bims-nenemi 2025-11-16 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–11–16
twelve papers selected by
Marco Tigano, Thomas Jefferson University

Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.
The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis.
Monitoring the complexity and dynamics of mitochondrial translation.
Secreted mitochondrial aspartyl-tRNA synthetase (DARS2) regulates TNFα signaling.
Estrogen receptor β deficiency increases the susceptibility to ulcerative colitis by inducing mitochondrial fission and consequently accelerating senescence of colonic epithelial cells.
MPTP mediated Ox-mtDNA release inducing macrophage pyroptosis and exacerbating MCD-induced MASH via promoting the ITPR3/Ca2+/NLRP3 pathway.
Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
Alternative start codon selection shapes mitochondrial function and rare human diseases.
The ARVC-5-associated protein TMEM43 controls mitochondrial energy metabolism by stabilising ER-mitochondrial contact sites.
ATGL-mediated lipolysis is essential for myocellular mitochondrial function, mitochondria-lipid droplet interaction and mitochondrial network connectivity.

Autophagy. 2025 Nov 13.

Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.

Tian Lan, Dantong Shang, Lan Lin, Haoyu Wang, Juan Zou, Mengxin Hu, Hanhua Cheng, Rongjia Zhou.

  Mitochondrial nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, yet its roles and mechanisms in mitophagy and innate immunity remain poorly understood. In this study, we identify mitochondrial NAD+ depletion that causes mitophagy dysfunction and inflammation. We find that depletion of mitochondrial NAD+ owing to deficiency of the mitochondrial NAD+ transporter SLC25A51 impairs BNIP3-mediated mitophagy. Loss of mitochondrial NAD+ inhibits SIRT3-mediated deacetylation of FOXO3, leading to transcriptional downregulation of BNIP3 and subsequent disruption of MAP1LC3B/LC3B recruitment. Notably, mitochondrial NAD+ depletion promotes mitochondrial DNA (mtDNA) release from mitochondria to the cytosol upon oxidative stress, thereby exacerbating the type I interferon response to free cytosolic mtDNA via activation of the CGAS-STING1 signaling pathway. Our findings reveal a novel mechanistic link among mitochondrial NAD+, mitophagy, and mtDNA-induced inflammation by genetic manipulation of cell lines, highlighting mitochondrial NAD+ as a potential therapeutic target for mitigating sterile inflammation triggered by free cytosolic mtDNA. Thus, the study provides new insights into the crosstalk among mitochondrial homeostasis, inflammation, and innate immunity.

Keywords:  Cytosolic mtDNA; SLC25A51; inflammation; innate immunity; mitochondrial NAD+; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2589909
Sci Adv. 2025 Nov 14. 11(46): eaea4660

The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.

Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.

Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.

DOI: https://doi.org/10.1126/sciadv.aea4660
Cells. 2025 Oct 23. pii: 1657. [Epub ahead of print]14(21):

Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.

Aya Attia, Katarzyna Majstrowicz, Samruddhi Shembekar, Ulrike Honnert, Petra Nikolaus, Birgit Lohmann, Martin Bähler.

  Mitochondrial dynamics are important for cellular health and include morphology, fusion, fission, vesicle formation, transport and contact formation with other organelles. Myosin XIX (Myo19) is an actin-based motor, which competes with TRAK1/2 adaptors of microtubule-based motors for binding to the outer mitochondrial membrane receptors Mitochondrial Rho GTPases 1/2 (Miro). Currently, it is poorly understood how Myo19 contributes to mitochondrial dynamics. Here, we report on a Myo19-deficient mouse model and the ultrastructure of the mitochondria from cells of Myo19-deficient mice and HEK cells, Miro-deficient HEK cells and TRAK1-deficient HAP1 cells. Myo19-deficient mitochondria in MEFs and HEK cells have morphological alterations in the inner mitochondrial membrane with reduced numbers of malformed cristae. In addition, mitochondria in Myo19-deficient cells showed fewer ER-mitochondria contact sites (ERMCSs). In accordance with the ultrastructural observations, Myo19-deficient MEFs had lower oxygen consumption rates and a reduced abundance of OXPHOS supercomplexes. The simultaneous loss of Miro1 and Miro 2 led to a comparable mitochondria phenotype and reduced ERMCSs as observed upon the loss of Myo19. However, the loss of TRAK1 caused only a reduction in the number of cristae, but not ERMCSs. These results demonstrate that both actin- and microtubule-based motors regulate cristae formation, but only Myo19 and its membrane receptor Miro regulate ERMCSs.

