bims-mitmed 2025-06-29 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–06–29
eighteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

The mitochondrial methylation potential gates mitoribosome assembly.
Mitochondrial DNA: leakage, recognition, and associated human diseases.
Correction of pathogenic mitochondrial DNA in patient-derived disease models using mitochondrial base editors.
Exosome-Mediated Mitochondrial Delivery of Antisense Oligonucleotides.
Age-dependent accumulation of mitochondrial tRNA mutations in mouse kidneys linked to mitochondrial kidney diseases.
Pharmacokinetics and Pharmacodynamics of Nomlabofusp in Non-clinical Studies of Friedreich's Ataxia.
OXA1L deficiency causes mitochondrial myopathy via reactive oxygen species regulated nuclear factor kappa B signalling pathway.
Mitochondrial DNA depletion syndrome and its cardiac complication.
Enhancing autophagy by redox regulation extends lifespan in Drosophila.
Homozygous COQ9 mutation: a new cause of potentially treatable hereditary spastic paraplegia.
"Therapeutic Transplantation of Mitochondria and Extracellular Vesicles: Mechanistic Insights into mitochondria bioenergetics, redox signaling, and organelle dynamics in preclinical models".
Interaction with AK2A links AIFM1 to cellular energy metabolism.
Branched metabolic pathways to generate heme and heat.
Mitochondrial Unfolded Protein Response (mtUPR) Activation Improves Pathological Alterations in Cellular Models of Ethylmalonic Encephalopathy.
Mitochondrial protein nmd regulates lipophagy and general autophagy during development.
Mdivi-1 promotes steroidogenesis in granulosa cells by inhibiting mitochondrial fission.
A host organelle integrates stolen chloroplasts for animal photosynthesis.
Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.

Nat Commun. 2025 Jun 25. 16(1): 5388

The mitochondrial methylation potential gates mitoribosome assembly.

Ruth I C Glasgow, Vivek Singh, Lucía Peña-Pérez, Alissa Wilhalm, Marco F Moedas, David Moore, Florian A Rosenberger, Xinping Li, Ilian Atanassov, Mira Saba, Miriam Cipullo, Joanna Rorbach, Anna Wedell, Christoph Freyer, Alexey Amunts, Anna Wredenberg.

S-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity.

DOI: https://doi.org/10.1038/s41467-025-60977-x
J Biochem. 2025 Jun 20. pii: mvaf037. [Epub ahead of print]

Mitochondrial DNA: leakage, recognition, and associated human diseases.

Hyota Takamatsu.

  Mitochondria are intracellular organelles originating from intracellular symbiotic bacteria that play essential roles in life activities such as energy production, metabolism, Ca2+ storage, signal transduction, and cell death. Mitochondria also function as hubs for host defense against harmful stimuli such as infection and inflammation control. However, when cells are exposed to stress, mitochondrial homeostasis is disrupted, and mitochondrial DNA (mtDNA) can leak into the cytoplasm or extracellular space. Leaked mtDNA activates innate immune sensors, causing severe inflammation and contributing to the pathogenesis of human diseases. In this review, we summarize the mechanisms by which mtDNA leaks from the mitochondria and subsequently induces inflammation. We also review the relationship between mtDNA leakage and human diseases.

Keywords:  human diseases; innate immune response; mitochondria quality control; mitochondrial DNA; mtDNA leakage

DOI:  https://doi.org/10.1093/jb/mvaf037
PLoS Biol. 2025 Jun;23(6): e3003207

Correction of pathogenic mitochondrial DNA in patient-derived disease models using mitochondrial base editors.

Indi P Joore, Sawsan Shehata, Irena Muffels, Jose Castro-Alpízar, Elena Jiménez-Curiel, Emilia Nagyova, Natacha Levy, Ziqin Tang, Kimberly Smit, Wilbert P Vermeij, Richard Rodenburg, Raymond Schiffelers, Edward E S Nieuwenhuis, Peter M van Hasselt, Sabine A Fuchs, Martijn A J Koppens.

Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells. Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity. To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate unique in vitro models to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.

DOI: https://doi.org/10.1371/journal.pbio.3003207
Nucleic Acid Ther. 2025 Jun 18.

Exosome-Mediated Mitochondrial Delivery of Antisense Oligonucleotides.

Dora von Trentini, Ivan J Dmochowski.

  We present a general method for in-cellulo delivery of 2'-O-methyl (2'-OMe) RNA oligonucleotides (oligos) to mitochondria for antisense applications, with potential for implementation in other mitochondrial DNA (mtDNA)-targeted therapies. Exosomes, which are nanoscale, naturally occurring extracellular vesicles (EVs), have been employed for biotechnology applications in oligonucleotide delivery in recent years. We discovered that exosomes from fetal bovine serum (FBS) can be used as a simple and biologically compatible delivery agent of 2'-OMe RNA antisense oligonucleotides to cellular mitochondria, leading to target protein knockdown. While most RNA interference and antisense mechanisms occur in the cytoplasm or nucleus, the need for mitochondrial targeting has become increasingly apparent. Mitochondrial disease describes a variety of currently incurable syndromes that especially affect organs requiring significant energy including the muscles, heart, and brain. Many of these syndromes result from mutations in mtDNA, which codes for the 13 proteins of the oxidative phosphorylation system and are thus often implicated in inherited metabolic disorders.

Keywords:  2′-OMe RNA; antisense oligonucleotides; exosome-based delivery; extracellular vesicles; fetal bovine serum; mitochondrial localization

DOI:  https://doi.org/10.1089/nat.2024.0067
Nat Aging. 2025 Jun 27.

Age-dependent accumulation of mitochondrial tRNA mutations in mouse kidneys linked to mitochondrial kidney diseases.

Leping Zhang, Zhe Xu, Jia Jing, Guoshi Chai, Guanglei Xie, Yanfei Ru, Qunyu Lv, Xiang Zuo, Qian Zhang, Jiatong Chen, He Jin, Ning Liu, Minghua Kong, Bin Shen, Mingxi Liu, Lei Jiang, Xi Wang, Yanxiao Zhang, Min Jiang.

Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are key drivers of mitochondrial diseases, yet their tissue-specific and cell-specific accumulation patterns during aging and the mechanistic links to pathology remain poorly understood. In this study, we employed DddA-derived cytosine base editor technology to generate three mouse models harboring distinct pathogenic mitochondrial tRNA mutations. These mutations exhibited age-dependent accumulation in the kidneys, leading to severe kidney defects that well recapitulate human mitochondrial kidney disease. Mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq) revealed unique heteroplasmy dynamics across different kidney cell types: podocytes exhibited a positive selection for mutant mtDNA, whereas tubular epithelial cells displayed neutral drift of mutations during aging. Integrative analyses combining mtscATAC-seq, single-cell RNA sequencing and spatially enhanced resolution omics sequencing further identified molecular changes in high-mutant defective cells, including increased AP-1 family transcription factor activity, tubular epithelial cell proliferation and immune activation, which contribute to disease progression. Our study underscores the importance of kidney function monitoring in patients with mitochondrial disease, particularly in older adults, and establishes robust preclinical models to facilitate the development of therapeutic strategies.

DOI: https://doi.org/10.1038/s43587-025-00909-y
AAPS J. 2025 Jun 25. 27(5): 112

Pharmacokinetics and Pharmacodynamics of Nomlabofusp in Non-clinical Studies of Friedreich's Ataxia.

Flavia De Toni, Vanessa Ragaglia, Devin Schecter, Angela S Miller, Eric Gonzalez, Erik J Wagner, Xin Xu, R Mark Payne, Jean-Nicholas Mess, Matthew G Baile, Adrienne Clements-Egan, Gopi Shankar.

