bims-mitmed 2025-06-22 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–06–22
23 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Modelling mitochondrial diseases in neurons In Vitro: A systematic review.
Doxecitine and doxribtimine treatment in an adult patient with thymidine kinase 2 deficiency.
One gene, many phenotypes: the role of KIF5A in neurodegenerative and neurodevelopmental diseases.
Friedreich's ataxia-a rare multisystem disease.
Dysfunctional mitochondria trap proteins in the intermembrane space.
Fumarate hits the brakes on mitophagy.
Lipid nanoparticle delivery of the CRISPR/Cas9 system directly into the mitochondria of cells carrying m.7778G>T mutation in MtDNA (mt-Atp8).
Tiny human hearts grown in pig embryos for the first time.
Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
Shaping the composition of the mitochondrial outer membrane.
Transcription arrest induces formation of RNA granules in mitochondria.
'Super-healing' animals inspire human treatments.
Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
Discovery of a Novel, Potent, and Selective 5‑Hydroxytryptamine 2B Receptor Antagonist that Induces Mitochondrial Biogenesis in the Kidney.
LSMEM2, Localized at the Neuromuscular Junction, Modulates Mitochondrial Integration in Skeletal Muscles.
Cardiolipin Remodeling in Cardiovascular Diseases: Implication for Mitochondrial Dysfunction.
Machine learning to predict mitochondrial diseases by phenotypes.
Biallelic SIDT2 loss-of-function in a child with cerebellar ataxia and lysosomal dysfunction mimics impairment of SIDT2 in mice.
Activation of STING pathway by mitochondrial fission negatively regulates adipogenic differentiation of 3 T3-L1 cells.
Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation.
The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.
Antioxidant therapy in inborn metabolic diseases.

J Neuromuscul Dis. 2025 Jun 19. 22143602241307198

Modelling mitochondrial diseases in neurons In Vitro: A systematic review.

Mariana Zarate-Mendez, Nihal A Basha, Oliver Podmanicky, Natalia Malig, Denisa Hathazi, Rita Horvath.

  Mitochondrial diseases, characterized by disruptions in cellular energy production, manifest diverse clinical phenotypes despite a shared molecular aetiology. Of note is the frequent involvement of the brain in these pathologies. Given the inherent challenges associated with accessing human tissue and the limitations of mouse models, especially concerning mitochondrial DNA (mtDNA), in vitro modelling is crucial in elucidating brain-related manifestations of mitochondrial diseases.In this review we recapitulate the current available in vitro models used to study neuronal cell types and advance our understanding of mitochondrial brain disease. This inquiry is especially pertinent considering the scarcity of suitable animal models, necessitating reliance on in vitro models to elucidate underlying molecular mechanisms. We found fifty papers modelling neuronal mechanisms of mitochondrial diseases in-vitro. While there was an even split between nuclear and mtDNA mutations, MELAS was the most commonly modelled syndrome. The emerging technologies in the stem cell field have revolutionized our approach to investigate cellular specificity in mitochondrial diseases, and we found a clear shift from neuroblastoma cell lines to iPSC-derived models. Interestingly, most of these studies reported impaired neuronal differentiation in mutant cells independent of the syndrome being modelled. The generation of appropriate in vitro models and subsequent mechanistic insights will be central for the development of novel therapeutic avenues in the mitochondrial field.

Keywords:  induced pluripotent stem cells; neuronal models; primary mitochondrial diseases

DOI:  https://doi.org/10.1177/22143602241307198
Mol Genet Metab. 2025 Jun 03. pii: S1096-7192(25)00150-7. [Epub ahead of print]145(4): 109159

Doxecitine and doxribtimine treatment in an adult patient with thymidine kinase 2 deficiency.

Elsbeth Chow, Lindsey Miller, Anna Clearman, Patricia Arnold, Mary Kay Koenig, S Nicholas Russo.