Keywords:  Miro1/2; Myosin 19; OXPHOS; TRAK; cristae; mitochondria; outer mitochondrial membrane

DOI:  https://doi.org/10.3390/cells14211657
Sci Adv. 2025 Nov 14. 11(46): eadx7809

The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis.

Sukrut C Kamerkar, Taewook Kang, Radu V Stan, Edward J Usherwood, Henry N Higgs.

Mitochondria are pivotal regulators of cellular homeostasis, integrating energy metabolism, biosynthesis, and programmed cell death (apoptosis). During apoptosis, mitochondrial outer membrane permeabilization by BCL-2-associated X protein/BCL-2 Homolog Antagonist Killer (BAX/BAK) pores facilitates release of apoptotic factors, while the role of inner mitochondrial membrane (IMM) remodeling remains less understood. Here, we identify serine beta-lactamase-like protein (LACTB), a filament-forming serine protease and tumor suppressor, as a regulator of IMM dynamics during apoptosis. LACTB suppression reduces cytochrome c release and apoptosis, whereas its overexpression promotes these effects. LACTB does not affect BAX or Drp1 recruitment to mitochondria. Rather, LACTB is required for apoptosis-induced mitochondrial remodeling, independent of OPA1 processing. Intriguingly, LACTB knockdown does not affect mitochondrial shape changes induced by CCCP treatment, suggesting that LACTB action is apoptosis-specific. Purified LACTB binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes, suggesting a direct effect in apoptotic membrane remodeling. Collectively, our findings suggest LACTB to be a mediator of apoptosis-induced IMM remodeling, a possible mechanism for tumor suppression in cancer.

DOI: https://doi.org/10.1126/sciadv.adx7809
Mol Cell. 2025 Nov 12. pii: S1097-2765(25)00863-9. [Epub ahead of print]

Monitoring the complexity and dynamics of mitochondrial translation.

Taisei Wakigawa, Mari Mito, Yushin Ando, Haruna Yamashiro, Kotaro Tomuro, Haruna Tani, Kazuhito Tomizawa, Takeshi Chujo, Asuteka Nagao, Takeo Suzuki, Osamu Nureki, Fan-Yan Wei, Yuichi Shichino, Yuzuru Itoh, Tsutomu Suzuki, Shintaro Iwasaki.

  Since mitochondrial translation leads to the synthesis of the essential oxidative phosphorylation (OXPHOS) subunits, exhaustive and quantitative delineation of mitoribosome traversal is needed. Here, we developed a variety of high-resolution mitochondrial ribosome profiling derivatives and revealed the intricate regulation of mammalian mitochondrial translation. Harnessing a translation inhibitor, retapamulin, our approach assessed the stoichiometry and kinetics of mitochondrial translation flux, such as the number of mitoribosomes on a transcript, the elongation rate, and the initiation rate. We also surveyed the impacts of modifications at the anticodon stem loop in mitochondrial tRNAs (mt-tRNAs), including all possible modifications at the 34th position, in cells deleting the corresponding enzymes and derived from patients, as well as in mouse tissues. Moreover, a retapamulin-assisted derivative and mito-disome profiling revealed mitochondrial translation initiation factor (mtIF) 3-mediated translation initiation from internal open reading frames (ORFs) and programmed mitoribosome collision sites across the mitochondrial transcriptome. Our work provides a useful platform for investigating protein synthesis within the energy powerhouse of the cell.

Keywords:  MELAS; Ribo-Seq; disome; kinetics; mitochondria; mitoribosomes; mtIF3; ribosome profiling; tRNA modification; translation

DOI:  https://doi.org/10.1016/j.molcel.2025.10.022
Physiol Rep. 2025 Nov;13(21): e70627

Secreted mitochondrial aspartyl-tRNA synthetase (DARS2) regulates TNFα signaling.

Benjamin S Johnson, Alex Cornwell, Daniela Farkas, Ilknur Yurtsever, Jessica A Joseph, Arun Pradhan, Laszlo Farkas, James D Londino, Joseph S Bednash, Rama K Mallampalli.

