochondrial protein biogenesis and quality control.

Abi S Ghifari, Carmela Vazquez-Calvo, Andreas Carlström, Martin Ott.

  Mitochondrial protein homeostasis (proteostasis) keeps the mitochondrial proteome functional. Thus, proteostasis is essential for mitochondrial activity and overall cellular functions, and a reduction in its function corresponds with diseases and aging in humans. Recent studies in various model organisms highlight components and mechanisms of mitochondrial proteostasis from biogenesis, through assembly, to turnover. Key findings include the identification of new components and mechanistic insights into protein import and mitochondrial translation processes, the interconnectivity of protein biogenesis and quality control, and proteolytic degradation machineries. In this review we discuss these advances that improve our current understanding of the inner workings and significance of the mitochondrial proteostasis network in maintaining functional mitochondria.

Keywords:  mitochondria; proteases; protein import; proteolysis; proteostasis; translation

DOI:  https://doi.org/10.1016/j.tibs.2025.09.004
Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2506761122

A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation.

Deborah G Murdock, Kevin A Janssen, Kierstin Keller, Katherine L Mitchell, Maina Beauplan, William T O'Brien, Lia D'Alessandro, Jeffrey A Haltom, Douglas C Wallace.

  MEPAN (Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration) is an early-onset movement disorder characterized by ataxia, dysarthria, and optic atrophy. Here, we report the creation of a mouse model of MEPAN with patient-similar compound heterozygous mutations in the Mecr gene. The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain. MECR catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII), and the mechanism by which loss of mtFASII leads to neurological disease is unknown. LC-MS/MS-based proteomic analysis of Mecr mutant cerebella identified loss of subunits of complex I of oxidative phosphorylation (OXPHOS) and subunits of the iron-sulfur cluster assembly (ISC) complex. Native gels revealed altered OXPHOS complex and supercomplex formation and changes in binding of the acyl carrier protein (ACP) to mitochondrial complexes. These results demonstrate that MECR plays a key role in the acylation of ACP which is necessary for ACP-LYRM-mediated supercomplex modulation and ISC biogenesis and suggest unique pathways for therapeutics.

Keywords:  genetics; iron; mitochondrial disease; mitochondrial fatty acid synthesis; mouse model

DOI:  https://doi.org/10.1073/pnas.2506761122
EMBO Mol Med. 2025 Sep 29.

Targeting mitochondrial Kv1.3 enables precise autoreactive T cell therapy for multiple sclerosis.

Stefano Pluchino, Cory M Willis.

DOI: https://doi.org/10.1038/s44321-025-00306-3
Front Cell Neurosci. 2025 ;19 1635775

Establishment of human Leber's hereditary optic neuropathy model using iPSC-derived retinal organoids.

Kota Aoshima, Yuya Takagi, Michinori Funato, Yoshiki Kuse, Shinsuke Nakamura, Masamitsu Shimazawa.

  Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease caused by mitochondrial DNA mutations, leading to central vision loss and retinal ganglion cell (RGC) degeneration. Progress in understanding LHON and developing treatments has been limited by the lack of human-like models. In this study, we aimed to establish a human retinal model of LHON using retinal organoids (ROs) from LHON patient-derived induced pluripotent stem cells (LHON-iPSCs). We first confirmed LHON-iPSCs were successfully differentiated into ROs (LHON-ROs). LHON-RO showed a reduction in RGC numbers and the density of neural axons. Additionally, both mitochondrial membrane potential and ATP production were decreased in LHON-RO. Finally, treatment with idebenone, the only approved therapeutic agent for LHON, improved RGC numbers in LHON-RO. This model replicates key clinical features of LHON, including RGC and axonal loss, and demonstrates idebenone's therapeutic potential. Furthermore, a comprehensive analysis of the LHON-RO model revealed impaired mitophagy, suggesting novel therapeutic targets for LHON. Thus, the LHON-RO model offers a valuable platform for studying LHON pathogenesis and evaluating treatments.

Keywords:  Leber’s hereditary optic neuropathy; in vitro disease modeling; mitochondrial disease; mitophagy; retinal organoid

DOI:  https://doi.org/10.3389/fncel.2025.1635775
J Endocrinol. 2025 Oct 01. pii: JOE-25-0135. [Epub ahead of print]

Developmental regulation of fetal mitochondrial respiratory function towards term: the role of glucocorticoid and thyroid hormones.

A L Fowden, K L Davies, E J Camm, A J Forhead, A J Murray.