  Thymidine kinase 2 (TK2) deficiency is an ultrarare mitochondrial depletion and deletion syndrome characterized by mutations in the nuclear TK2 gene responsible for encoding the mitochondrial thymidine kinase 2 enzyme. TK2's role is to phosphorylate the nucleosides deoxycytidine (dC) and deoxythymidine (dT) required for mitochondrial DNA (mtDNA) replication; therefore, deficient TK2 enzymes result in dysfunctional replication of mtDNA. TK2 deficiency presents in children as progressive muscle weakness, respiratory difficulty, and mtDNA depletion. Fewer than 120 patients have been described in medical literature, and there are currently no FDA-approved treatments for TK2 deficiency. Provision of exogenous deoxynucleosides (dC/dT) allow for replication of mtDNA via cytosolic enzymes thymidine kinase 1 (TK1) and deoxycytidine kinase (dCK), as well as any residual TK2 activity. Here we describe a 26-year-old female with childhood-onset TK2 deficiency characterized by progressive myopathy, fatigue, weight loss, atrophy, bone fractures, dysphagia, neuropathy, and respiratory failure. With initiation of deoxynucleoside therapy and multiple therapy modalities (physical, occupational, and speech), her rate of decline slowed and she has shown steady improvement.

Keywords:  Deoxynucleoside therapy; Mitochondria; Mitochondrial depletion; Thymidine kinase deficiency

DOI:  https://doi.org/10.1016/j.ymgme.2025.109159
Cell Commun Signal. 2025 Jun 16. 23(1): 287

One gene, many phenotypes: the role of KIF5A in neurodegenerative and neurodevelopmental diseases.

Marta Cozzi, Barbara Tedesco, Veronica Ferrari, Marta Chierichetti, Paola Pramaggiore, Laura Cornaggia, Rocio Magdalena, Maria Brodnanova, Ali Mohamed, Carmelo Milioto, Margherita Piccolella, Mariarita Galbiati, Paola Rusmini, Valeria Crippa, Cinzia Gellera, Stefania Magri, Franco Taroni, Riccardo Cristofani, Angelo Poletti.



Keywords:  Amyotrophic lateral sclerosis; Charcot-Marie-Tooth disease; Hereditary spastic paraplegia; KIF5A; Neonatal intractable myoclonus

DOI:  https://doi.org/10.1186/s12964-025-02277-x
Lancet Neurol. 2025 Jul;pii: S1474-4422(25)00175-9. [Epub ahead of print]24(7): 614-624

Friedreich's ataxia-a rare multisystem disease.

FACROSS study group

Friedreich's ataxia is a rare autosomal recessive neurodegenerative disease. Most patients have a homozygous GAA repeat expansion in the FXN gene, resulting in a deficiency of the mitochondrial protein frataxin. Disease onset occurs typically in adolescence but can vary widely, ranging from early childhood to late adulthood. Friedreich's ataxia is increasingly recognised as a multisystem disorder, affecting not only the nervous system, but also the heart and musculoskeletal system, and metabolism. Common extraneural manifestations include cardiomyopathy, which is the most common cause of mortality, and also scoliosis and diabetes. Despite research advances, the phenotypical heterogeneity of patients with Friedrich's ataxia remains inadequately explained by current knowledge of the underlying genetics. The approval of omaveloxolone by the US Food and Drug Administration and the European Medicines Agency has been a pharmacological milestone; however, further research addressing complex interorgan interactions is crucial for a better understanding of the multisystem nature of Friedreich's ataxia and the development of targeted treatment approaches.

DOI: https://doi.org/10.1016/S1474-4422(25)00175-9
EMBO J. 2025 Jun 16.

Dysfunctional mitochondria trap proteins in the intermembrane space.

Tamara Flohr, Markus Räschle, Johannes M Herrmann.

  The accumulation of mitochondrial precursor proteins in the cytosol due to mitochondrial dysfunction compromises cellular proteostasis and is a hallmark of diseases. Why non-imported precursors are toxic and how eukaryotic cells prevent their accumulation in the cytosol is still poorly understood. Using a proximity labeling-based assay to globally monitor the intramitochondrial location of proteins, we show that, upon mitochondrial dysfunction, many mitochondrial matrix proteins are sequestered in the intermembrane space (IMS); something we refer to as "mitochondrial triage of precursor proteins" (MitoTraP). MitoTraP is not simply the result of a general translocation block at the level of the inner membrane, but specifically directs a subgroup of matrix proteins into the IMS, many of which are constituents of the mitochondrial ribosome. Using the mitoribosomal protein Mrp17 (bS6m) as a model, we found that IMS sequestration prevents its mistargeting to the nucleus, potentially averting interference with assembly of cytosolic ribosomes. Thus, MitoTraP represents a novel, so far unknown mechanism of the eukaryotic quality control system that protects the cellular proteome against the toxic effects of non-imported mitochondrial precursor proteins.

