bims-obesme 2026-08-02 papers

Sci Adv. 2026 Jul 31. 12(31): eaef0140

Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.

Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.

Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.

DOI: https://doi.org/10.1126/sciadv.aef0140

Science. 2026 Jul 30. 393(6810): eady0832

Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.

Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.

DOI: https://doi.org/10.1126/science.ady0832

Diabetes. 2026 Jul 31. pii: db260029. [Epub ahead of print]

A Selective Cullin 3 RING E3 Ligase Inhibitor Attenuates Hyperglycemia via Dual Insulin Sensitizing and Insulinotropic Action.

Lijie Gu, Lei Xiong, Mohammad Nazmul Hasan, Yanhong Du, Timothy Wu, Tiangang Li.

ARTICLE HIGHLIGHTS: Pan-neddylation inhibitors exhibit potent hypoglycemic effect. The target organs and mechanisms underlying the hypoglycemia effect of pan-neddylation inhibitors are incompletely understood. We found that inhibition of cullin 3 leads to a dual insulin sensitization and insulinotropic effect. Selective inhibition of cullin 3 neddylation is a feasible approach to lower hyperglycemia.

DOI: https://doi.org/10.2337/db26-0029

Nature. 2026 Jul 29.

Mitochondrial metabolism and epigenetic crosstalk drive SASP.

Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP)1. Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme2,3. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes. Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.

DOI: https://doi.org/10.1038/s41586-026-10791-2

Signal Transduct Target Ther. 2026 Jul 29. pii: 295. [Epub ahead of print]11(1):

Mitochondrial quality control in health and disease: mechanisms and therapeutic targets.

Agustina Creus, Shrestha Mohapatra, Leonardo Ortega, David Sebastián.

Mitochondria are essential for cellular homeostasis, integrating various signals to control key cellular functions such as metabolism, apoptosis, inflammation, cell proliferation and redox balance. Given their multifaceted functions, it is not surprising that mitochondrial dysfunction has been implicated as a key contributor to the pathogenesis of numerous human diseases. Consequently, preserving mitochondrial integrity and functionality is vital for overall organismal health. Mitochondrial health is safeguarded by a sophisticated and tightly regulated network of quality control systems. These include mitochondrial proteostasis, which ensures proper protein folding and degradation; mitochondrial biogenesis, which governs the synthesis of new mitochondria; mitochondrial dynamics, encompassing fusion and fission processes; and mitophagy, the selective autophagic removal of damaged mitochondria. Additionally, these core systems are intricately connected to other crucial mitochondrial processes, such as the maintenance of mitochondrial DNA integrity, the regulation of cristae architecture, and the control of mitochondrial permeability transition, all of which are indispensable for optimal mitochondrial performance. Preclinical and clinical studies consistently demonstrate a strong link between impairments in these quality control mechanisms and both aging and the development of a wide spectrum of diseases. These include cancer, metabolic disorders, cardiovascular conditions, neurodegenerative diseases and autoimmune pathologies. In this review, we explore the different facets of mitochondrial quality control and discuss their implications in disease progression and aging. Furthermore, we highlight recent advances in interventions and therapies aimed at modulating mitochondrial quality control, providing an overview of their potential to mitigate disease burden and promote healthy aging.

DOI: https://doi.org/10.1038/s41392-026-02813-2

Nat Cell Biol. 2026 Jul 28.

Nuclear class 3 PI3K co-activates fasting-specific chromatin remodelling.

Nathaniel F Henneman, Genki Kawamura, Ying Luo, Catia Oliveira Dias, Jiaqi Su, Arianna Segaloni, Ivan Nemazanyy, Samuel le Cam, Calvin Rodrigues, Nicolas Kuperwasser, Nicolas Cagnard, Karim Hnia, Raphaël Margueron, Dominik Lutter, Takeaki Ozawa, Ganna Panasyuk.

Transcriptional remodelling during fasting ensures metabolic adaptation and provides health benefits across species. Although several regulators of fasting-induced transcription and chromatin are known, how nutrient levels directly influence RNA polymerase II (RNAPII) and epigenetic writers remains unclear. Here we show that lipid kinase class 3 phosphatidylinositol 3-kinase (PI3K-3), a master regulator of autophagy, also functions on chromatin as a co-activator of epigenetic writers to promote RNAPII transcription. PI3K-3 overlaps with transcriptionally engaged RNAPII phosphorylated at Ser5 and with Setd1a/COMPASS, the complex that deposits the activating H3K4me3 mark. Nuclear PI3K-3 interacts with RNAPII and Setd1a/COMPASS and promotes their chromatin binding. PI3K-3 loss reduces RNAPII-S5p and H3K4me3 at selected genes, whereas PI3K-3 overexpression co-activates p300/CBP and chromatin-targeted PI3K-3 increases H3K4me3. During starvation, PI3K-3 induces autophagy genes and drives fasted liver towards ketogenesis and lipid degradation. These findings link nutrient stress to chromatin-mediated transcriptional activation.

DOI: https://doi.org/10.1038/s41556-026-02030-7

J Endocr Soc. 2026 Aug;10(8): bvag155

Unraveling the natural history of lipodystrophy syndromes: insights from the prospective LD-Lync study.

Context: Lipodystrophy syndromes represent a diverse group of rare disorders characterized by deficiency and abnormal distribution of adipose tissue that may be generalized (GL) or partial (PL), leading to significant metabolic abnormalities.
Objective: To elucidate the natural history of critical comorbidities of lipodystrophy.
Methods: Ongoing, prospective, multicenter, registry study (LD Lync; NCT03087253). This analysis reports 266 patients with lipodystrophy enrolled until October 11, 2023.
Results: The median age was 39 years ([28-54], range: 6-76 years; male/female: 50/216). Hypertriglyceridemia (n = 202, 75.9%) was the most common comorbidity, followed by diabetes (n = 190, 72.0%), hepatic steatosis (n = 182, 68.4%), and hypertension (n = 130, 48.8%). Pancreatitis was detected in 21.8% of patients (n = 58), and cirrhosis in 7.1% of patients (n = 19). The median age at diagnosis was significantly earlier in patients with GL compared to those with PL for both diabetes (16 [14-32] years in GL vs 35 [25-50] years in PL) and hypertriglyceridemia (20 [15-26] years in GL vs 30 [22-49] years in PL) (P < .0001). Seven (2.6%) patients died during follow-up. Multiple medications were used to treat metabolic disease. Eighty-one (30.4%) patients received at least one dose of metreleptin during clinical studies or commercially during follow-up.
Conclusion: Our findings confirm that patients with lipodystrophy face a significant risk of comorbidities, with an earlier onset of diabetes, hypertriglyceridemia, and hepatic steatosis in those with GL compared to PL. This registry will serve as a crucial resource for gaining insights into the burden of disease in lipodystrophy.

Keywords: diabetes; hypertriglyceridemia; insulin resistance; leptin; lipodystrophy; pancreatitis

DOI: https://doi.org/10.1210/jendso/bvag155