  Mitochondria are unique intracellular organelles that have their own DNA and are inherited intact in the oocyte. They have multiple functions, the most important of which is producing energy in the form of ATP by oxidative phosphorylation (OXPHOS) using a range of metabolic substrates. As energy requirements increase with intrauterine growth and the onset of new postnatal functions at birth, mitochondria develop structurally and functionally in utero to meet these energy demands. In part, the developmental and prepartum maturational changes in mitochondrial OXPHOS capacity depend on the endocrine environment and the natural rise in the fetal concentrations of hormones, such as cortisol and tri-iodothyronine (T3), towards term. This review discusses the development of mitochondrial respiratory function during late gestation with an emphasis on tissue OXPHOS capacity. It considers the role of cortisol and thyroid hormones, in particular, in the intrauterine development and prepartum maturation of mitochondrial OXPHOS capacity in preparation for extrauterine life. Finally, it briefly examines the potential longer-term consequences of abnormal hormonal exposure before birth on mitochondrial OXPHOS function later in postnatal life. Endocrine regulation of mitochondrial OXPHOS in the fetus is shown to be multifactorial, dynamic and tissue specific with a central role in determining functional development. It optimises energetics for survival both in utero and at birth and has implications for adult metabolic fitness and the inheritance of mitochondrial phenotype.

Keywords:  Glucocorticoids; Mitochondria; Oxidative phosphorylation; Thyroid hormones

DOI:  https://doi.org/10.1530/JOE-25-0135
Nat Commun. 2025 Sep 30. 16(1): 8685

Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.

Sirikrishna Thatavarthy, Luciano A Abriata, Fernando Teixeira Pinto Meireles, Kelly E Zuccaro, Akhil Gargey Iragavarapu, Gabriela May Sullivan, Frank R Moss, Adam Frost, Matteo Dal Peraro, Halil Aydin.

Cardiolipin is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which cardiolipin influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics simulations, we determined that cardiolipin molecules extensively engage with the paddle domain of mitochondrial fusion protein OPA1, which controls membrane-shaping mechanisms. Structure-function analysis confirmed the interactions between cardiolipin and two conserved motifs of OPA1 at the membrane-binding sites. We further developed a bromine-labeled cardiolipin probe to enhance cryoEM contrast and characterized the structure of OPA1 assemblies bound to the cardiolipin brominated lipid bilayers. Our images provide direct evidence of cardiolipin enrichment within the OPA1-binding leaflet. Last, we observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin. This suggests that the partial replacement of cardiolipin by monolyso-cardiolipin, as observed in Barth syndrome, alters the malleability of the membrane and compromises proper remodeling. Together, these data provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.

DOI: https://doi.org/10.1038/s41467-025-63813-4
Sci Adv. 2025 Oct 03. 11(40): eadw7376

The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.

Valentina Cianfanelli, Monica Nanni, Samantha Corrà, Sofia Mauri, David Sumpton, Sergio Lilla, Rossella De Cegli, Matteo Bordi, Giacomo Milletti, Caterina Ferraina, Arnaldur Hall, Michele Petraroia, Valentina Clausi, Ezio Giorda, Marco Scarsella, Alessandra Barbiera, Giulia Cadeddu, Marco Colasanti, Tiziana Persichini, Kenji Maeda, Apolinar Maya-Mendoza, Jiri Bartek, Chiara Di Malta, Franco Locatelli, Sara Zanivan, Shehab Ismail, Elena Ziviani, Francesco Cecconi.

Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the insult, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS. PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.

DOI: https://doi.org/10.1126/sciadv.adw7376
Pharmacol Res. 2025 Sep 25. pii: S1043-6618(25)00398-6. [Epub ahead of print]221 107973

Imaging of mitochondrial matrix pH dynamics reveals a functional interaction between the ADP/ATP carrier and ATP synthase to regulate H+ distribution.

Bernard Ribalet, Scott John, Madeleine G Milner, Leia Salongo, Ambre M Bertholet.