  Nomlabofusp is a cell penetrant peptide-based recombinant fusion protein designed to enter cells and deliver human frataxin into the mitochondria of adults and children with Friedreich's ataxia. In this article we present non-clinical studies evaluating the pharmacology of nomlabofusp, including in a murine striated muscle tissue frataxin knockout model of Friedreich's ataxia. We demonstrate that subcutaneous administration of nomlabofusp distributes in a dose-dependent manner to several organs including the dorsal root ganglion, heart, and skeletal muscle, which are known to be predominantly affected in Friedreich's ataxia, as well as to other tissues, including skin. Plasma nomlabofusp concentrations correlated with levels of human frataxin delivered by nomlabofusp into tissues, and the increases in frataxin were correlated amongst tissues, especially with skin. In the knockout mice, we show that the pharmacokinetics and processing of nomlabofusp were comparable with wild type animals and that treatment with nomlabofusp halts the progression of cardiac dysfunction and significantly increased survival. Together, the findings from these non-clinical studies demonstrate that nomlabofusp exposure increases human frataxin in Friedreich's ataxia-relevant tissues and provide evidence of pharmacologic effects.

Keywords:  Animal model; Frataxin; Friedreich’s ataxia; Mitochondria; Nomlabofusp; Non-clinical; Pharmacokinetics

DOI:  https://doi.org/10.1208/s12248-025-01093-y
Clin Transl Med. 2025 Jun;15(6): e70385

OXA1L deficiency causes mitochondrial myopathy via reactive oxygen species regulated nuclear factor kappa B signalling pathway.

Yongkun Zhan, Qian Wang, Ya Wang, Yanjie Fan, Dan Yan, Xianlong Lin, Yaoting Chen, Tingting Hu, Nan Li, Weiqian Dai, Hezhi Fang, Yongguo Yu.

   BACKGROUND: OXA1L is crucial for mitochondrial protein insertion and assembly into the inner mitochondrial membrane, and its variants have been recently linked to mitochondrial encephalopathy. However, the definitive pathogenic link between OXA1L variants and mitochondrial diseases as well as the underlying pathogenesis remains elusive.
METHODS: In this study, we identified bi-allelic variants of c.620G>T, p.(Cys207Phe) and c.1163_1164del, p.(Val388Alafs*15) in OXA1L gene in a mitochondrial myopathy patient using whole exome sequencing. To unravel the genotype-phenotype relationship and underlying pathogenic mechanism between OXA1L variants and mitochondrial diseases, patient-specific human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into myotubes, while OXA1L knockout human immortalised skeletal muscle cells (IHSMC) and a conditional skeletal muscle knockout mouse model was generated using clustered regularly interspaced short palindromic repeats/Cas9 genomic editing technology.
RESULTS: Both patient-specific hiPSC differentiated myotubes and OXA1L knockout IHSMC showed combined mitochondrial respiratory chain defects and oxidative phosphorylation (OXPHOS) impairments. Notably, in OXA1L-knockout IHSMC, transfection of wild-type human OXA1L but not truncated mutant form rescued the respiratory chain defects. Moreover, skeletal muscle conditional Oxa1l knockout mice exhibited OXPHOS deficiencies and skeletal muscle morphofunctional abnormalities, recapitulating the phenotypes of mitochondrial myopathy. Further functional investigations revealed that impaired OXPHOS resulting of OXA1L deficiency led to elevated reactive oxygen species production, which possibly activated the nuclear factor kappa B signalling pathway, triggering cell apoptosis.
CONCLUSIONS: Together, our findings reinforce the genotype-phenotype association between OXA1L variations and mitochondrial diseases and further delineate the potential molecular mechanisms of how OXA1L deficiency causes skeletal muscle deficits in mitochondrial myopathy.
KEYPOINTS: OXA1L gene bi-allelic variants cause mitochondrial myopathy. OXA1L deficiency results in combined mitochondrial respiratory chain defects and OXPHOS impairments. OXA1L deficiency leads to elevated ROS production, which may activate the NF-κB signalling pathway, disturbing myogenic gene expression and triggering cell apoptosis.

