bims-mitmed 2025-04-06 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–04–06
twenty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Diagnosis of Primary Mitochondrial Diseases.
An inherited mtDNA rearrangement, mimicking a single large-scale deletion, associated with MIDD and a primary cardiological phenotype.
Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial.
An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer.
Perceived association of mood and symptom severity in adults with mitochondrial diseases.
Profiling mitochondrial DNA variant segregation during human preimplantation development: a prerequisite to preimplantation genetic testing for mitochondrial DNA-related disorders.
Retromer promotes the lysosomal turnover of mtDNA.
FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome: A rare cause of hyperammonemia.
What can ATP content tell us about Barth syndrome muscle phenotypes?
Mitochondrial heat production: the elephant in the lab….
What Is the Role of Inner Membrane Metalloproteases in Mitochondrial Quality Control and Disease?
Mitochondrial fusion protein: a new therapeutic target for lung injury diseases.
The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.
Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.
Mitochondrial fission regulates midgut muscle assembly and tick feeding capacity.
Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential-dependent accumulation.
Targeting mitochondria-regulated ferroptosis: A new frontier in Parkinson's Disease therapy.
Friedreich's ataxia treatment's sexual dimorphism.
Mitochondrial quality control: A promising target of traditional Chinese medicine in the treatment of cardiovascular disease.
Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics.
The mitochondria-gut microbiota crosstalk - A novel frontier in cardiovascular diseases.
A novel SLC44A gene variant in a patient with neonatal cholestasis and liver failure.
Restoration of Miro1's N-terminal GTPase function alleviates prenatal stress-induced mitochondrial fission via Drp1 modulation.
Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.
Pluripotent cell states and fates in human embryo models.
Mpf1 affects the dual distribution of tail-anchored proteins between mitochondria and peroxisomes.

Muscle Nerve. 2025 Apr 03.

Diagnosis of Primary Mitochondrial Diseases.

Salman Bhai, Michio Hirano.

  Primary mitochondrial diseases are clinically heterogeneous and present diagnostic challenges due to the highly variable genotype-phenotype correlation. Clinical symptoms can range from non-specific fatigue, exercise intolerance, and weakness to syndromic phenotypes. Though multiple testing modalities exist to identify mitochondrial diseases, most of these tests are nonspecific, or results are associated with other diseases. Molecular testing can provide an efficient path toward diagnosis, as molecular detection techniques have improved and become less costly. A "genetics first" approach can reduce diagnostic delay and improve management, where the diagnostic pathway can be an invasive or noninvasive combination of targeted or comprehensive molecular testing. Prior to ordering these tests, clinicians must consider the ambiguities and nuances of various testing modalities during the work-up for mitochondrial diseases. Therefore, due to the diagnostic challenges associated with primary mitochondrial diseases, diagnosis should be made in the context of clinical and molecular data, potentially supplemented with histochemical and biochemical evidence. Confirmation of a diagnosis leads to improvements in the management of the disease, decreases unnecessary testing, informs reproductive planning, and improves research pipelines.

Keywords:  genetic testing; mitochondria; mitochondrial disease; mitochondrial myopathy; primary mitochondrial disease

DOI:  https://doi.org/10.1002/mus.28387
Mitochondrion. 2025 Mar 29. pii: S1567-7249(25)00034-0. [Epub ahead of print]83 102037

An inherited mtDNA rearrangement, mimicking a single large-scale deletion, associated with MIDD and a primary cardiological phenotype.

Piervito Lopriore, Andrea Legati, Christiane Michaela Neuhofer, Annalisa Lo Gerfo, Robert Kopajtich, Marco Barresi, Giulia Cecchi, Martin Pavlov, Rossella Izzo, Vincenzo Montano, Maria Adelaide Caligo, Riccardo Berutti, Michelangelo Mancuso, Holger Prokisch, Daniele Ghezzi.

   AIM: To identify the genetic cause in a previously unsolved pedigree, with mother and two daughters suffering of dilated cardiomyopathy with prevailing arrhythmic burden associated with diabetes mellitus and sensorineural hearing loss, without clear evidence of progressive external ophthalmoplegia.
METHODS: Several genetic tests were performed over the years including single-gene sequencing, mitochondrial DNA (mtDNA) sequencing, NGS panel for mitochondrial diseases and cardiomyopathies, clinical exome sequencing and whole exome sequencing. Specific amplifications and long-read NGS were used to evaluate mtDNA structural alterations.
RESULTS: By means of whole exome sequencing we found a novel heteroplasmic 12 kb-long single deletion in the mtDNA in all affected family members, confirmed by long-range PCR. However, a deeper investigation by long-read NGS revealed indeed the presence of rearranged mtDNA species, formed by a wild-type plus a deleted molecule. This mtDNA duplication turned out to be inherited in our pedigree and present in all tested specimens.
CONCLUSION: While mtDNA single large-scale deletions are generally considered sporadic, few old reports described maternally inherited mtDNA duplication We suggest that mtDNA large rearrangements should be considered as possible disease causes in familial cases with unusual mitochondrial phenotypes. Long-read sequencing is useful for the detection of these variants, particularly mtDNA duplications.

Keywords:  MIDD (Maternally Inherited Diabetes and Deafness); Mitochondrial DNA; Single large-scale deletion; Structural rearrangement; mtDNA; mtDNA duplication

DOI:  https://doi.org/10.1016/j.mito.2025.102037
J Neurol. 2025 Apr 02. 272(4): 307

Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial.