  In mitochondria, the energy derived from the proton gradient across the mitochondrial inner membrane (IMM) is converted into ATP and heat. For these conversions to occur, H+ is pumped out of the matrix via the electron transport chain (ETC) and then re-enters either via the ATP synthase to produce ATP or via the ADP/ATP carrier (AAC) to release heat. Due to its dual functions of ADP/ATP exchange and H+ transport, AAC may be considered a major regulator of the energy distribution of mitochondria between ATP synthesis and thermogenesis. Using real-time imaging of pH with a fluorescent pH probe targeted to the mitochondrial matrix, we investigated in a myoblast cell model how H+ fluxes across the IMM are regulated by AAC and the ATP synthase. Our data show that activation of AAC-dependent H+ transport by the mitochondrial uncoupler BAM15 causes an acidification of the matrix followed by a re-alkalization phase due to the reversed activity of the ATP synthase. Similar re-alkalization and reversal of ATP synthase activity were observed after acidification caused by inhibition of the electron transport chain. Lastly, the discovery that strong protonophoric activity independent of AAC suppresses the re-alkalization phase and consequently the reverse action of the ATP synthase, suggests the need for strict control of the H+ flux through the IMM by AAC. Thus, real-time imaging of matrix pH reveals a functional interaction between AAC and the ATP synthase for the control of H+ fluxes across the IMM.

Keywords:  ADP/ATP carrier; ATP synthase; BAM15; Electron transport chain; FCCP; Mitochondria; PH sensor; Proton transport; Uncoupling protein

DOI:  https://doi.org/10.1016/j.phrs.2025.107973
J Hum Genet. 2025 Oct 03.

A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.

Qianyun Cai, Haijiao Wang, Rong Luo, Xiao Qian, Zhongjie Zhou.

Mitochondrial complex IV (cytochrome c oxidase, COX) is essential for oxidative phosphorylation, and pathogenic variants of COX-related genes, such as COX6A1, are associated with neuromuscular disorders. While recessive COX6A1 variants are linked to Charcot-Marie-Tooth disease (CMT), the phenotypic spectrum and molecular mechanism remain incompletely understood. Here we report a 2-year-4-month-old girl who presented with global developmental delay, axonal CMT disease, and elevated lactate levels. WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T, p.110Leuext41) that is absent in population databases. This variant is 41 amino acids longer than the wild-type protein. Functional assays demonstrated significantly reduced mutant protein levels (p < 0.01), supporting the pathogenicity of this mutation. The patient experienced rapid decompensation and died following febrile illness at the age of 3.5 years. This study revealed a novel pathogenic COX6A1 variant that causes developmental delay and mitochondrial dysfunction, highlighting stop-loss mutations as a mechanism of disease. We report the first COX6A1 stop-loss variant, and our findings expand the phenotypic and genetic spectrum of COX6A1-related disorders.

DOI: https://doi.org/10.1038/s10038-025-01411-4
J Clin Invest. 2025 Sep 30. pii: e182480. [Epub ahead of print]

Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.

Cameron McDonald-Hyman, Ethan G Aguilar, Ewoud B Compeer, Michael C Zaiken, Stephanie Y Rhee, Fathima A Mohamed, Jemma H Larson, Michael L Loschi, Christopher Lees, Govindarajan Thangavelu, Margaret L Sleeth, Kyle D Smith, Jennifer S Whangbo, Jerome Ritz, Tim D Sparwasser, Roddy S O'Connor, Peter A Crawford, Jeffrey C Rathmell, Leslie S Kean, Robert Zeiser, Keli L Hippen, Michael L Dustin, Bruce R Blazar.

  Regulatory T-cells (Treg) are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Treg predominantly depend upon oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg "effector" differentiation, but FAO activity is inhibited by coordinated activity of isoenzymes acetyl-CoA Carboxylase-1 and -2 (ACC1/2). Here, we show that small molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic GVHD. ACC1 inhibition skewed Treg towards an "effector" phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg suppressive potency. Ex vivo expanded, ACC1 inhibitor treated human Treg similarly augmented suppressor function as observed with murine Treg. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.

Keywords:  Bone marrow transplantation; Immunology; Metabolism; Mitochondria; T cells

DOI:  https://doi.org/10.1172/JCI182480
Curr Res Transl Med. 2025 Sep 09. pii: S2452-3186(25)00051-0. [Epub ahead of print]73(4): 103542

Successful treatment of congenital sideroblastic anemia with low-dose decitabine in a patient with NDUFB11 gene mutation (c.276_278del): A case report.

Juan Wang, Heng Li, Nan Lv, Min Wang, Hongyu Zhao.