  Aminoacyl-tRNA Synthetases (aaRS) are important regulators of cytokine signaling. Multiple cytoplasmic aaRS family members have been observed to be secreted in response to various stimuli to modulate downstream responses, however, agonist-induced cellular release of aaRS from mitochondria has not been described. In particular, TNFα is a potent mediator of aaRS release. BEAS-2B cells were utilized to study the release of mitochondrial Aspartyl-tRNA Synthetase (DARS2) in response to various cytokines. The role of DARS2 in paracrine signaling was evaluated using adoptive media transfer from BEAS-2B to recipient THP1 cells. To identify pathways governing DARS2 secretion, blocking antibodies chemical inhibitors and siRNA technology was employed. Herein, we describe DARS2 as the first mitochondrial aaRS released in response to TNFα from airway epithelia. Once secreted, DARS2 binds to macrophages, is internalized, thereby inducing an M1-like phenotype in recipient macrophages. DARS2 release from airway epithelia is in part, TNFα-receptor 1 dependent, and requires the endosomal sorting complex required for extracellular transport.

Keywords:  DARS2; cytokine; lung epithelia; mitochondria

DOI:  https://doi.org/10.14814/phy2.70627
Redox Biol. 2025 Nov 05. pii: S2213-2317(25)00432-X. [Epub ahead of print]88 103919

Estrogen receptor β deficiency increases the susceptibility to ulcerative colitis by inducing mitochondrial fission and consequently accelerating senescence of colonic epithelial cells.

Yilei Guo, Yue He, Yanrong Zhu, Wenjie Zhang, Haochang Lin, Mianjiang Zhao, Jiafeng Zhang, Yawen Bai, Zhifeng Wei, Yufeng Xia, Yue Dai.

  The incidence of ulcerative colitis (UC) is significantly higher among individuals with colonic estrogen receptor β (ERβ) deficiency, such as postmenopausal women, but the involvement of ERβ deficiency in UC pathogenesis remains obscure. Here, we showed that colonic ERβ expression level in UC patients was negatively correlated with disease severity. In mice, ERβ knockout induced spontaneous colitis-like symptoms and increased susceptibility to dextran sulfate sodium-induced colitis, with earlier onset and aggravated severity, whereas ERβ overexpression reduced colitis susceptibility. Transcriptomic analysis and subsequent validation in UC patient samples revealed that ERβ deficiency in colonic epithelial cells accelerated cellular senescence, which concurrently causing disruption of epithelial barrier and release of proinflammatory cytokines, ultimately increasing susceptibility to colitis. Mechanistically, ERβ deficiency induced mitochondrial fission, resulting in mitochondrial DNA leakage and cGAS-STING pathway activation, thereby accelerating colonic epithelial cell senescence. Consistently, pre-administration of the phytoestrogens genistein and arctigenin attenuated mitochondrial fission-induced colonic epithelial cell senescence of mice through upregulating ERβ expression, thereby markedly reducing susceptibility to colitis. In summary, our findings identify ERβ as a susceptibility gene and therapeutic target for UC, unveil mitochondrial fission induced-colonic epithelial cell senescence as a novel UC pathogenic mechanism, and suggest that high dietary intake of phytoestrogen-rich foods may mitigate susceptibility to UC.

Keywords:  Epithelial cell senescence; Estrogen receptor β; Mitochondrial fission; Phytoestrogen; Susceptibility; Ulcerative colitis

DOI:  https://doi.org/10.1016/j.redox.2025.103919
J Transl Med. 2025 Nov 14. 23(1): 1289

MPTP mediated Ox-mtDNA release inducing macrophage pyroptosis and exacerbating MCD-induced MASH via promoting the ITPR3/Ca2+/NLRP3 pathway.

Qi Zhang, Li Chen, Jun-Yan Liu, Tao Liu, Rui Wang, Xin-Yi Wu, Sheng-Wei Li.