Keywords:  Intermembrane Space; Mitochondria; Nucleolus; Protein Targeting; Ribosome

DOI:  https://doi.org/10.1038/s44318-025-00486-1
Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00471-X. [Epub ahead of print]85(12): 2261-2263

Fumarate hits the brakes on mitophagy.

Ana Paula Magalhães Rebelo, Christian Frezza.

In this issue of Molecular Cell, Ham et al.1 demonstrate that the metabolite fumarate, when accumulated in cells, can influence mitochondrial quality control by inhibiting Parkin translocation to mitochondria and blocking its E3 ligase activity via the fumarate-dependent post-translational modification called succination.

DOI: https://doi.org/10.1016/j.molcel.2025.05.032
Sci Rep. 2025 Jun 19. 15(1): 18717

Lipid nanoparticle delivery of the CRISPR/Cas9 system directly into the mitochondria of cells carrying m.7778G>T mutation in MtDNA (mt-Atp8).

Kaede Norota, Sen Ishizuka, Misa Hirose, Yusuke Sato, Masatoshi Maeki, Manabu Tokeshi, Saleh M Ibrahim, Hideyoshi Harashima, Yuma Yamada.

  Mitochondrial genome mutations are associated with various diseases and gene therapy targeted to mitochondria has the potential to effectively treat such diseases. Here, we targeted a point mutation in mitochondrial DNA (mtDNA) that can cause mitochondrial diseases via delivery of the clustered, regularly interspaced, short palindromic repeats/Cas9 (CRISPR/Cas9) system to mitochondria using an innovative lipid nanoparticle (LNP) delivery system. To overcome the major barrier of the mitochondrial membrane structure, we investigated a strategy to deliver ribonucleoprotein (RNP) directly to mitochondria via membrane fusion using MITO-Porter, a mitochondria-targeting lipid nanoparticle. First, we constructed RNP-MITO-Porter, in which an RNP was loaded into MITO-Porter using a microfluidic device. Sequence-specific double-strand breaks were confirmed when the constructed RNP-MITO-Porter was applied to isolated mitochondria. Next, the RNP-MITO-Porter was applied to HeLa cells, and a portion of the RNP-MITO-Porter was colocalized with mitochondria and caused sequence-specific double-strand breaks in mtDNA. Finally, RNP-MITO-Porter was successfully delivered to mitochondria of cells derived from a mouse carrying a point mutation (m.7778G > T) in mtDNA (mt-Atp8) (LMSF-N-MTFVB cells), and created double-strand breaks at the target sequence. RNP-MITO-Porter is expected to contribute significantly to the clinical application of mitochondrion-targeted gene therapy.

Keywords:  CRISPR/Cas9 ribonucleoprotein (RNP); Lipid nanoparticle (LNP); MITO-Porter; Mitochondrial genome editing; Mitochondrial-targeted delivery

DOI:  https://doi.org/10.1038/s41598-025-03671-8
Nature. 2025 Jun 13.

Tiny human hearts grown in pig embryos for the first time.

Smriti Mallapaty.



Keywords:  Cardiovascular biology; Cell biology; Stem cells

DOI:  https://doi.org/10.1038/d41586-025-01854-x
Nat Commun. 2025 Jun 17. 16(1): 5328

Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.

Prince Saforo Amponsah, Jan-Eric Bökenkamp, Olha Kurpa, Svenja Lenhard, Anna Myronova, Daniel Osmar Vega Velazquez, Celina Hirschelmann, Christian Behrends, Johannes M Herrmann, Markus Räschle, Zuzana Storchová.

Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.

DOI: https://doi.org/10.1038/s41467-025-60857-4
Nat Cell Biol. 2025 Jun;27(6): 890-901

Shaping the composition of the mitochondrial outer membrane.

Gayathri Muthukumar, Jonathan S Weissman.