Saoussen Berrahmoune, Christelle Dassi, Heather Pekeles, Anthony C T Cheung, Tommy Gagnon, Paula J Waters, Daniela Buhas, Kenneth A Myers.

   OBJECTIVE: Mitochondrial DNA depletion disorders are rare genetic disorders involving mitochondrial dysfunction. These diseases are genetically and clinically heterogeneous but share the common feature of progressively degenerative courses. At present, there are no approved treatments for mitochondrial DNA depletion disorders, though recent reports have suggested that treatment with deoxycytidine/deoxythymidine could be effective for subtypes caused by pathogenic variants in two specific genes, POLG and TK2. We investigated the therapeutic potential of deoxycytidine/deoxythymidine for people with mitochondrial DNA depletion disorders due to pathogenic variants in genes other than POLG and TK2.
METHODS: We analyzed interim data from an open-label clinical trial of deoxycytidine/deoxythymidine for treatment of mitochondrial DNA depletion disorders, specifically examining disorders due to pathogenic variants in genes other than POLG and TK2. Outcome measures included Newcastle Mitochondrial Disease Scale score and serum growth differentiation factor 15, a mitochondrial function biomarker.
RESULTS: Data were available from eight individuals having pathogenic variants in FBXL4, SUCLG1, SUCLA2, or RRM2B. Newcastle Mitochondrial Disease Scale score improved in all individuals except for one who withdrew before the first follow-up visit; group level analysis was significant at 1-month and 6-month timepoints. Five patients had elevated growth differentiation factor 15 at baseline; of these, levels improved in four, including three whose values normalized.
CONCLUSION: These data suggest deoxycytidine/deoxythymidine is a safe and therapeutically promising intervention for a broad range of mitochondrial DNA depletion disorders.

Keywords:  Deoxycytidine; Deoxynucleoside; Deoxythymidine; FBXL4; Pyrimidine; SUCLG1

DOI:  https://doi.org/10.1007/s00415-025-13060-w
Mol Ther. 2025 Apr 03. pii: S1525-0016(25)00260-6. [Epub ahead of print]

An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer.

Jie Liu, Jun Chen, Shisheng Huang, Junfan Guo, Xiangyang Li, Ying Yan, Ruijing Chen, Guanglei Li, Ming Liu, Jiao Wei, Xingxu Huang, Yunbo Qiao.

Double-stranded DNA (dsDNA) cytosine deaminase DddA orthologs from multiple types of bacteria have been fused with TALE system for mitochondrial DNA (mtDNA) base editing, while the efficiencies remain limited and its nuclear off-targeting activity cannot be ignored yet. Here we identified a DddA ortholog from Burkholderia gladioli (BgDddA) and generated nuclear or mitochondrial DNA cytosine base editors (mitoCBEs), exhibiting higher C•G-to-T•A editing frequencies compared to canonical DdCBE, and fusion with transactivator Rta remarkably improved editing efficiencies by up to 6.4-fold at non-TC targets. Referring to DddA11, we further introduced six substitutions into BgDddA and generated mitoCBE3.2, which efficiently induced disease-associated mtDNA mutations in mouse and human cell lines at both TC and non-TC targets with efficiency reaching up to 99.2%. Using mitoCBE3.2, single clones containing homoplasmic mtDNA mutations or premature stop codons associated with human diseases were generated, and the functions of these mutations have been evaluated upon the treatment of ROS inducers. Importantly, mitochondria harboring these homoplasmic mutations were transplanted into wildtype cells, enabling precise base conversions, without risk of nuclear gene off-targets. Thus, we have engineered an efficient mitoCBE using BgDddA, facilitating mitochondrial disease modeling and potential mutation correction with the aid of mitochondrial transplantation.

DOI: https://doi.org/10.1016/j.ymthe.2025.03.051
Mitochondrion. 2025 Mar 29. pii: S1567-7249(25)00030-3. [Epub ahead of print] 102033

Perceived association of mood and symptom severity in adults with mitochondrial diseases.

Catherine Kelly, Marissa Cross, Alex Junker, Kris Englestad, Xiomara Rosales, Michio Hirano, Caroline Trumpff, Martin Picard.

  Individuals with genetic mitochondrial diseases suffer from multisystem symptoms that vary in severity and over time, but the factors influencing disease manifestations are poorly understood. Based upon i) patient and family reports that stressful life events trigger or exacerbate symptoms, ii) biologically plausible pathways whereby psychological states and stress hormones influence mitochondrial energy production capacity, and iii) epidemiological literature linking traumatic/stressful life events and multiple neurologic disorders, we hypothesized that mitochondrial disease symptom severity may in part vary with daily mood. To examine patients' perception around potential psycho-biological mechanisms known to operate in other chronic illnesses, we administered the Stress, Health and Emotion Survey (SHES) to 70 adults with self-reported mitochondrial diseases. Participants rated how severe each of their symptom(s) was over the past year, separately for either 'good' (happy, calm) or 'bad' (stress, sad) emotional days. On average, patients reported that most symptoms were better on "good" emotional days (p < 0.0001) and worse on "bad" emotional days (p < 0.0001). Of the 29 symptoms assessed, 27 were associated with daily mood (p < 0.01). Some but not all symptoms were reported to be less or more severe on good and bad days, respectively, including fatigue, exercise intolerance, brain fog, and fine motor coordination (ps < 0.0001). These associative results suggest that on average individuals living with mitochondrial diseases perceive a connection between their mood and symptoms severity. These preliminary findings constitute an initial step towards developing more comprehensive models of the psychobiological factors that influence the course of mitochondrial diseases.