Keywords:  NF‐κB signalling pathway; OXA1L; mitochondrial myopathy; oxidative phosphorylation; reactive oxygen species

DOI:  https://doi.org/10.1002/ctm2.70385
Front Cardiovasc Med. 2025 ;12 1582219

Mitochondrial DNA depletion syndrome and its cardiac complication.

Shengfang Bao, Jiajun Ye, Jiaqi Zhou, Chen Zheng, Yuejuan Xu, Sun Chen.

  Mitochondrial depletion syndrome (MTDPS) is a heterogeneous group of genetic disorders characterized by a significant reduction in mitochondrial DNA (mtDNA) copy number, leading to the impaired mitochondrial function. The pathogenesis of MTDPS includes impaired mtDNA replication, damaged nucleotide metabolism and dysregulated mitochondrial dynamics. Due to its high energy demands, the heart is sensitive to the mitochondrial dysfunction. And the energy deficiency caused by the MTDPS contributes to the development of the mitochondrial cardiomyopathy. In this review, we summarize the cardiac phenotypes in the MTDPS, and the role of the mitochondrial injury in the myocardial damage. In specific, the association of the MTDPS-causing genes and their cardiac phenotypes are detailed. Moreover, the current treatment strategies for MTDPS are summarized. This review aims to integrate the current knowledge on the MTDPS and its cardiac phenotypes in order to provide insights for the further research and the clinic management.

Keywords:  cardiomyopathy; mitochondrial DNA depletion syndrome; mitochondrial damage; mitochondrial dynamics; mitochondrial dysfunction; mtDNA replication; nucleotide metabolism

DOI:  https://doi.org/10.3389/fcvm.2025.1582219
Nat Commun. 2025 Jun 25. 16(1): 5379

Enhancing autophagy by redox regulation extends lifespan in Drosophila.

Claudia Lennicke, Ivana Bjedov, Sebastian Grönke, Katja E Menger, Andrew M James, Jorge Iván Castillo-Quan, Lucie A G van Leeuwen, Andrea Foley, Marcela Buricova, Jennifer Adcott, Alex Montoya, Holger B Kramer, Pavel V Shliaha, Angela Logan, Filipe Cabreiro, Michael P Murphy, Linda Partridge, Helena M Cochemé.

Dysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H2O2 in vivo, we established a redox-shifted model by manipulating levels of the H2O2-degrading enzyme catalase in Drosophila. Here we report that ubiquitous over-expression of catalase robustly extends lifespan in females. As anticipated, these flies are strongly resistant to a range of oxidative stress challenges, but interestingly are sensitive to starvation, which could not be explained by differences in levels of energy reserves. This led us to explore the contribution of autophagy, which is an important mechanism for organismal survival in response to starvation. We show that autophagy is essential for the increased lifespan by catalase upregulation, as the survival benefits are completely abolished upon global autophagy knock-down. Furthermore, using a specific redox-inactive knock-in mutant, we highlight the in vivo role of a key regulatory cysteine residue in Atg4a, which is required for the lifespan extension in our catalase model. Altogether, these findings confirm the redox regulation of autophagy in vivo as an important modulator of longevity.

DOI: https://doi.org/10.1038/s41467-025-60603-w
Eur J Hum Genet. 2025 Jun 27.

Homozygous COQ9 mutation: a new cause of potentially treatable hereditary spastic paraplegia.

Fanny Fontaine, Audrey Labalme, Chloé Laurencin, Julian Theuriet, Arnaud Jacquier, Nicolas Lacoste, Nathalie Streichenberger, Gaëtan Lesca, Stéphane Allouche.