Mitochondria are critical double-membraned organelles that act as biosynthetic and bioenergetic cellular factories, with the outer membrane providing an interface with the rest of the cell. Mitochondrial outer membrane proteins regulate a variety of processes, including metabolism, innate immunity and apoptosis. Although the biophysical and functional diversity of these proteins is highly documented, the mechanisms of their biogenesis and the integration of that into cellular homeostasis are just starting to take shape. Here, focusing on α-helical outer membrane proteins, we review recent insights into the mechanisms of synthesis and cytosolic chaperoning, insertion and assembly in the lipid bilayer, and quality control of unassembled or mislocalized transmembrane domains. We further discuss the role convergent evolution played in this process, comparing key biogenesis players from lower eukaryotes, including yeast and trypanosomes, with multicellular metazoan systems, and draw comparisons with the endoplasmic reticulum biogenesis system, in which membrane proteins face similar challenges.

DOI: https://doi.org/10.1038/s41556-025-01683-0
Life Sci Alliance. 2025 Sep;pii: e202403082. [Epub ahead of print]8(9):

Transcription arrest induces formation of RNA granules in mitochondria.

Katja G Hansen, Autum Baxter-Koenigs, Caroline Am Weiss, Erik McShane, L Stirling Churchman.

Mitochondrial gene expression regulation is required for the biogenesis of oxidative phosphorylation (OXPHOS) complexes, yet the spatial organization of mitochondrial RNAs (mt-RNAs) remains unknown. Here, we investigated the spatial distribution of mt-RNAs during various cellular stresses using single-molecule RNA-FISH. We discovered that transcription inhibition leads to the formation of distinct RNA granules within mitochondria, which we term inhibition granules. These structures differ from canonical mitochondrial RNA granules and form in response to multiple transcription arrest conditions, including ethidium bromide treatment, specific inhibition or stalling of the mitochondrial RNA polymerase, and depletion of the SUV3 helicase. Inhibition granules appear to stabilize certain mt-mRNAs during prolonged transcription inhibition. This phenomenon coincides with an imbalance in OXPHOS complex expression, where mitochondrial-encoded transcripts decrease while nuclear-encoded subunits remain stable. We found that cells recover from transcription inhibition via resolving the granules, restarting transcription, and repopulating the mitochondrial network with mt-mRNAs within hours. We suggest that inhibition granules may act as a reservoir to help overcome OXPHOS imbalance during recovery from transcription arrest.

DOI: https://doi.org/10.26508/lsa.202403082
Nature. 2025 Jun 20.

'Super-healing' animals inspire human treatments.

Smriti Mallapaty.



Keywords:  Cell biology; Genomics; Proteomics; Stem cells

DOI:  https://doi.org/10.1038/d41586-025-01901-7
Cell Commun Signal. 2025 Jun 19. 23(1): 290

Mitochondrial dysfunction in the regulation of aging and aging-related diseases.

Xianhong Zhang, Yue Gao, Siyu Zhang, Yiqi Wang, Xinke Pei, Yufei Chen, Jinhui Zhang, Yichen Zhang, Yitian Du, Shauilin Hao, Yujiong Wang, Ting Ni.

  Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.

Keywords:  Aging-related diseases; Cellular senescence; Chronic inflammation; Metabolic remodelling; Mitochondria

DOI:  https://doi.org/10.1186/s12964-025-02308-7
ACS Pharmacol Transl Sci. 2025 Jun 13. 8(6): 1741-1755

Discovery of a Novel, Potent, and Selective 5‑Hydroxytryptamine 2B Receptor Antagonist that Induces Mitochondrial Biogenesis in the Kidney.

Paul Victor Santiago Raj, Giri Gnawali, Jaroslav Janda, Natalie E Scholpa, Vishal Kaleeswaran, Ishika Girdhar, Wei Wang, Rick G Schnellmann.

  Serotonin, or 5-hydroxytryptamine (5-HT), is a multifaceted neurotransmitter that plays a vital role in the central nervous system (CNS). Beyond the CNS, 5-HT is intricately involved in modulating hemostasis, immune response, blood pressure, and metabolism in tissues such as skeletal muscle, heart, and kidney. Accumulating evidence highlights the interplay between 5-HT receptors and mitochondrial bioenergetics. Here, we report the discovery of a novel, potent, and selective 5-hydroxytryptamine 2B receptor (5-HT2BR) antagonist, MARY1, which induces mitochondrial biogenesis (MB) in the kidney. MARY1 is a small molecule belonging to the pyridinylpiperazine class that exhibits selectivity and moderate affinity (K i = 764 nM) for the human 5-HT2BR, as well as efficacy (IC50 = 380 nM; E max = 90%) in cellular-based binding and functional assays. Treatment with MARY1 (1 nM) increases mitochondrial respiratory capacity, mitochondrial protein levels, and mitochondrial number in renal proximal tubule cells (RPTCs). Mechanistically, the MB effects of MARY1 in RPTCs are mediated through 5-HT2BR and the activation of dual cell signaling pathways: PI3K/AKT and RAS/MEK/ERK. Moreover, MARY1 administration in mice and rats induces renal cortical MB, and increases levels of mitochondrial and fatty acid oxidation proteins. These findings identify MARY1 as a selective and potent 5-HT2BR antagonist that induces MB and enhances mitochondrial function in the kidney, offering a potential therapeutic strategy for metabolic and mitochondrial dysfunction-associated renal disorders.