Keywords:  Clinical survey; Disease severity; Emotions; Mitochondrial disease; Patient care; Stress

DOI:  https://doi.org/10.1016/j.mito.2025.102033
Hum Reprod. 2025 Apr 02. pii: deaf050. [Epub ahead of print]

Profiling mitochondrial DNA variant segregation during human preimplantation development: a prerequisite to preimplantation genetic testing for mitochondrial DNA-related disorders.

Paula Rubens, Anne Mayeur, Kalliopi Chatzovoulou, Nadine Gigarel, Sophie Monnot, Agnès Rötig, Arnold Munnich, Nelly Frydman, Julie Steffann.

   STUDY QUESTION: Is preimplantation genetic testing for mitochondrial DNA (mtDNA) disorders (PGT-mt) feasible at early compaction and blastocyst stages?
SUMMARY ANSWER: Pathogenic mtDNA variants segregate evenly among cell types and various lineages of a given embryo during preimplantation development, supporting the relevance of genetic analyses performed on Day 4 blastomere and on Day 5 or 6 trophectoderm (TE) samples.
WHAT IS KNOWN ALREADY: PGT-mt is validated at cleavage stage (Day 3 of development). However, its feasibility at later stages is questionable, as little is known regarding the segregation of pathogenic mtDNA variants during preimplantation development. Since mtDNA replication is silenced until the blastocyst stage (Day 5 or 6), uneven mtDNA segregation between preimplantation embryo cellular lineages known as a 'bottleneck' effect, cannot be excluded, posing a challenge for PGT-mt.
STUDY DESIGN, SIZE, DURATION: We analyzed 112 'mito' embryos carrying pathogenic mtDNA variants and 28 control embryos with mtDNA polymorphism. Heteroplasmy levels were assessed in single cells of the TE, in different parts of blastocysts (inner cell mass and TE), and at three time points of development, namely cleavage (Day 3), early compaction (Day 4), and blastocyst stages (Day 5 or 6).
PARTICIPANTS/MATERIALS, SETTING, METHODS: As part of clinical PGT, a blastomere biopsy was performed at cleavage or early compaction stages (Day 3 or 4) on 112 'mito' and 21/28 control embryos. Further analysis was carried out at Day 5 or 6 on 51 embryos deemed unsuitable for uterine transfer and donated to research. Heteroplasmy levels were determined by semi-quantitative PCR amplification of (i) the mtDNA pathogenic variants with additional enzymatic digestion or (ii) the mtDNA polymorphic hypervariable region 2.
MAIN RESULTS AND THE ROLE OF CHANCE: Here, we first show that mtDNA variants segregate evenly among blastomeres during early compaction (Day 4), supporting the feasibility of PGT-mt at this stage. We also found that mtDNA ratios remain stable between cleavage and blastocyst stages. Yet, the substantial variation of heteroplasmy levels occurring among single TE cells in 1/8 embryos suggests that PGT is only feasible when at least 5-10 cells are collected by standard TE biopsy.
LIMITATIONS, REASONS FOR CAUTION: This study sheds light on mtDNA segregation in human preimplantation embryo development. Its limitation lies in the scarcity of the material and the small number of embryos carrying a specific pathogenic mtDNA variant. Furthermore, the study of single cells from TE was performed on control embryos only.
WIDER IMPLICATIONS OF THE FINDINGS: By supporting the relevance of blastocyst biopsy in the context of PGT for pathogenic mtDNA variants, this study contributes to the general trend of postponing the biopsy to later stages of embryonic development. However, particular attention should be paid to the number of TE cells tested. Due to the potential variation of mutant load during in utero development, a control amniocentesis for evolutive pregnancies following the transfer of heteroplasmic embryos is still recommended.
STUDY FUNDING/COMPETING INTEREST(S): This work was funded by 'Association Française contre les Myopathies/AFM Téléthon' (22112, 24317, 28525); and EUR G.E.N.E. (No. ANR-17-EURE-0013). The authors have no competing interests to declare.
TRIAL REGISTRATION NUMBER: N/A.

Keywords:  heteroplasmy; human preimplantation embryo; mitochondria; mitochondrial DNA; morula biopsy; mtDNA segregation; pathogenic mtDNA variants; preimplantation genetic testing; trophectoderm biopsy

DOI:  https://doi.org/10.1093/humrep/deaf050
Sci Adv. 2025 Apr 04. 11(14): eadr6415

Retromer promotes the lysosomal turnover of mtDNA.

Parisa Kakanj, Mari Bonse, Arya Kshirsagar, Aylin Gökmen, Felix Gaedke, Ayesha Sen, Belén Mollá, Elisabeth Vogelsang, Astrid Schauss, Andreas Wodarz, David Pla-Martín.

Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria's association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.

DOI: https://doi.org/10.1126/sciadv.adr6415
Mol Genet Metab Rep. 2025 Jun;43 101206

FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome: A rare cause of hyperammonemia.

Ayça Burcu Kahraman, Halil Çelik, Zafer Bagci, Abdullah Sezer, Mustafa Kılıç.