   BACKGROUND: Congenital sideroblastic anemias (CSAs) are an inherited group of blood disorders due to defects of mitochondrial proteins. The NDUFB11 gene is essential for the assembly of mitochondrial complex Ⅰ protein. Mutations in the NDUFB11 gene can cause sideroblastic anemia with hyperlacticemia, microphthalmia, cardiomyopathy and encephalomyopathy with limited therapeutic options.
CASE PRESENTATION: We reported a 35-year-old man with congenital sideroblastic anemia, skeletal dysplasias and hyperlacticemia. The skeletal muscle stains indicated probability of mitochondrial disorders. By whole-exome sequencing, we identified a mutation (c.276_278delCTT) in NDUFB11 gene in this patient which was inherited from his mother. He was unresponsive to the treatment of vitamin B2, vitamin B6, Coenzyme Q10, idebenone, or EPO but achieved hemoglobin concentration rise, transfusion independence and improvement of quality life after treated with low dose decitabine.
CONCLUSIONS: We proposed that epigenetic factors might play a role in pathogenesis in patients with c.276_278del (p.F93del) mutation in NDUFB11 gene and low dose decitabine may be a novel treatment in CSA patients with c.276_278del (p.F93del) mutation in NDUFB11 gene.

Keywords:  Congenital sideroblastic anemias; Low dose decitabine; Mitochondrial disorder; NDUFB11; Whole-exome sequencing

DOI:  https://doi.org/10.1016/j.retram.2025.103542
HGG Adv. 2025 Sep 29. pii: S2666-2477(25)00128-9. [Epub ahead of print] 100525

Biallelic variants in BCAT1 impair mitochondrial function and are associated with a candidate neurometabolic disorder.

Brianna L DiSanza, Giulia S Porcari, Livia Sertori Finoti, Leonardo Ramos-Rodriguez, Devin M Burris, Justin A McDonough, Gang Ning, Grace Fagan, Guy T Helman, Erin Weiss, Ryan J Taft, Amy Pizzino, Matthew T Whitehead, Amy Waldman, Cas Simons, Xilma Ortiz-Gonzalez, William C Skarnes, Adeline Vanderver, Elizabeth J Bhoj, Rebecca C Ahrens-Nicklas.

Branched-chain amino acid transaminase-1 (BCAT1) initiates the catabolism of branched-chain amino acids (BCAA), which are essential for neurologic function. However, the role of BCAT1 in neurodevelopment is largely unknown. Here, we identify compound heterozygous BCAT1 variants in a patient with a severe progressive neurodevelopmental syndrome. To investigate the functional consequences, we established patient variant (BCAT1: c.792T>A p.(Phe264Leu); c.1042G>A p.(Glu348Lys)) and BCAT1 knockout hiPSC models. Both disease models show profound defects in cortical neuron differentiation and neurite outgrowth. Furthermore, metabolic analysis revealed evidence of mitochondrial dysfunction associated with increased levels of tricarboxylic acid (TCA) cycle intermediates, glutamate, and glutamine. This increase is linked to altered oxygen consumption rates, superoxide production, and upregulation of UCP2 in BCAT1-disease neurons, suggesting a downstream impact on electron-transport chain homeostasis. These findings establish a regulatory role for BCAT1 in mitochondrial function and further define a role for genomic variants in BCAT1 in neurometabolic disorders.

DOI: https://doi.org/10.1016/j.xhgg.2025.100525
Mitochondrion. 2025 Sep 28. pii: S1567-7249(25)00079-0. [Epub ahead of print] 102082

COXFA4L3 enhances mitochondrial complex IV function to boost ATP synthesis and drive sperm motility.

Reiji Tokito, Kosei Oishi, Tomoya Sugiyama, Yusuke Fujisawa, Fujino Kuba, Kaito Yoshida, Kaoru Yoshida, Manabu Yoshida, Yoichiro Tanaka, Taku Amo, Noritaka Yamaguchi, Taishin Akiyama, Yuji Imai, Kazuto Yoshimi, Tsuyoshi Koide, Yasuyuki Kurihara.

  COXFA4L3 is a testis-specific cytochrome c oxidase subunit that enhances mitochondrial complex IV activity during spermatogenesis. From the analysis of Coxfa4l3 knockout mice, the isoform switch from COXFA4 to COXFA4L3 may increase the potential COX activity, although this activity does not appear in the testis. This latent enhancement becomes evident in sperm, where COXFA4L3 promotes higher respiratory capacity, increasing sperm motility and ATP production. These findings indicate that COXFA4L3 is a key regulator of mitochondrial energy metabolism and may provide insights into the mechanisms underlying male infertility.

Keywords:  Electron transport chain; Mitochondria; Spermatogenesis

DOI:  https://doi.org/10.1016/j.mito.2025.102082
Pediatr Res. 2025 Oct 02.