Keywords:  5-HT2B receptor antagonist; mitochondrial biogenesis; mitochondrial dysfunction; piperazine

DOI:  https://doi.org/10.1021/acsptsci.5c00161
FASEB J. 2025 Jun 30. 39(12): e70609

LSMEM2, Localized at the Neuromuscular Junction, Modulates Mitochondrial Integration in Skeletal Muscles.

Eman Elrefaei, Satoru Yamazaki, Issei Yazawa, Yusuke Takahashi, Naoki Ito, Nozomi Hayashiji, Yuya Nishida, Ichizo Nishino, Seiji Takashima, Yasunori Shintani.

  In addition to the canonical metabolism-regulating function, Adenosine monophosphate-activated protein kinase (AMPK) has noncanonical functions, in which AMPK spatiotemporally phosphorylates specific sets of substrates. Recently, we identified LSMEM2, a novel substrate of AMPK in the heart. LSMEM2 is a membrane protein localized at the intercalated disc (ICD), whose function is currently under investigation. Interestingly, LSMEM2 is also expressed in the skeletal muscles. As skeletal muscles lack a homophilic intercellular junction corresponding to the ICD in the heart, predicting the role of LSMEM2 in skeletal muscles is difficult. In this study, we identified that LSMEM2 is expressed in skeletal muscles, specifically at the neuromuscular junction (NMJ). LSMEM2-knockout mice showed no histological abnormalities, suggesting that LSMEM2 is not essential for skeletal muscle development. The overexpression of full-length wild-type or C-del mutant of LSMEM2 led to the tubular aggregate formation with functional abnormality in male mice. RNA sequence analysis revealed that the gene sets of mitochondrial oxidative phosphorylation and vesicle-mediated transport are enriched in LSMEM2 overexpression. Furthermore, histological analysis demonstrated the accumulation of swollen subsarcolemmal mitochondria in LSMEM2-overexpressing skeletal muscles. The study findings suggest that LSMEM2 may play a role in the pathogenesis of skeletal muscle diseases.

Keywords:  intercalated disc (ICD); membrane protein; neuromuscular junction (NMJ); skeletal muscle diseases; subsarcolemmal mitochondria; tubular aggregate

DOI:  https://doi.org/10.1096/fj.202402152R
Acta Physiol (Oxf). 2025 Jul;241(7): e70073

Cardiolipin Remodeling in Cardiovascular Diseases: Implication for Mitochondrial Dysfunction.

Huijie Zhang, Fengzhi Yu, Zhenjun Tian, Dandan Jia.

   AIM: Mitochondrial dysfunction is pivotal in both the development and progression of cardiovascular diseases (CVDs), though its exact mechanisms remain unclear. Cardiolipin (CL), a key mitochondrial phospholipid, is involved in various mitochondrial functions, including dynamics, membrane integrity, oxidative phosphorylation, mitochondrial DNA maintenance, and mitophagy. Due to enzyme limitations in the CL biosynthesis pathway, premature CL undergoes remodeling to acquire the proper acyl content for its function. Disruption in CL composition leads to mitochondrial dysfunction, contributing significantly to CVDs. The purpose of this review is to explore the role of CL remodeling in the mechanism of mitochondrial dysfunction that occurs in CVDs.
METHODS: This review examines CL's critical role in mitochondrial function, the consequences of CL deficiencies in CVDs, and the impact of mutations or deficiencies in CL remodeling enzymes-tafazzin (TAZ), Acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1), and Monolysocardiolipin acyltransferase (MLCLAT1)-on CL homeostasis, mitochondrial function, and CVDs pathogenesis. Emerging CL-targeted therapies are also reviewed.
RESULTS: Proper CL function is crucial for mitochondrial health and cardioprotection. Pathological CL remodeling due to mutations or deficiencies in TAZ, ALCAT1, or MLCLAT1, drives mitochondrial dysfunction and accelerates CVDs progression. Based on these insights, current CL-based therapeutic strategies are also summarized, including precision medicine/gene therapy, targeted pharmacotherapy, and dietary interventions.
CONCLUSION: Targeting CL may represent a promising clinical therapeutic strategy for CVDs.