   Introduction: FBXL4- related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is caused by pathogenic variants in the FBXL4 gene, resulting in mitochondrial dysfunction and multisystem involvement. Hyperammonemia is reported in 45 % of cases but extremely elevated ammonia levels are rare.
Case presentation: A male infant presented with dysmorphic features, hypotonia, failure to thrive, and lactic acidosis and severe hyperammonemia (ammonia: 1495 μmol/L). Genetic testing identified a homozygous FBXL4 pathogenic variant.
Conclusion: To our knowledge, this report presents a neonatal case of FBXL4-related mtDNA depletion syndrome with the highest hyperammonemia level. This case emphasizes the importance of FBXL4 genetic testing in neonates with multisystem involvement, hyperammonemia, and dysmorphic features.

Keywords:  Encephalopathy; FBXL4 gene; Hyperammonemia; Lactic acidosis; Mitochondrial DNA depletion syndromes

DOI:  https://doi.org/10.1016/j.ymgmr.2025.101206
J Transl Genet Genom. 2025 ;9(1): 1-10

What can ATP content tell us about Barth syndrome muscle phenotypes?

Jeffrey J Brault, Simon J Conway.

  Adenosine triphosphate (ATP) is the energy currency within all living cells and is involved in many vital biochemical reactions, including cell viability, metabolic status, cell death, intracellular signaling, DNA and RNA synthesis, purinergic signaling, synaptic signaling, active transport, and muscle contraction. Consequently, altered ATP production is frequently viewed as a contributor to both disease pathogenesis and subsequent progression of organ failure. Barth syndrome (BTHS) is an X-linked mitochondrial disease characterized by fatigue, skeletal muscle weakness, cardiomyopathy, neutropenia, and growth delay due to inherited TAFAZZIN enzyme mutations. BTHS is widely hypothesized in the literature to be a model of defective mitochondrial ATP production leading to energy deficits. Prior patient data have linked both impaired ATP production and reduced phosphocreatine to ATP ratios (PCr/ATP) in BTHS children and adult hearts and muscles, suggesting a primary role for perturbed energetics. Moreover, although only limited direct measurements of ATP content and ADP/ATP ratio (an indicator of the energy available from ATP hydrolysis) have so far been carried out, analysis of divergent BTHS animal models, cultured cell types, and diverse organs has failed to uncover a unifying understanding of the molecular mechanisms linking TAFAZZIN deficiency to perturbed muscle energetics. This review mainly focuses on the energetics of striated muscle in BTHS mitochondriopathy.

Keywords:  Barth syndrome; TAFAZZIN; adenosine triphosphate; cardiolipin; energetics; mitochondria; striated muscle

DOI:  https://doi.org/10.20517/jtgg.2024.83
Trends Biochem Sci. 2025 Mar 31. pii: S0968-0004(25)00051-9. [Epub ahead of print]

Mitochondrial heat production: the elephant in the lab….

Pierre Rustin, Howard T Jacobs, Mügen Terzioglu, Paule Bénit.

  It has long been established that heat represents a major part of the energy released during the oxidation of mitochondrial substrates. However, with a few exceptions, the release of heat is rarely mentioned other than as being produced at the expense of ATP, without having any specific function. Here, after briefly surveying the literature on mitochondrial heat production, we argue for its cellular and organismal importance, sharing our opinions as to what could account for this unbalanced portrayal of mitochondrial energy transactions.

Keywords:  ATP; H(+)-ATPase; heat diffusion; mitochondria; nanoscale; respiratory chain

DOI:  https://doi.org/10.1016/j.tibs.2025.03.002
Neurology. 2025 Apr 22. 104(8): e213532

What Is the Role of Inner Membrane Metalloproteases in Mitochondrial Quality Control and Disease?

Eduardo Benarroch.

DOI: https://doi.org/10.1212/WNL.0000000000213532
Front Physiol. 2025 ;16 1500247

Mitochondrial fusion protein: a new therapeutic target for lung injury diseases.

Guiyang Jia, Erqin Song, Qianxia Huang, Miao Chen, Guoyue Liu.

  Mitochondria are essential organelles responsible for cellular energy supply. The maintenance of mitochondrial structure and function relies heavily on quality control systems, including biogenesis, fission, and fusion. Mitochondrial fusion refers to the interconnection of two similar mitochondria, facilitating the exchange of mitochondrial DNA, metabolic substrates, proteins, and other components. This process is crucial for rescuing damaged mitochondria and maintaining their normal function. In mammals, mitochondrial fusion involves two sequential steps: outer membrane fusion, regulated by mitofusin 1 and 2 (MFN1/2), and inner membrane fusion, mediated by optic atrophy 1 (OPA1). Dysfunction in mitochondrial fusion has been implicated in the development of various acute and chronic lung injuries. Regulating mitochondrial fusion, maintaining mitochondrial dynamics, and improving mitochondrial function are effective strategies for mitigating lung tissue and cellular damage. This study reviews the expression and regulatory mechanisms of mitochondrial fusion proteins in lung injuries of different etiologies, explores their relationship with lung injury diseases, and offers a theoretical foundation for developing novel therapeutic approaches targeting mitochondrial fusion proteins in lung injury.

Keywords:  lung injury; mitochondria; mitochondrial fusion; mitofusin 1/2; optic atrophy 1

DOI:  https://doi.org/10.3389/fphys.2025.1500247
Life Sci Alliance. 2025 Jun;pii: e202402921. [Epub ahead of print]8(6):

The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.

Mashiat Zaman, Govinda Sharma, Walaa Almutawa, Tyler Gb Soule, Rasha Sabouny, Matt Joel, Armaan Mohan, Cole Chute, Jeffrey T Joseph, Gerald Pfeffer, Timothy E Shutt.