Identification of novel NDUFA3 variants in a patient with mitochondrial disorders.

Yu Sun, Xiujuan Wei, Bing Xiao, Yongfeng Luo, Ya Wang, Ripeng Liu, Yongkun Zhan, Xiantao Ye, Xudong Cai, Shiyi Xu, Jianxin Lyu, Hezhi Fang, Yongguo Yu.

BACKGROUND: Mitochondrial respiratory chain (RC) dysfunction constitutes the biochemical defect underlining a group of heterogenous clinical presentations known as mitochondrial disorders. NDUFA3 is an accessory subunit of Complex I (CI) and has recently been associated with Leigh Syndrome. However, the genetic evidence is limited and no functional analysis is available on the molecular mechanism.
METHODS: We investigated the clinical features of the second family with biallelic NDUFA3 variants. The patient's cells and HEK293T cells with NDUFA3 knock down (KD) were assessed to study the RC dysfunction. A zebrafish model with the morpholino targeting on ndufa3 were generated to study the phenotypes caused by ndufa3 disruption.
RESULTS: The affected boy demonstrated global developmental delay, neurosensory hearing impairment, strabismus, muscle weakness, and hypertonia. He harbored a paternal exonic deletion NC_000019.9:g.54608143_54614387delinsCG and a maternally-inherited missense variant NM_004542.4:c.173G>A; p.(Arg58His). In patient's cells and HEK293T cells with NDUFA3 KD, reduced levels of NDUFA3 and CI and Complex IV (CIV) were observed, which further impaired endogenous respiration and ATP generation. Re-expression of the wild-type but not the mutant NDUFA3 restored the CI and CIV levels in NDUFA3 deficient cells. Zebrafish with ndufa3 disruption demonstrated ndufa3 KD affected locomotor development.
CONCLUSIONS: Our findings confirm the association between NDUFA3 molecular defects and Leigh syndrome spectrum.
IMPACT: NDUFA3 deficiency causes a mitochondrial respiration complex deficiency disorder. A family with biallelic NDUFA3 variants demonstrates phenotype resembling mitochondrial respiration complex defects. NDUFA3 defects reduce the amount of respiration complex I and IV; impair endogenous respiration and ATP generation. Zebrafish with ndufa3 knock down manifests delayed locomotor development. With this reported patient, the relationship between the gene and disease can be upgraded from "limited" to "moderate".

DOI: https://doi.org/10.1038/s41390-025-04403-4
Nat Metab. 2025 Sep 30.

DDHD2 provides a flux of saturated fatty acids for neuronal energy and function.

Saber H Saber, Nyakuoy Yak, Xuan Ling Hilary Yong, Yih Tyng Bong, Hannah Leeson, Chuan-Yang Dai, Tobias Binder, Siyuan Lu, Reshinthine Purushothaman, An-Sofie Lenaerts, Leonardo Almeida-Souza, Lidiia Koludarova, Safak Er, Irena Hlushchuk, Arnaud Gaudin, Sachin Singh, Tuula A Nyman, Jeffrey R Harmer, Steven Zuryn, Ernst Wolvetang, Gert Hoy Talbo, Mikko Airavaara, Brendan J Battersby, Ashley J van Waardenberg, Victor Anggono, Giuseppe Balistreri, Merja Joensuu.

Although fatty acids support mitochondrial ATP production in most tissues, neurons are believed to rely exclusively on glucose for energy. Here we show that genetic ablation of the triglyceride and phospholipid lipase Ddhd2 impairs mitochondrial respiration and ATP synthesis in cultured neurons, despite increased glycolysis. This defect arises from reduced levels of long-chain saturated free fatty acids, particularly myristic, palmitic and stearic acids, normally released in an activity-dependent manner by Ddhd2. Inhibition of mitochondrial fatty acid import in wild-type neurons similarly reduced mitochondrial respiration and ATP production. Saturated fatty acyl-coenzyme A treatment restored mitochondrial energy production in Ddhd2 knockout neurons. When provided in combination, these activated fatty acyl-CoA supplements also rescued defects in membrane trafficking, synaptic function and protein homeostasis. These findings uncover that neurons perform β-oxidation of endogenous long-chain free fatty acids to meet ATP demands and reveal a potential therapeutic strategy for hereditary spastic paraplegia 54 caused by DDHD2 mutations.

DOI: https://doi.org/10.1038/s42255-025-01367-x
EMBO Mol Med. 2025 Sep 29.

Selective inhibition of mitochondrial Kv1.3 prevents and alleviates multiple sclerosis in vivo.