Primary Coenzyme Q10 (CoQ10) deficiencies are a group of clinically heterogenous mitochondrial disorders that result from defects in CoQ10 biosynthesis. Their diagnosis is complicated by the absence of pathognomonic signs and poor genotype-phenotype correlations. Pathogenic variants in the COQ9 gene are a rare cause of CoQ10 deficiency: few cases have been reported, and the clinical presentation was described as a very severe multisystemic disorder with neonatal onset, ultimately leading to premature death. Through exome sequencing, we identified a novel homozygous splicing variant c.73 G > A in the COQ9 gene (NG_027696.1, NM_020312.4) in two adult siblings who presented with pure spastic paraplegia with onset in childhood. mRNA analysis from different tissues of one of the siblings revealed that this variant alters COQ9 splicing, resulting in undetectable levels of COQ9 and COQ7 proteins and reduced concentrations of CoQ10 in muscle and fibroblasts. Additionally, the accumulation of 6-demethoxycoenzyme Q10, the substrate of COQ7, was observed in both plasma and fibroblasts. Furthermore, fibroblast proliferation rate was reduced when enhancing the mitochondrial metabolism by replacing glucose with galactose in the culture medium, and was rescued by the addition of exogenous CoQ10, suggesting a therapeutic avenue for these patients. Altogether, we report here the first example of hereditary spastic paraplegia related to a mutation of the COQ9 gene that expands the spectrum of clinical manifestations and opens new therapeutic opportunities.

DOI: https://doi.org/10.1038/s41431-025-01895-w
Free Radic Biol Med. 2025 Jun 24. pii: S0891-5849(25)00789-0. [Epub ahead of print]

"Therapeutic Transplantation of Mitochondria and Extracellular Vesicles: Mechanistic Insights into mitochondria bioenergetics, redox signaling, and organelle dynamics in preclinical models".

Quentin Perrier, Veronica Lisi, Kelsey Fisherwellman, Sandrine Lablanche, Amish Asthana, Giuseppe Orlando, Sophie Maiocchi.

  Mitochondrial and extracellular vesicles (EV) transplantation have emerged as promising therapeutic strategies targeting mitochondrial dysfunction, a central feature of numerous pathologies. This review synthesizes preclinical data on artificial mitochondrial and EV transfer, emphasizing their therapeutic potential and underlying mechanisms. A systematic analysis of 123 animal studies revealed consistent benefits across diverse models, including ischemia-reperfusion injury (IRI), neurological disorders, drug-induced toxicities, and sepsis. Mitochondrial transfer improved organ function, reduced inflammation and apoptosis, and enhanced survival. Mechanistic insights revealed restored bioenergetics, increased oxidative phosphorylation, redox balance through activation of specific pathways, and modulation of mitochondrial dynamics via fusion/fission proteins. Mitochondrial homeostasis was supported through elevated mitophagy and biogenesis, alongside the preservation of mitochondrial-associated membranes. EV demonstrated similar effects, offering a potentially more targeted therapeutic alternative. Although pre-clinical studies have demonstrated safety and feasibility, broader application is limited by variability in isolation methods, lack of mechanistic clarity, and minimal human data. Standardization and mechanistic validation are critical to advance clinical translation. This review underscores the therapeutic promise of mitochondrial and EV transfer while highlighting the need for continued research to refine these interventions and unlock their full potential in regenerative medicine.

Keywords:  Artificial Mitochondrial transfer; Extracellular vesicles; Microvesicles; Mitochondrial Transplantation; Pre-clinical data; Therapeutic; Treatment

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.040
Mol Cell. 2025 Jun 24. pii: S1097-2765(25)00500-3. [Epub ahead of print]

Interaction with AK2A links AIFM1 to cellular energy metabolism.

Robin Alexander Rothemann, Egor Pavlenko, Mrityunjoy Mondal, Sarah Gerlich, Pavel Grobushkin, Sebastian Mostert, Julia Racho, Konstantin Weiss, Dylan Stobbe, Katharina Stillger, Kim Lapacz, Silja Lucia Salscheider, Carmelina Petrungaro, Dan Ehninger, Thi Hoang Duong Nguyen, Jörn Dengjel, Ines Neundorf, Daniele Bano, Simon Poepsel, Jan Riemer.