Pathogenic variants in the mitochondrial protein MFN2 are typically associated with a peripheral neuropathy phenotype, but can also cause a variety of additional pathologies including myopathy. Here, we identified an uncharacterized MFN2 variant, Q367H, in a patient diagnosed with late-onset distal myopathy, but without peripheral neuropathy. Supporting the hypothesis that this variant contributes to the patient's pathology, patient fibroblasts and transdifferentiated myoblasts showed changes consistent with impairment of several MFN2 functions. We also observed mtDNA outside of the mitochondrial network that colocalized with early endosomes, and measured activation of both TLR9 and cGAS-STING inflammation pathways that sense mtDNA. Re-expressing the Q367H variant in MFN2 KO cells also induced mtDNA release, demonstrating this phenotype is a direct result of the variant. As elevated inflammation can cause myopathy, our findings linking the Q367H MFN2 variant with elevated TLR9 and cGAS-STING signalling can explain the patient's myopathy. Thus, we characterize a novel MFN2 variant in a patient with an atypical presentation that separates peripheral neuropathy and myopathy phenotypes, and establish a potential pathomechanism connecting MFN2 dysfunction to mtDNA-mediated inflammation.

DOI: https://doi.org/10.26508/lsa.202402921
Sci Adv. 2025 Apr 04. 11(14): eadt4955

Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.

Ana G Dumitras, Giorgia Piccoli, Frederik Tellkamp, Lena Keufgens, Martina Baraldo, Sabrina Zorzato, Laura Cussonneau, Leonardo Nogara, Marcus Krüger, Bert Blaauw.

Skeletal muscle fibers are classified as glycolytic or oxidative, with differing susceptibilities to muscle wasting. However, the intracellular signaling pathways regulating fiber-specific muscle trophism remain unclear because of a lack of experimental models measuring protein synthesis. We developed a mouse model overexpressing a mutated transfer RNA synthetase in muscle fibers, enabling specific protein labeling using an artificial methionine substitute, which can be revealed through click chemistry. This model revealed that denervation increases protein labeling in oxidative muscle fibers through mammalian target of rapamycin complex 1 (mTORC1) activation, while deleting the mTORC1 scaffold protein Raptor reduces labeling in glycolytic fibers. On the other hand, increased muscle activity acutely decreases protein synthesis, accompanied by reduced mTORC1 signaling, glycogen depletion, and adenosine 5'-monophosphate kinase activation. Our findings identify nerve activity as an inhibitory signal for mTORC1-dependent protein synthesis in skeletal muscle, enhancing the understanding of fiber-specific responses to exercise and pathological conditions.

DOI: https://doi.org/10.1126/sciadv.adt4955
Cell Rep. 2025 Apr 03. pii: S2211-1247(25)00276-1. [Epub ahead of print]44(4): 115505

Mitochondrial fission regulates midgut muscle assembly and tick feeding capacity.

Zhengwei Zhong, Kun Wang, Ting Zhong, Jingwen Wang.

  Ticks ingest over 100 times their body weight in blood. As the primary tissue for blood storage and digestion, the tick midgut's regulation in response to this substantial blood volume remains unclear. Here, we show that blood intake triggers stem cell proliferation and mitochondrial fission in the midgut of Haemaphysalis longicornis. While inhibiting stem cell proliferation does not impact feeding behavior, disruption of mitochondrial fission impairs tick feeding capacity. Mitochondrial fission mediated by dynamin 2 (DNM2) regulates ATP generation, which in turn influences the expression of the tropomyosin-anchoring subunit troponin T (TNT). Knockdown of TNT disrupts muscle fiber assembly, hindering midgut enlargement and contraction, thereby preventing blood ingestion. These findings underscore the indispensable role of musculature in facilitating midgut expansion during feeding in ticks.

Keywords:  CP: Cell biology; Haemaphysalis longicornis; dynamin 2; feeding capacity; mitochondrial fission; muscle assembly

DOI:  https://doi.org/10.1016/j.celrep.2025.115505
FASEB J. 2025 Apr 15. 39(7): e70490

Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential-dependent accumulation.

Liping Yu, Brian D Fink, William I Sivitz.

  Oxaloacetate (OAA) is a central liver metabolite fundamental to critical metabolic pathways. However, understanding OAA metabolism in the liver has been limited because the compound is very difficult to measure by mass spectroscopy and not abundant enough for detection by other methods. Here we describe a novel approach to quantifying OAA in liver mitochondria. Moreover, we provide evidence for membrane potential-dependent OAA accumulation in mitochondria during complex II-energized respiration consistent with OAA inhibition of succinate dehydrogenase.

Keywords:  inner membrane potential; liver; metabolites; mitochondria; oxaloacetate; respiration

DOI:  https://doi.org/10.1096/fj.202500039R
Neuropharmacology. 2025 Mar 31. pii: S0028-3908(25)00145-5. [Epub ahead of print] 110439

Targeting mitochondria-regulated ferroptosis: A new frontier in Parkinson's Disease therapy.