Beatrice Angi, Tatiana Varanita, Marco Puthenparampil, Valentina Scattolini, Michael Donadon, Mitra Tavakoli, Marta Favero, Maguie El Boustani, Matthias Soddemann, Lucia Biasutto, Diletta Arcidiacono, Alberto Ongaro, Andrea Mattarei, Livio Trentin, Gregory Wilson, Erich Gulbins, Paolo Gallo, Ildiko Szabo.

  Multiple sclerosis (MS) is characterized by invasion of the brain by effector memory T (TEM) lymphocytes that have been activated by repeated auto-antigen stimulation. Existing therapies target these and other autoreactive lymphocytes but their side effects include general immunosuppression and toxicity. Because the Kv1.3 potassium channel is highly expressed by chronically activated autoreactive TEMs, we investigated whether specific targeting of mitochondrial Kv1.3 using the pharmacological inhibitor PAPTP could selectively kill these TEMs in patients and mice with MS. 1 µM PAPTP targeted and reduced the number of autoreactive TEMs in blood samples from relapsing-remitting MS (RRMS) patients, leaving other T cell populations unaffected. Remarkably, pre-treatment of the entire T cell population with PAPTP during adoptive transfer of experimental autoimmune encephalomyelitis (EAE) killed TEMs and completely prevented disease onset in this mouse model. Moreover, PAPTP selectively eliminated activated TEMs and halted EAE progression when administered following disease onset. Our findings reveal the potential of PAPTP as an effective treatment for MS without adverse side effects.

Keywords:  Effector Memory T Cell; Experimental Autoimmune Encephalomyelitis; Mitochondrial Kv1.3 Channel Inhibition; Multiple Sclerosis

DOI:  https://doi.org/10.1038/s44321-025-00307-2
Front Cell Dev Biol. 2025 ;13 1646072

Mitochondrial fission process 1 protein: a comprehensive review of its core roles in mitochondrial dynamics, disease, and therapeutic targets.

Qingzhi Ran, Chen Gao, Chunrong Xiang, Xuanhui He, Yongkang Zhang, Yin Zhang, Hengwen Chen.

  Mitochondrial fission process 1 (MTFP1) has emerged as a central regulator of mitochondrial dynamics, playing indispensable roles in maintaining organellar integrity, bioenergetic homeostasis, and stress adaptation - particularly in high-energy-demand tissues such as cardiac and skeletal muscle. Mounting evidence implicates MTFP1 dysfunction in the pathogenesis of diverse diseases including cardiovascular disorders, myopathies, and cancer. Beyond its canonical role in mediating mitochondrial fusion-fission balance, recent studies have unveiled MTFP1's multifaceted involvement in calcium signaling modulation, ROS metabolism, and mitochondria-ER communication networks, substantially expanding its functional repertoire in cellular physiology. The protein's pleiotropic effects stem from its ability to integrate metabolic status with organelle dynamics and quality control mechanisms. Particularly noteworthy is MTFP1's cell-type-specific regulation of the ROS-calcium axis, which appears critical for its differential impacts in disease states. These discoveries position MTFP1 as both a mechanistic linchpin connecting mitochondrial dynamics to cellular homeostasis and a promising but challenging therapeutic target requiring precise contextual modulation. Current research frontiers focus on elucidating tissue-specific regulatory mechanisms of MTFP1 activity, developing microenvironment-sensitive targeting strategies, and exploring its potential as a biomarker for mitochondrial dysfunction-related pathologies. This evolving understanding of MTFP1's integrative functions opens new avenues for developing precision therapies targeting mitochondrial dynamics in energy-metabolism-linked diseases.

Keywords:  Mitochondria; Tumor; autophagy; cardiovascular disease; drug Targets; inflammation; mitochondrial fission process 1 protein

DOI:  https://doi.org/10.3389/fcell.2025.1646072
Dev Biol. 2025 Sep 30. pii: S0012-1606(25)00280-5. [Epub ahead of print]

A zebrafish model of nicotinamide adenine dinucleotide (NAD+) deficiency-derived congenital disorders.

Visakuo Tsurho, Carla Gilliland, Jessica Ensing, Elizabeth A VanSickle, Nathan J Lanning, Paul R Mark, Stephanie Grainger.