Keywords:  ALCAT1; cardiolipin remodeling; cardiovascular diseases; mitochondrial dysfunction; tafazzin

DOI:  https://doi.org/10.1111/apha.70073
Mitochondrion. 2025 Jun 18. pii: S1567-7249(25)00058-3. [Epub ahead of print] 102061

Machine learning to predict mitochondrial diseases by phenotypes.

Chieh-Wen Kuo, Hui-An Chen, Rai-Hseng Hsu, Chaoszu Wu, Ching Hsu, Ming-Jen Lee, Yin-Hsiu Chien, Hsueh-Wen Hsueh, Feng-Jung Yang, Pi-Chuan Fan, Wen-Chin Weng, Ru-Jen Lin, Ta-Ching Chen, Chih-Chao Yang, Wang-Tso Lee, Wuh-Liang Hwu, Ni-Chung Lee.

  Diagnosing mitochondrial diseases remains challenging because of the heterogeneous symptoms. This study aims to use machine learning to predict mitochondrial diseases from phenotypes to reduce genetic testing costs. This study included patients who underwent whole exome or mitochondrial genome sequencing for suspected mitochondrial diseases. Clinical phenotypes were coded, and machine learning models (support vector machine, random forest, multilayer perceptron, and XGBoost) were developed to classify patients. Of 103 patients, 43 (41.7%) had mitochondrial diseases. Myopathy and respiratory failure differed significantly between the two groups. XGBoost achieved the highest accuracy (67.5%). In conclusion, machine learning improves patient prioritization and diagnostic yield.

Keywords:  Machine learning; Mitochondrial diseases; Phenotype

DOI:  https://doi.org/10.1016/j.mito.2025.102061
J Med Genet. 2025 Jun 20. pii: jmg-2025-110654. [Epub ahead of print]

Biallelic SIDT2 loss-of-function in a child with cerebellar ataxia and lysosomal dysfunction mimics impairment of SIDT2 in mice.

Tan Nguyen, Grace Yoon, Blake R C Smith, Martine Tétreault, Jeiwook Chae, Sean Massey, Simranpreet Kaur, John Christodoulou, Craig P Hunter, Ken C Pang.

  SIDT2 (Systemic Interference Deficient 1 Transmembrane Family Member 2) is a lysosomal membrane protein involved in RNA degradation via RNAutophagy. While animal models have indicated a link between SIDT2 deficiency and lysosomal storage disorders, no human cases have been reported. Here, we report a child with biallelic SIDT2 missense variants (p.Arg529Trp, p.Arg678Trp), who developed progressive neurological decline with cerebellar atrophy and Parkinsonian features. Functional studies revealed that the affected individual's variants disrupted the ability of SIDT2 to interact with RNA. Fibroblasts from the affected individual showed impaired autophagy, characterised by abnormal accumulation of autophagy markers. In mouse models, Sidt2 was found to be highly expressed in the brain, particularly in the hippocampus and cerebellum. Sidt2 loss-of-function in mice resulted in not only impaired autophagy in the brain but also neurological dysfunction, including motor incoordination and eventual seizures. These findings suggest that SIDT2 deficiency contributes to both autophagic dysfunction and neurodegenerative processes, providing insight into a potential role in human neurological disease.

Keywords:  Genetic Diseases, Inborn; Neurodegenerative Diseases

DOI:  https://doi.org/10.1136/jmg-2025-110654
Cell Signal. 2025 Jun 16. pii: S0898-6568(25)00363-8. [Epub ahead of print] 111948

Activation of STING pathway by mitochondrial fission negatively regulates adipogenic differentiation of 3 T3-L1 cells.

Kai Ma, Haoxuan Sun, Xiaoyun Wu, Jinping Quan, Rong Tang, Weiwei Liu, Toshihiko Hayashi, Kazunori Mizuno, Shunji Hattori, Hitomi Fujisaki, Takashi Ikejima.