Wenjun Wang, Elizabeth Rosalind Thomas, Ruyue Xiao, Tianshun Chen, Shiting Xia, Qulian Guo, Kezhi Liu, You Yang, Xiang Li.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantial nigra. Mitochondrial dysfunction and mitochondrial oxidative stress are central to the pathogenesis of PD, with recent evidence highlighting the role of ferroptosis - a type of regulated cell death dependent on iron metabolism and lipid peroxidation. Mitochondria, the central organelles for cellular energy metabolism, play a pivotal role in PD pathogenesis through the production of Reactive oxygen species (ROS) and the disruption of iron homeostasis. This review explores the intricate interplay between mitochondrial dysfunction and ferroptosis in PD, focusing on key processes such as impaired electron transport chain function, tricarboxylic acid (TCA) cycle dysregulation, disruption of iron metabolism, and altered lipid peroxidation. We discuss key pathways, including the role of glutathione (GSH), mitochondrial ferritin, and the regulation of the mitochondrial labile iron pool (mLIP), which collectively influence the susceptibility of neurons to ferroptosis. Furthermore, this review emphasizes the importance of mitochondrial quality control mechanisms, such as mitophagy and mitochondrial biogenesis, in mitigating ferroptosis-induced neuronal death. Understanding these mechanisms linking the interplay between mitochondrial dysfunction and ferroptosis may pave the way for novel therapeutic approaches aimed at preserving mitochondrial integrity and preventing neuronal loss in PD.

Keywords:  Ferroptosis; Mitochondria; Parkinson's disease; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110439
Lab Anim (NY). 2025 Apr;54(4): 75

Friedreich's ataxia treatment's sexual dimorphism.

Jorge Ferreira.

DOI: https://doi.org/10.1038/s41684-025-01535-2
Pharmacol Res. 2025 Mar 26. pii: S1043-6618(25)00137-9. [Epub ahead of print]215 107712

Mitochondrial quality control: A promising target of traditional Chinese medicine in the treatment of cardiovascular disease.

Deng Pan, Pengfei Chen, He Zhang, Qian Zhao, Wei Fang, Siyan Ji, Tielong Chen.

  Cardiovascular disease remains the leading cause of death globally, and drugs for new targets are urgently needed. Mitochondria are the primary sources of cellular energy, play crucial roles in regulating cellular homeostasis, and are tightly associated with pathological processes in cardiovascular disease. In response to physiological signals and external stimuli in cardiovascular disease, mitochondrial quality control, which mainly includes mitophagy, mitochondrial dynamics, and mitochondrial biogenesis, is initiated to meet cellular requirements and maintain cellular homeostasis. Traditional Chinese Medicine (TCM) has been shown to have pharmacological effects on alleviating cardiac injury in various cardiovascular diseases, including myocardial ischemia/reperfusion, myocardial infarction, and heart failure, by regulating mitochondrial quality control. Recently, several molecular mechanisms of TCM in the treatment of cardiovascular disease have been elucidated. However, mitochondrial quality control by TCM for treating cardiovascular disease has not been investigated. In this review, we aim to decipher the pharmacological effects and molecular mechanisms of TCM in regulating mitochondrial quality in various cardiovascular diseases. We also present our perspectives regarding future research in this field.

Keywords:  Cardiovascular disease; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Traditional Chinese medicine

DOI:  https://doi.org/10.1016/j.phrs.2025.107712
Brain Commun. 2025 ;7(2): fcaf114

Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics.

Simone Scarcella, Lorenzo Brambilla, Lorenzo Quetti, Mafalda Rizzuti, Valentina Melzi, Noemi Galli, Luca Sali, Gianluca Costamagna, Giacomo Pietro Comi, Stefania Corti, Delia Gagliardi.

  Amyotrophic lateral sclerosis is the most common motor neuron disease and manifests as a clinically and genetically heterogeneous neurodegenerative disorder mainly affecting the motor systems. To date, despite promising results and accumulating knowledge on the pathomechanisms of amyotrophic lateral sclerosis, a specific disease-modifying treatment is still not available. In vitro and in vivo disease models coupled with multiomics techniques have helped elucidate the pathomechanisms underlying this disease. In particular, omics approaches are powerful tools for identifying new potential disease biomarkers that may be particularly useful for diagnosis, prognosis and assessment of treatment response. In turn, these findings could support physicians in stratifying patients into clinically relevant subgroups for the identification of the best therapeutic targets. Here, we provide a comprehensive review of the most relevant literature highlighting the importance of proteomics approaches in determining the role of pathogenic misfolded/aggregated proteins and the molecular mechanisms involved in the pathogenesis and progression of amyotrophic lateral sclerosis. In addition, we explored new findings arising from metabolomic and lipidomic studies, which can aid to elucidate the intricate metabolic alterations underlying amyotrophic lateral sclerosis pathology. Moreover, we integrated these insights with microbiomics data, providing a thorough understanding of the interplay between metabolic dysregulation and microbial dynamics in disease progression. Indeed, a greater integration of these multiomics data could lead to a deeper understanding of disease mechanisms, supporting the development of specific therapies for amyotrophic lateral sclerosis.

Keywords:  ALS; lipidomics; metabolomics; microbiomics; proteomics

DOI:  https://doi.org/10.1093/braincomms/fcaf114
Eur J Pharmacol. 2025 Mar 27. pii: S0014-2999(25)00316-4. [Epub ahead of print]998 177562

The mitochondria-gut microbiota crosstalk - A novel frontier in cardiovascular diseases.

Hrushikesh Kulkarni, Anil Bhanudas Gaikwad.