  Apoptosis-inducing factor 1 (AIFM1) is a flavoprotein essential for mitochondrial function and biogenesis. Its interaction with MIA40/CHCHD4, the central component of the mitochondrial disulfide relay, accounts for some, but not all, aspects of AIFM1 function. We provide a high-confidence AIFM1 interactome that elucidates functional partners within the mitochondrial intermembrane space. We found that AIFM1 binding to adenylate kinase 2 (AK2), an essential enzyme that maintains cellular adenine nucleotide pools, depends on the AK2 C-terminal domain. High-resolution cryoelectron microscopy (cryo-EM) and biochemical analyses showed that both MIA40 and AK2A bind the AIFM1 C-terminal β-sheet domain. Their binding enhances NADH oxidoreductase activity by locking an active dimer conformation and, in the case of MIA40, affecting the cofactor-binding site. The AIFM1-AK2A interaction is important during mitochondrial respiration because AIFM1 serves as a recruiting hub within the IMS, regulating mitochondrial bioenergetic output by creating hotspots of metabolic enzymes.

Keywords:  AIFM1; AK2; ATP; ATP transport; MIA40/CHCHD4; MICOS; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.molcel.2025.05.036
Trends Endocrinol Metab. 2025 Jun 24. pii: S1043-2760(25)00128-6. [Epub ahead of print]

Branched metabolic pathways to generate heme and heat.

Takeshi Yoneshiro, Makoto Arai, Juro Sakai.

  Heme has remarkable functions in mitochondrial energetics. Recently, Duerre et al. found that branched-chain amino acids (BCAA) are preferentially utilized for heme biosynthesis to facilitate mitochondrial thermogenesis in brown fat. Disrupting heme biosynthesis shifts the metabolic fate of BCAAs toward histone propionylation, inhibiting the transcription of thermogenic genes.

Keywords:  branched-chain amino acids; brown adipose tissue; heme synthesis; histone propionylation; mitochondria

DOI:  https://doi.org/10.1016/j.tem.2025.06.005
Antioxidants (Basel). 2025 Jun 16. pii: 741. [Epub ahead of print]14(6):

Mitochondrial Unfolded Protein Response (mtUPR) Activation Improves Pathological Alterations in Cellular Models of Ethylmalonic Encephalopathy.

José Manuel Romero-Domínguez, Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Diana Reche-López, Ana Romero-González, Mónica Álvarez-Córdoba, Alejandra López-Cabrera, Marta Castro De Oliveira, Andrés Rodríguez-Sacristán, Susana González-Granero, José Manuel García-Verdugo, Angeles Aroca, José A Sánchez-Alcázar.

  Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, and its main features are high levels of acidic compounds in body fluids and decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy. ETHE1 is a mitochondrial sulfur dioxygenase that plays the role of hydrogen sulfide (H2S) detoxification, and, when altered, it leads to the accumulation of this gaseous molecule due to its deficient elimination. In this article, we characterised the pathophysiology of ETHE1 deficiency in cellular models, fibroblasts, and induced neurons, derived from a patient with a homozygous pathogenic variant in ETHE1. Furthermore, we evaluated the effect of the activation of the mitochondrial unfolded protein response (mtUPR) on the mutant phenotype. Our results suggest that mutant fibroblasts have alterations in ETHE1 protein expression levels, associated with elevated levels of H2S and protein persulfidation, mitochondrial dysfunction, iron/lipofuscin accumulation, and oxidative stress. We also identified a cocktail of compounds consisting of pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid, and L-carnitine that improved the cellular and metabolic alterations. The positive effect of the cocktail was dependent on sirtuin 3 activation (SIRT3) and was also confirmed in induced neurons obtained by direct reprogramming. In conclusion, personalised precision medicine in EE using patient-derived cellular models can be an interesting approach for the screening and evaluation of potential therapies. In addition, the activation of the SIRT3 axe of mtUPR is a promising therapeutic strategy for rescuing ETHE1 pathogenic variants.