  Adipocyte hyperplasia refers to the increase in the number of adipocytes, whereas adipocyte hypertrophy pertains to the enlargement of individual adipocytes resulting from the accumulation of lipid droplets. In this study, we found that activation of the STING signalling pathway occurs during adipogenic differentiation of 3 T3-L1 preadipocytes. Interestingly, inhibiting the STING pathway by using STING antagonist H151 or siRNA targeting STING promotes adipocyte differentiation and increases adipocyte numbers, while activation of STING inhibits adipogenic differentiation. Silencing the STING canonical downstream IRF3, or inhibiting the proton channel activity of STING enhances adipogenic differentiation, confirming the negative modulation of adipogenic differentiation by STING. In vivo, intraperitoneal injection of H151 into mice with a high-fat diet further enhances the adipocyte hyperplasia, as shown by the increased volume of adipose tissues, but consistent sizes of adipocytes. During the adipogenic differentiation of 3 T3-L1 cells, DRP1-mediated mitochondrial fission is enhanced, and causes mitochondrial DNA leakage, which in turn activates the STING pathway. However, inhibition of mitochondrial fission represses adipogenic differentiation of 3 T3-L1 cells in spite of the down-regulation of STING pathway. Therefore, our results indicate that adipogenic differentiation is associated with DRP1-induced mitochondrial fission. However, the leakage of mitochondrial DNA caused by DRP1-induced mitochondrial fission activates the STING signalling pathway, which negatively regulates adipogenic differentiation. Tissue specific reduction of DRP1-associated mitochondrial fission or STING enhancement might be new strategies for the therapy of obesity-associated diseases.

Keywords:  3 T3-L1 cells; Adipocyte differentiation; DRP1; Mitochondria; STING

DOI:  https://doi.org/10.1016/j.cellsig.2025.111948
Nat Immunol. 2025 Jun 17.

Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation.

Hongxu Xian, Kosuke Watari, Masafumi Ohira, Jonathan S Brito, Peng He, Janset Onyuru, Elina I Zuniga, Hal M Hoffman, Michael Karin.

Stress-induced oxidized mitochondrial DNA (Ox-mtDNA) fragments enter the cytoplasm, activating the NLRP3 inflammasome and caspase-1 and enabling gasdermin-D-mediated circulatory release of mtDNA. Elevated amounts of circulating mtDNA, presumably oxidized, have been detected in older individuals and patients with metabolic or autoimmune disorders. Here we show that sustained Ox-mtDNA release, triggered by a prototypical NLRP3 inflammasome activator, induces autoantibody production and glomerulonephritis in mice. Similar autoimmune responses, dependent on plasmacytoid dendritic cells (pDCs) and follicular helper T (TFH) cells, are elicited by in vitro-generated Ox-mtDNA, but not by non-oxidized mtDNA. Although both mtDNA forms are internalized by pDCs and induce interferon-α, only Ox-mtDNA stimulates autocrine interleukin (IL)-1β signaling that induces co-stimulatory molecules and IL-21, which enable mouse and human pDCs to induce functional TFH differentiation, supportive of autoantibody production. These findings underscore the role of pDC-generated IL-1β in autoantibody production and highlight Ox-mtDNA as an important autoimmune trigger, suggesting potential therapeutic opportunities.

DOI: https://doi.org/10.1038/s41590-025-02179-7
Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00266-9. [Epub ahead of print]

The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.

Jesse S S Novak, Lisa Polak, Sanjeethan C Baksh, Douglas W Barrows, Marina Schernthanner, Benjamin T Jackson, Elizabeth A N Thompson, Anita Gola, M Deniz Abdusselamoglu, Alain R Bonny, Kevin A U Gonzales, Julia S Brunner, Anna E Bridgeman, Katie S Stewart, Lynette Hidalgo, June Dela Cruz-Racelis, Ji-Dung Luo, Shiri Gur-Cohen, H Amalia Pasolli, Thomas S Carroll, Lydia W S Finley, Elaine Fuchs.