   BACKGROUND: Metabolic Dysfunction-Associated Steatohepatitis (MASH) is a severe and progressive form of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), with approximately 25% of adults worldwide suffering from MASLD, of which 20%-30% progress to MASH, and the global incidence continues to rise. Oxidized mitochondrial DNA (Ox-mtDNA) release is a key contributor to MASH. However, its underlying mechanism remains unclear. Clarifying this process may provide a theoretical foundation for MASH treatment.
METHODS: In this study, we separately established MASH models using methionine- and choline deficient diet (MCD) fed mice in vivo and free fatty acid (FFA)-stimulated THP-1 derived macrophages in vitro. Cyclosporin A (CsA: mitochondrial permeability transition pore, mPTP, channel inhibitor) was used to inhibit the release of Ox-mtDNA. 8-OH-dG detection and fluorescent probe were used to evaluate Ox-mtDNA release. Liver lipid deposition was analyzed by Triglyceride (TG) and Oil Red O, and tissue damage were analyzed by aspartate transaminase and alanine aminotransferase (ALT, AST) and H&E staining. Pyroptosis markers, such as cleaved-Caspase1, GSDMD-N, and inflammatory cytokines, such as interleukin - 1β, interleukin 18 (IL-1β, IL-18), were detected by WB, ELISA and transmission electron microscopy (TEM) experiments, and the key pyroptosis pathways activated by Ox-mtDNA were screened by RNA-seq. Finally, ITPR3 was silenced by siRNA in vitro and by Adeno-associated virus (AAV) in vivo respectively, which confirmed the role of ITPR3/Ca2+/NLRP3 axis in Ox-mtDNA regulating macrophage pyroptosis mediated MASH.
RESULTS: The cytosolic Ox-mtDNA level was significantly increased during MASH. Inhibition of Ox-mtDNA release alleviated macrophage pyroptosis to improve the pathological phenotype of MASH. RNA-seq analysis showed that cytosolic Ox-mtDNA triggered an inflammatory response by activating the NOD-like receptor pathway, in which FFA induced upregulation of inositol 1,4,5-Trisphosphate Receptor Type 3 (ITPR3, IP3R) expression, and Inhibition of Ox-mtDNA release could relieve this effect. ITPR3 silencing significantly reduced Ca²⁺ release, which in turn inhibited nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome activation and macrophage pyroptosis. Cytosolic Ox-mtDNA promotes Ca²⁺ release by upregulating ITPR3, activates NLRP3-dependent macrophage pyroptosis, and ultimately exacerbates liver injury and MASH progression.
CONCLUSIONS: This study demonstrates that Ox-mtDNA drives MASH progression by promoting macrophage pyroptosis via the ITPR3/Ca²⁺/NLRP3 axis, providing a novel therapeutic strategy for targeted intervention.

Keywords:  Ca2+ ; ITPR3; MASH; NLRP3; Ox-mtDNA; Pyroptosis

DOI:  https://doi.org/10.1186/s12967-025-07302-8
Nature. 2025 Nov 12.

Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.

Yifan Zhang, Xiao Shen, Yuan Shen, Chao Wang, Chengping Yu, Jiangxue Han, Siyi Cao, Lin Qian, Miaolian Ma, Shijing Huang, Wenyu Wen, Miao Yin, Qun-Ying Lei.

Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY), mitochondrial citrate/malate antiporter (encoded by SLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA-NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.

DOI: https://doi.org/10.1038/s41586-025-09745-x
Mol Cell. 2025 Nov 07. pii: S1097-2765(25)00854-8. [Epub ahead of print]

Alternative start codon selection shapes mitochondrial function and rare human diseases.

Jimmy Ly, Matteo Di Bernardo, Yi Fei Tao, Ekaterina Khalizeva, Christopher J Giuliano, Sebastian Lourido, Mark D Fleming, Iain M Cheeseman.

  Rare genetic diseases collectively affect millions of individuals. A common target of many rare diseases is the mitochondria, intracellular organelles that originated through endosymbiosis. Eukaryotic cells require related proteins to function both within the mitochondria and in the host cell. By analyzing N-terminal protein isoforms generated through alternative start codon selection, we identify hundreds of differentially localized isoform pairs, including dual-localized isoforms that are essential for both mitochondrial and host cell function. Subsets of dual mitochondria-localized isoforms emerged during early eukaryotic evolution, coinciding with mitochondrial endosymbiosis. Importantly, we identify dozens of rare disease alleles that affect these alternative protein variants with unique molecular and clinical consequences. Alternative start codon selection can bypass pathogenic nonsense and frameshift mutations, thereby selectively eliminating specific isoforms, which we term isoform-selective alleles (ISAs). Together, our findings illuminate the evolutionary and pathological relevance of alternative translation, offering insights into the molecular basis of rare human diseases.

Keywords:  TRNT1; alternative N-terminal isoforms; alternative translation; mitochondria; proteomic diversity; rare diseases; start codon selection; translation initiation

DOI:  https://doi.org/10.1016/j.molcel.2025.10.013
Cell Mol Life Sci. 2025 Nov 14. 82(1): 400

The ARVC-5-associated protein TMEM43 controls mitochondrial energy metabolism by stabilising ER-mitochondrial contact sites.