  Cardiovascular diseases (CVDs), including hypertension, atherosclerosis, and cardiomyopathy among others, remain the leading cause of global morbidity and mortality. Despite advances in treatment, the complex pathophysiology of CVDs necessitates innovative approaches to improve patient outcomes. Recent research has uncovered a dynamic interplay between mitochondria and gut microbiota, fundamentally altering our understanding of cardiovascular health. However, while existing studies have primarily focused on individual components of this axis, this review examines the bidirectional communication between these biological systems and their collective impact on cardiovascular health. Mitochondria, serving as cellular powerhouses, are crucial for maintaining cardiovascular homeostasis through oxidative phosphorylation (OXPHOS), calcium regulation, and redox balance. Simultaneously, the gut microbiota influences cardiovascular function through metabolite production, barrier integrity maintenance, and immune system modulation. The mitochondria-gut microbiota axis operates through various molecular mechanisms, including microbial metabolites such as trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFA), and secondary bile acids, which directly influence mitochondrial function. Conversely, mitochondrial stress signals and damage-associated molecular patterns (DAMPs) affect gut microbial communities and barrier function. Key signalling pathways, including AMP-activated protein kinase (AMPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and the silent information regulator 1-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (SIRT1-PGC-1α) axis, integrate these interactions, highlighting their role in CVD pathogenesis. Understanding these interactions has revealed promising therapeutic targets, suggesting new therapies aimed at both mitochondrial function and gut microbiota composition. Thus, this review provides a comprehensive framework for leveraging the mitochondria-gut microbiota axis in providing newer therapeutics for CVDs by targeting the AMPK/SIRT-1/PGC-1α/NF-κB signalling.

Keywords:  Cardiovascular disease; Gut microbiota; Mitochondria; Novel biomarkers; Therapy

DOI:  https://doi.org/10.1016/j.ejphar.2025.177562
Mol Genet Metab Rep. 2025 Jun;43 101204

A novel SLC44A gene variant in a patient with neonatal cholestasis and liver failure.

Dogan Barut, Emine Burçe Dörtkardeşler, Miray Karakoyun, Ebru Canda, Huseyin Onay, Sema Aydogdu.

  SLC44A1 gene variants (MIM # 618868) are associated with a choline transporter deficiency with a rare autosomal recessive genetic disorder characterized by neurodegeneration, childhood-onset with ataxia, tremor, optic atrophy, and cognitive decline. Variants in the SLC44A1 gene are considered to be responsible for the syndrome. We reported a four-month-old baby with neonatal cholestasis and liver failure, but neurological development and examination were normal. During the patient's initial physical examination, height, weight, and head circumference were < -2 SDS. He was alert, with eye tracking and a smile present, appeared icteric, and exhibited hepatosplenomegaly, with a history of second-degree consanguinity between his parents. The patient showed signs of neonatal jaundice, elevated transaminases, and episodes of hypoglycemia. After excluding biliary atresia, tyrosinemia, and other metabolic diseases, mitochondrial hepatopathy, vascular pathologies, and congenital infectious diseases through all standard examinations for neonatal cholestasis, a genetic analysis test and whole exome analysis were conducted. Molecular analysis of the whole exome revealed a novel inherited mutation, one inherited from each parent. This novel variant in the SLC44A1 gene is c.1632 + 1G > A. A thorough physical examination and laboratory tests should be conducted for patients presenting with neonatal cholestasis. Subsequently, whole exome analysis from the parents identified the same mutation as heterozygous c.1632 + 1G > A in the SLC44A1 gene. Genetic examinations should be considered in patients whose cause remains undetermined, particularly when there is a family history.
Conclusion: We describe a novel childhood-onset liver failure and metabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.

Keywords:  Choline transporter deficiency; Liver failure; Neonatal cholestasis

DOI:  https://doi.org/10.1016/j.ymgmr.2025.101204
Cell Commun Signal. 2025 Apr 02. 23(1): 166

Restoration of Miro1's N-terminal GTPase function alleviates prenatal stress-induced mitochondrial fission via Drp1 modulation.

Gee Euhn Choi, Ji Yong Park, Mo Ran Park, Chang Woo Chae, Young Hyun Jung, Jae Ryong Lim, Jee Hyeon Yoon, Ji Hyeon Cho, Ho Jae Han.

   BACKGROUND: Prenatal stress exposure irreversibly impairs mitochondrial dynamics, including mitochondrial trafficking and morphology in offspring, leading to neurodevelopmental and neuropsychiatric disorders in adulthood. Thus, understanding the molecular mechanism controlling mitochondrial dynamics in differentiating neurons is crucial to prevent the prenatal stress-induced impairments in behavior. We investigated the interplay between mitochondrial transport and fusion/fission in differentiating neurons exposed to prenatal stress, leading to ensuing behavior impairments, and then tried to identify the primary regulator that modulates both phenomena.
METHODS: We used primary hippocampal neurons of mice exposed to prenatal stress and human induced-pluripotent stem cell (hiPSC)-derived neurons, for investigating the impact of glucocorticoid on mitochondrial dynamics during differentiation. For constructing mouse models, we used AAV vectors into mouse pups exposed to prenatal stress to regulate protein expressions in hippocampal regions.
RESULTS: We first observed that prenatal exposure to glucocorticoids induced motility arrest and fragmentation of mitochondria in differentiating neurons derived from mouse fetuses (E18) and human induced pluripotent stem cells (hiPSCs). Further, glucocorticoid exposure during neurogenesis selectively downregulated Miro1 and increased Drp1 phosphorylation (Ser616). MIRO1 overexpression restored mitochondrial motility and increased intramitochondrial calcium influx through ER-mitochondria contact (ERMC) formation. Furthermore, we determined that the N-terminal GTPase domain of Miro1 plays a critical role in ERMC formation, which then decreased Drp1 phosphorylation (Ser616). Similarly, prenatal corticosterone exposure led to impaired neuropsychiatric and cognitive function in the offspring by affecting mitochondrial distribution and synaptogenesis, rescued by Miro1WT, but not N-terminal GTPase active form Miro1P26V, expression.
CONCLUSION: Prenatal glucocorticoid-mediated Miro1 downregulation contributes to dysfunction in mitochondrial dynamics through Drp1 phosphorylation (Ser616) in differentiating neurons.