Keywords:  ETHE1; H2S; SIRT3; bioenergetics; ethylmalonic encephalopathy; mitochondrial diseases; mtUPR; protein persulfidation

DOI:  https://doi.org/10.3390/antiox14060741
Autophagy. 2025 Jun 26.

Mitochondrial protein nmd regulates lipophagy and general autophagy during development.

Wei Wang, Xufeng Wang, Xiaoqi Zhou, Lu Jiang, Weina Shang, Liquan Wang, Chao Tong.

  Lipophagy engulfs lipid droplets and delivers them to lysosomes for degradation. We found that lipophagy levels were low in most fly tissues, except for the prothoracic gland (PG) during larval development. Therefore, we performed a small-scale screening in the PG to identify regulators of lipophagy. We discovered that the loss of nmd, a gene encoding a mitochondrial AAA-ATPase, led to developmental failure and reduced lipophagy in the PG. Further studies indicated that nmd was not only required for lipophagy but also essential for general macroautophagy/autophagy in both PG and fat body tissues. Autophagy was induced but blocked at the autophagosome-lysosome fusion stage upon nmd reduction. Additionally, nmd interacted with mitochondrial protein import machinery, such as Tom20, Tom40, and the import cargo, such as Idh. Loss of nmd decreased protein import into mitochondria. Similar to the loss of nmd, reduction of Tom20 or Tom40 also resulted in reduced lipophagy in the PG. In adult flies, reducing nmd expression in the eyes caused lipid droplet accumulation and severe degeneration during aging. Overexpression of bmm, a triglyceride lipase, reduced lipid droplets in the eye but did not rescue the eye degeneration caused by the reduction of nmd.

Keywords:  Drosophila; lipophagy; mitochondrial protein import; neuronal homeostasis; nmd; prothoracic gland

DOI:  https://doi.org/10.1080/15548627.2025.2522124
Mol Cell Endocrinol. 2025 Jun 24. pii: S0303-7207(25)00157-1. [Epub ahead of print] 112606

Mdivi-1 promotes steroidogenesis in granulosa cells by inhibiting mitochondrial fission.

Ying He, Xiaoyan Li, Dan Kuai, Huiying Zhang, Yingmei Wang, Kan Wang, Wenyan Tian.

  Targeted metabolomics and ELISAs shown that Mdivi-1 treatment increased the levels of steroid hormones (progesterone and estradiol) in the supernatants of KGN cell culture medium. The purpose of this study was to explore the mechanism of Mdivi-1 promoting steroid hormone synthesis in granulosa cells (GCs). In vitro experiments revealed that Mdivi-1 did not affect the total protein expression of Drp1 in KGN cells or human luteinized GCs but increased Drp1 Ser637 phosphorylation, reduced Drp1 Ser616 phosphorylation, inhibited Drp1 mitochondrial translocation, and upregulated mitochondrial fusion proteins, promoting mitochondrial fusion. In terms of energy production, Mdivi-1 increased the expression of mitochondrial complexes I and V and the ATP concentration in GCs, increasing the energy supply for steroidogenesis. Mdivi-1 exposure significantly increased the expression and mitochondrial localization of StAR and CYP11A1 in the steroid production pathway of GCs. Further in vivo experiments demonstrated that, compared with the controls, Mdivi-1 treatment significantly increased the levels of Drp1 Ser637, StAR and CYP11A1 in ovarian tissue and the serum levels of progesterone and estradiol. Taken together, these findings suggest that Mdivi-1 induces mitochondrial fusion by increasing Drp1 phosphorylation at Ser637 and weakening the interaction between Drp1 and mitochondria. Moreover, mitochondrial fusion increases the cellular bioenergetics and the expression of StAR and CYP11A1 as well as their mitochondrial localization, thereby enhancing the activity of steroidogenesis in GCs.