  Developmental NAD+ deficiency is associated with diverse congenital malformations. Congenital NAD deficiency disorder (CNDD) is a multisystem developmental condition characterized by cardiac, renal, vertebral, and limb anomalies, among others. It is caused by biallelic pathogenic variants in genes involved in the nicotinamide adenine dinucleotide (NAD+) synthesis pathway. CNDD anomalies overlap with clinical features described in vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL) association, suggesting a possible shared etiological link through NAD+ deficiency. However, the aberrant developmental mechanisms of NAD+-deficient congenital anomalies remain poorly understood. To dynamically explore NAD+-deficiency-induced congenital malformations, we developed a zebrafish model of NAD+ disruption. Zebrafish embryos treated with 2-amino-1,3,4-thiadiazole (ATDA), a known NAD+ metabolism disruptor, exhibited cardiac, tail, spinal cord, and craniofacial defects, which were partially rescued by nicotinamide (NAM) in a dose-dependent manner. Our work establishes zebrafish as a useful model for investigating how NAD+ deficiency contributes to multisystem congenital anomalies.

Keywords:  2-Amino-1,3,4-thiadiazole (ATDA); birth defects; congenital NAD deficiency disorder (CNDD); nicotinamide (NAM); nicotinamide adenine dinucleotide (NAD(+)); vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL) association; zebrafish

DOI:  https://doi.org/10.1016/j.ydbio.2025.09.022
Commun Biol. 2025 Oct 03. 8(1): 1423

Metabolomic landscape of fetal organ development during late gestation in mice.

Chanyi Li, Wuping Liu, Xiaodong Li, Bo Lv, Jiaying Qin, Ning Yi, Bianling Xu, Jing Xu, Zhigang Xue, Hongli Yan, Jinfeng Xue.

Metabolism is the critical basis for mammalian physiological functions. The systematic metabolic characteristics of major organ development during late gestation to adapt to postnatal environmental changes are still absent. Here, we detected metabolic patterns of the ICR mouse fetal organs, including the heart, stomach, liver, brain, and placenta, from embryonic days (E)15.5 to 19.5 using liquid chromatography-mass spectrometry combined with RNA sequencing and proteomics data. Our metabolic and multi-omics data showed that organs exhibited their unique metabolic characteristics during late gestation, and significant metabolic pattern transitions, especially the enhancement of digesting the fatty acids and proteins, occurred at the E16.5 to E18.5 stage. Additionally, we found the abundance of carnosine and histidine in the placenta may serve as a way to test their levels in the newborn brain in vitro. Our dataset provides a comprehensive metabolic landscape of mammalian organ development in late gestation.

DOI: https://doi.org/10.1038/s42003-025-08820-3
Neuropharmacology. 2025 Sep 26. pii: S0028-3908(25)00408-3. [Epub ahead of print]281 110700

AMPK activation mitigates α-synuclein pathology and dopaminergic degeneration in cellular and mouse models of Parkinson's disease.

Yoonha Kim, Jong Sam Lee, Sumin Son, Seobin Park, Hyungkeun Oh, Yoon Kyung Choi, Dong-Eun Kim.

  Parkinson's disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and pathological accumulation of p-α-Synuclein (p-α-Syn). AMP-activated protein kinase (AMPK) has emerged as a regulator of cellular energy homeostasis, yet its role in PD pathology remains unclear. Here, we examined the effects of AMPK activation in SH-SY5Y neuroblastoma cells and in an MPTP-induced PD mouse model. In both undifferentiated and retinoic acid-differentiated SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA), pharmacological AMPK activation with AICAR reduced reactive oxygen species (ROS) production and p-α-Syn aggregation. These effects were associated with enhanced mitophagy, increased lysosomal degradation, and stimulation of mitochondrial biogenesis, collectively restoring mitochondrial integrity and improving dopaminergic features. In vivo, AICAR treatment attenuated nigrostriatal dopaminergic degeneration in MPTP-exposed mice, reduced p-α-Syn accumulation, and preserved tyrosine hydroxylase expression. Moreover, systemic cytokine analysis revealed that AMPK activation suppressed IL-6-mediated inflammation, while modulating IL-1β levels in a context-dependent manner. These results demonstrate that AMPK activation mitigates α-synuclein pathology, preserves mitochondrial function, and protects dopaminergic neurons in both cellular and animal PD models. Our findings support AMPK as a potential therapeutic target for disease modification in PD.

Keywords:  AMP-Activated protein kinase; Mitochondrial homeostasis; Oxidative stress; Parkinson's disease; p-α-Syn

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110700
Front Pediatr. 2025 ;13 1608840

Case Report: Biallelic variants in MRPS36, encoding a component of the 2-oxoglutarate dehydrogenase complex, cause leigh syndrome.