Kai Jürgens, Lena Menzel, Nora Klinke, Lisa Schäper, Leonhard Breitsprecher, Michael Holtmannspötter, Olympia-Ekaterini Psathaki, Stefan Walter, Sandra Ratnavadivel, Anders Malmendal, Heiko Meyer, Hendrik Milting, Achim Paululat.

  Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC-5) is a fully penetrant form of ARVC caused by the missense mutation in the gene TMEM43p.S358L. Despite extensive research, the molecular basis underlying the detrimental effects of TMEM43p.S358L still needs to be discovered. TMEM43 is a phylogenetically conserved protein. We previously analysed the Drosophila homologue (CG8111 or Dmel\Tmem43) to understand the protein's physiological relevance and the mutation p.S358L. Drosophila Tmem43 is localised at the ER/SR membrane and interacts with the outer mitochondrial membrane protein Porin/VDAC. This interaction is lost in a Tmem43p.S333L mutant that resembles the human p.S358L mutation. In addition, Tmem43p.S333L caused a breakdown in mitochondrial membrane potential and increased cellular reactive oxygen species, suggesting impaired mitochondrial function as a major pathomechanism. Complementary ultrastructural analyses revealed severe structural defects in the affected mitochondria, including degeneration of the organelles. Highly similar ultrastructural defects were observed in the human right ventricular myocardium of a TMEM43p.S358L trait carrier, suggesting a common molecular basis for the detrimental effects of the mutation in flies and humans. We propose that both the p.S358L mutation in humans and the p.S333L mutation in Drosophila impair TMEM43/VDAC interaction, which affects the stability of ER/SR-mitochondrial contact sites and, thus, proper mitochondrial function and oxidative phosphorylation rates. The consequential undersupply of ATP likely results in cardiac cell death and, ultimately, heart failure.

Keywords:  ARVC type 5; Cardiogenesis; Cardiomyopathy; Drosophila model; TMEM43

DOI:  https://doi.org/10.1007/s00018-025-05942-z
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Nov 10. pii: S1388-1981(25)00111-8. [Epub ahead of print]1871(1): 159703

ATGL-mediated lipolysis is essential for myocellular mitochondrial function, mitochondria-lipid droplet interaction and mitochondrial network connectivity.

Anne Gemmink, Tineke van de Weijer, Gert Schaart, Gernot F Grabner, Esther Kornips, Kèvin Knoops, Rudolf Zechner, Martina Schweiger, Matthijs K C Hesselink.

  Defects in Adipose tissue TriGlyceride Lipase (ATGL)-mediated myocellular lipid droplet (LD) lipolysis results in mitochondrial dysfunction of unknown origin, which can be rescued by PPAR agonists. Here we examine if ATGL-mediated lipolysis is required to maintain mitochondrial network connectivity and function. Moreover, we explored if the functional implications of ATGL deficiency for mitochondrial network dynamics and function can be alleviated by promoting PPARα and/or PPARδ transcriptional activity. To this end, we cultured human primary myotubes from patients with neutral lipid storage disease with myopathy (NLSDM), a rare metabolic disorder caused by a mutation in the gene encoding for ATGL. These myotubes possess dysfunctional ATGL and compromised LD lipolysis. In addition, mitochondria-LD contact, mitochondrial network connectivity, and mitochondrial membrane potential were affected. Using a humanized ATGL inhibitor in myotubes (cultured form healthy donors) revealed similar results. Upon stimulating PPARδ transcriptional activity, mitochondrial respiration improved by more than 50 % in human primary myotubes from healthy lean individuals. This increase in respiration was dampened in myotubes with dysfunctional ATGL. Stimulation of PPARδ transcriptional activity had no effect on mitochondria-LD contacts, mitochondrial network connectivity, and mitochondrial membrane potential. Our results demonstrate that dysfunctional ATGL results in compromised mitochondrial-LD contacts and mitochondrial network connectivity, and that functional ATGL is required to improve mitochondrial respiratory capacity upon stimulation of PPARδ transcriptional activity.

Keywords:  ATGL; Lipid droplets; Microscopy; Mitochondrial networks; NLSDM; PPAR transcriptional activity; Skeletal muscle

DOI:  https://doi.org/10.1016/j.bbalip.2025.159703