Keywords:  Drp1 phosphorylation; Granulosa cells; Mdivi-1; Mitochondrial dynamics; Steroidogenesis

DOI:  https://doi.org/10.1016/j.mce.2025.112606
Cell. 2025 Jun 21. pii: S0092-8674(25)00637-3. [Epub ahead of print]

A host organelle integrates stolen chloroplasts for animal photosynthesis.

Corey A H Allard, Angus B Thies, Rishav Mitra, Patric M Vaelli, Olivia D Leto, Brittany L Walsh, Elise M J Laetz, Martin Tresguerres, Amy S Y Lee, Nicholas W Bellono.

  Eukaryotic life evolved over a billion years ago when ancient cells engulfed and integrated prokaryotes to become modern mitochondria and chloroplasts. Sacoglossan "solar-powered" sea slugs possess the ability to acquire organelles within a single lifetime by selectively retaining consumed chloroplasts that remain photosynthetically active for nearly a year. The mechanism for this "animal photosynthesis" remains unknown. Here, we discovered that foreign chloroplasts are housed within novel, host-derived organelles we term "kleptosomes." Kleptosomes use ATP-sensitive ion channels to maintain a luminal environment that supports chloroplast photosynthesis and longevity. Upon slug starvation, kleptosomes digest stored chloroplasts for additional nutrients, thereby serving as a food source. We leveraged this discovery to find that organellar retention and digestion of photosynthetic cargo has convergently evolved in other photosynthetic animals, including corals and anemones. Thus, our study reveals mechanisms underlying the long-term acquisition and evolutionary incorporation of intracellular symbionts into organelles that support complex cellular function.

Keywords:  cell biology; endosymbiosis; evolution; kleptoplasty; organellar ion channels; photosynthetic animal

DOI:  https://doi.org/10.1016/j.cell.2025.06.003
Nat Metab. 2025 Jun 27.

Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.

Marcus J Tol, Yuta Shimanaka, Alexander H Bedard, Jennifer Sapia, Liujuan Cui, Mariana Colaço-Gaspar, Peter Hofer, Alessandra Ferrari, Kevin Qian, John P Kennelly, Stephen D Lee, Yajing Gao, Xu Xiao, Jie Gao, Julia J Mack, Thomas A Weston, Kevin J Williams, Baolong Su, Calvin Pan, Aldons J Lusis, Daniel P Pike, Alex Reed, Natalia Milosevich, Benjamin F Cravatt, Makoto Arita, Stephen G Young, David A Ford, Rudolf Zechner, Stefano Vanni, Peter Tontonoz.

Genetic and dietary cues are known drivers of obesity, yet how they converge at the molecular level is incompletely understood. Here we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, an endoplasmic reticulum (ER)-resident O-acyltransferase that selectively enriches diet-derived omega-6 polyunsaturated fatty acids (n-6 PUFAs) in the membrane lipidome. In mice fed a high-fat diet, lowering membrane n-6 PUFA levels through genetic or dietary interventions results in aberrant adipose triglyceride (TG) turnover, ectopic fat deposition and insulin resistance. Additionally, we detail a non-canonical adaptive response in 'lipodystrophic' Lpcat3-/- adipose tissues that engages a futile lipid cycle to increase metabolic rate and offset lipid overflow to ectopic sites. Live-cell imaging, lipidomics and molecular dynamics simulations reveal that adipocyte LPCAT3 activity enriches n-6 arachidonate in the phosphatidylethanolamine (PE)-dense ER-lipid droplet interface. Functionally, this localized PE remodelling optimizes TG storage by driving the formation of large droplets that exhibit greater resistance to adipose TG lipase activity. These findings highlight the PPARγ-LPCAT3 axis as a mechanistic link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.

DOI: https://doi.org/10.1038/s42255-025-01320-y