Keywords:  ER-mitochondria contacts; Miro; Mitochondrial dynamics; Neurodegeneration; Prenatal glucocorticoid

DOI:  https://doi.org/10.1186/s12964-025-02172-5
Autophagy. 2025 Mar 31.

Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.

Yuyuan Zhu, Min Cao, Yancheng Tang, Yifan Liu, Haiji Wang, Jiaqi Qi, Cainian Huang, Chenghao Yan, Xu Liu, Sijia Jiang, Yufei Luo, Shaogui Wang, Bo Zhou, Haodong Xu, Ying-Ying Lu, Liming Wang.

  Mitochondria serve as the primary source of intracellular reactive oxygen species (ROS), which play a critical role in orchestrating cell death pathways such as pyroptosis in various types of cancers. PINK1-mediated mitophagy effectively removes damaged mitochondria and reduces detrimental ROS levels, thereby promoting cell survival. However, the regulation of pyroptosis by PINK1 and ROS in neuroblastoma remains unclear. In this study, we demonstrate that inhibition or deficiency of PINK1 sensitizes ROS signaling and promotes pyroptosis in neuroblastoma cells via the BAX-caspase-GSDME signaling pathway. Specifically, inhibition of PINK1 by AC220 or knockout of PINK1 impairs mitophagy and enhances ROS production, leading to oxidation and oligomerization of TOMM20, followed by mitochondrial recruitment and activation of BAX. Activated BAX facilitates the release of CYCS (cytochrome c, somatic) from the mitochondria into the cytosol, activating CASP3 (caspase 3). Subsequently, activated CASP3 cleaves and activates GSDME, inducing pyroptosis. Furthermore, inhibition or deficiency of PINK1 potentiates the anti-tumor effects of the clinical ROS-inducing drug ethacrynic acid (EA) to inhibit neuroblastoma progression in vivo. Therefore, our study provides a promising intervention strategy for neuroblastoma through the induction of pyroptosis.

Keywords:  Cell death; GSDME; PINK1; mitochondrial ROS; mitophagy; neuroblastoma

DOI:  https://doi.org/10.1080/15548627.2025.2487037
Development. 2025 Apr 01. pii: dev204565. [Epub ahead of print]152(7):

Pluripotent cell states and fates in human embryo models.

Berna Sozen, Patrick P L Tam, Martin F Pera.

  Pluripotency, the capacity to generate all cells of the body, is a defining property of a transient population of epiblast cells found in pre-, peri- and post-implantation mammalian embryos. As development progresses, the epiblast cells undergo dynamic transitions in pluripotency states, concurrent with the specification of extra-embryonic and embryonic lineages. Recently, stem cell-based models of pre- and post-implantation human embryonic development have been developed using stem cells that capture key properties of the epiblast at different developmental stages. Here, we review early primate development, comparing pluripotency states of the epiblast in vivo with cultured pluripotent cells representative of these states. We consider how the pluripotency status of the starting cells influences the development of human embryo models and, in turn, what we can learn about the human pluripotent epiblast. Finally, we discuss the limitations of these models and questions arising from the pioneering studies in this emerging field.

Keywords:  Cell fate; Epiblast; Human embryo model; Peri-implantation development; Pluripotent stem cell

DOI:  https://doi.org/10.1242/dev.204565
EMBO Rep. 2025 Apr 02.

Mpf1 affects the dual distribution of tail-anchored proteins between mitochondria and peroxisomes.

Nitya Aravindan, Daniela G Vitali, Julia Breuer, Jessica Oberst, Einat Zalckvar, Maya Schuldiner, Doron Rapaport.

  Most cellular proteins require targeting to a distinct cellular compartment to function properly. A subset of proteins is distributed to two or more destinations in the cell and little is known about the mechanisms controlling the process of dual/multiple targeting. Here, we provide insight into the mechanism of dual targeting of proteins between mitochondria and peroxisomes. We perform a high throughput microscopy screen in which we visualize the location of the model tail-anchored proteins Fis1 and Gem1 in the background of mutants in virtually all yeast genes. This screen identifies three proteins, whose absence results in a higher portion of the tail-anchored proteins in peroxisomes: the two paralogues Tom70, Tom71, and the uncharacterized gene YNL144C that we rename mitochondria and peroxisomes factor 1 (Mpf1). We characterize Mpf1 to be an unstable protein that associates with the cytosolic face of the mitochondrial outer membrane. Furthermore, our study uncovers a unique contribution of Tom71 to the regulation of dual targeting. Collectively, our study reveals, for the first time, factors that influence the dual targeting of proteins between mitochondria and peroxisomes.

Keywords:  Dual Targeting; Fis1; Mitochondria; Peroxisomes; Tail-anchored Proteins

DOI:  https://doi.org/10.1038/s44319-025-00440-6