  Epidermal stem cells produce the skin's barrier that excludes pathogens and prevents dehydration. Hair follicle stem cells (HFSCs) are dedicated to bursts of hair regeneration, but upon injury, they can also reconstruct, and thereafter maintain, the overlying epidermis. How HFSCs balance these fate choices to restore physiologic function to damaged tissue remains poorly understood. Here, we uncover serine as an unconventional, non-essential amino acid that impacts this process. When dietary serine dips, endogenous biosynthesis in HFSCs fails to meet demands (and vice versa), slowing hair cycle entry. Serine deprivation also alters wound repair, further delaying hair regeneration while accelerating re-epithelialization kinetics. Mechanistically, we show that HFSCs sense each fitness challenge by triggering the integrated stress response, which acts as a rheostat of epidermal-HF identity. As stress levels rise, skin barrier restoration kinetics accelerate while hair growth is delayed. Our findings offer potential for dietary and pharmacological intervention to accelerate wound healing.

Keywords:  dietary intervention; epidermal stem cells; fate selection; hair follicle stem cells; hair regrowth; integrated stress response; serine metabolism; tissue regeneration; tissue repair; wound healing

DOI:  https://doi.org/10.1016/j.cmet.2025.05.010
Front Neurosci. 2025 ;19 1602149

Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.

Luis Armando Valenzuela-Ahumada, Octavio Fabián Mercado-Gómez, Rubi Viveros-Contreras, Rosalinda Guevara-Guzmán, Alberto Camacho-Morales.

  Neurodegenerative diseases affect up to 349.2 million individuals worldwide. Preclinical and clinical advances have documented that altered energy homeostasis and mitochondria dysfunction is a hallmark of neurological disorders. Diet-derived ceramides species might target and disrupt mitochondria function leading to defective energy balance and neurodegeneration. Ceramides as bioactive lipid species affect mitochondria function by several mechanism including changes in membrane chemical composition, inhibition of the respiratory chain, ROS overproduction and oxidative stress, and also by activating mitophagy. Promising avenues of intervention has documented that intermittent fasting (IF) is able to benefit and set proper energy metabolism. IF is an eating protocol that involves alternating periods of fasting with periods of eating which modulate ceramide metabolism and mitochondria function in neurons. This review will address the detrimental effect of ceramides on mitochondria membrane composition, respiratory chain, ROS dynamics and mitophagy in brain contributing to neurodegeneration. We will focus on effect of IF on ceramide metabolism as a potential avenue to improve mitochondria function and prevention of neurodegeneration.

Keywords:  ceramides; intermittent fasting; microglia; mitophagy; neurodegeneration

DOI:  https://doi.org/10.3389/fnins.2025.1602149
Mol Genet Metab. 2025 Jun 16. pii: S1096-7192(25)00167-2. [Epub ahead of print]145(4): 109176

Antioxidant therapy in inborn metabolic diseases.

Felix Heimes, Lea-Sophie Berendes, Luciana Hannibal, Julien Park.

  Oxidative stress contributes to the pathophysiology of several inherited metabolic diseases (IMDs). The quality and extent of clinical evidence for the use of antioxidant therapies in IMDs have yet to be ascertained. Despite frequent clinical use, robust evidence from large-scale trials is limited. The strongest support comes from studies on idebenone in Leber's hereditary optic neuropathy, showing improvements in visual outcomes. For other antioxidants and conditions, evidence is mixed or constrained by small sample sizes and short trial durations. Coenzyme Q10 in mitochondrial diseases, vitamin E in lipid disorders, and N-acetylcysteine in various IMDs have shown some promise, but evidence is heterogeneous. Challenges include optimizing dosing, dissecting oxidative stress mechanisms across disorders, and overcoming pharmacokinetic limitations. High-grade evidence exists for the clinical efficacy of N-acetyl-L-leucine for both Niemann Pick type C disease and other lysosomal storage diseases, though its potential antioxidant effect is indirect. This review highlights the need for larger trials with standardized, clinically relevant outcomes. Future research should explore oxidative stress mechanisms, targeted therapies, and combination approaches. While antioxidants hold potential, evidence remains limited, warranting cautious use and further investigation to define their role in these rare but cumulatively impactful disorders. SYNOPSIS: This review finds limited robust evidence for antioxidant therapies in inherited metabolic diseases, highlighting the need for larger trials and more targeted approaches.

Keywords:  Antioxidant therapy; Clinical trials; Oxidative damage; ROS scavenging

DOI:  https://doi.org/10.1016/j.ymgme.2025.109176