Huafang Jiang, Chaolong Xu, Zhimei Liu, Ruoyu Duan, Xingfeng Yao, Xiaona Fu, Jiatong Xu, Xuejing Kang, Tenghui Yu, Yuanyuan Wang, Fang Fang.

   Background: The MRPS36 gene encodes the E4 subunit of the 2-oxoglutarate dehydrogenase complex (OGDHC), a critical enzyme in the tricarboxylic acid cycle. OGDHC deficiency can lead to metabolic disorders with a clinical spectrum ranging from fatal neonatal lactic acidosis to variable degrees of global developmental delay and movement disorders. To date, a homozygous MRPS36 variant has been reported as a novel cause of Leigh syndrome in only two siblings, who presented with developmental delay, movement disorders, bilateral striatal necrosis, and reduced OGDHC activity.
Case presentation: We report a third case of Leigh syndrome associated with MRPS36 variants in a 2-year-old boy. The patient exhibited with global developmental delay, dystonia, early-onset chorea, and elevated serum lactate levels. Follow-up brain magnetic resonance imaging at 2 years revealed progressive degenerative lesions in the bilateral basal ganglia. Muscle biopsy showed abnormal mitochondrial accumulation beneath the sarcolemma, and the oxygen consumption rate was reduced in skin fibroblasts. Whole-exome sequencing identified two novel compound heterozygous MRPS36 variants: c.42+1G>A (p.?) and c.296G>C (p.Arg99Pro).
Conclusion: This case supports MRPS36 as a novel pathogenic cause of Leigh syndrome, further expanding the genetic spectrum of the disorder. Key clinical features include developmental delay, involuntary movement disorders, progressive basal ganglia atrophy, and a slowly progressive disease course.

Keywords:  2-oxoglutarate dehydrogenase complex; Leigh syndrome; MRPS36 gene; OGDHC; case report; choreic movement; movement disorder

DOI:  https://doi.org/10.3389/fped.2025.1608840
Eur J Med Res. 2025 Sep 29. 30(1): 901

Dysphagia linked to clinical phenotype and disease progression in spinocerebellar ataxia type 3.

Cai-Ping Chen, Mao-Lin Cui, Wei Lin, Zhuo-Ying Huang, Bei-Ning Ye, Bin Cai, Shi-Rui Gan.

   BACKGROUND: Spinocerebellar Ataxia type 3 (SCA3) is a widely recognized autosomal dominant disorder characterized by cerebellar ataxia, particularly prevalent in China. Dysphagia frequently arises in SCA3 and other neurological disorders, representing a significant threat to patient survival.
OBJECTIVE: Examining the Prevalence of Dysphagia among SCA3 Patients and Its correlation with Clinical phenotype and Disease Progression.
METHODS: We retrospectively analyzed 183 SCA3 patients, divided into dysphagia and non-dysphagia groups. Dysphagia, as an item within INAS, was assessed by ataxia specialists primarily based on patient-reported symptoms, supplemented by caregiver or family input when available. Spearman's rho tested factor associations with dysphagia, logistic regression identified dysphagia risk factors, and multivariable linear regression assessed dysphagia's effect on ataxia severity. Kaplan-Meier curves with first derivative fitting explored dysphagia progression over the disease duration.
RESULTS: The study found 77.0% of SCA3 patients had dysphagia, with disease duration most strongly linked to its onset (r = 0.456, p < 0.001). Sex (p = 0.001; OR = 4.69, 95% CI = 1.85 to 11.88), AAO (p = 0.031; OR = 0.93, 95% CI = 0.87 to 0.99), SARA scores (p = 0.034; OR = 1.12, 95% CI = 1.01 to 1.25), and disease duration (p < 0.001; OR = 1.34, 95% CI = 1.14 to 1.57) were independent dysphagia risk factors. Dysphagia also affected SARA scores (p = 0.048). Dysphagia progression rate peaks within the first decade of disease onset, reaching maximal velocity at 6.5 years, with a median time to dysphagia onset of 9 years.
CONCLUSION: In China, dysphagia frequently occurs in SCA3 patients and can impact the severity of ataxia. The prevalence of dysphagia varies as the disease advances. These findings highlight the importance of timely intervention for dysphagia in SCA3 patients, particularly during the late stages of the first decade.

Keywords:  Clinical phenotype; Disease progression; Dysphagia; Spinocerebellar ataxia type 3

DOI:  https://doi.org/10.1186/s40001-025-03154-6