bims-tofagi 2026-09-13 papers

Issue of 2026–09–13
five papers selected by
Michele Frison, University of Cambridge

Trends Pharmacol Sci. 2026 Sep 12. pii: S0165-6147(26)00206-3. [Epub ahead of print]

Deubiquitinases in mitophagy: therapeutic control of mitochondrial quality.

Yang Xu, Bahareh Behrouz, Andrew Lee, Gang Xin, Nuo Sun.

Mitochondrial quality control is essential for maintaining cellular and tissue homeostasis. Mitophagy, the selective autophagic removal of damaged mitochondria, is a central component of this process, and defects in mitophagy are increasingly linked to neurodegeneration, cardiovascular disease, cancer, and inherited mitochondrial disorders. Ubiquitin-dependent tagging of outer mitochondrial membrane proteins is a major mechanism for marking damaged mitochondria for clearance; however, recent advances reveal that mitochondrial deubiquitinases (DUBs) shape ubiquitin signaling at damaged mitochondria, thereby influencing the efficiency and selectivity of mitochondrial turnover. Moreover, DUBs are emerging as context-dependent editors of the mitochondrial ubiquitin code that link mitophagy to disease pathogenesis and therapeutic intervention. Here, we synthesize current understanding of mitochondrial DUBs in physiology and disease and discuss emerging pharmacological strategies to guide the development of mitophagy-targeted therapeutics.

DOI: https://doi.org/10.1016/j.tips.2026.08.009

Autophagy. 2026 Sep 09. 1-19

Targeting USP7 lactylation suppresses NSCLC tumorigenesis by promoting PINK1 ubiquitination and degradation.

Zhangjie Wang, Chaoyi Li, Ruiqiu Zhu, Minghao Duan, Zhenyu Kuang, Xin Li, Weifang Cui, Chaojun Duan, Chunfang Zhang.

Lactylation is an emerging post-translational modification that is well established for its involvement in epigenetic regulation. However, its functional significance and regulatory mechanisms in non-small cell lung cancer (NSCLC) remain poorly understood. In this study, integrated proteomic and lactylomic analyses of clinical NSCLC specimens and matched adjacent normal tissues showed that USP7 (ubiquitin specific peptidase 7) was upregulated and USP7 K1084 lactylation was increased in NSCLC. Knockout of USP7 or inhibition of USP7 lactylation impaired cellular mitophagy, resulting in mitochondrial damage and attenuated NSCLC tumorigenicity. We identified CREBBP/CBP (CREB binding lysine acetyltransferase) as the key lactyltransferase responsible for USP7 K1084 lactylation. USP7 lactylation induced its localization to mitochondria and increased its interaction with PINK1 (PTEN induced kinase 1), promoting PINK1 deubiquitination and stabilization. Pharmacological inhibition of CREBBP reduced USP7 lactylation levels and promoted PINK1 ubiquitination and degradation, exerting antitumor effects in vitro and in vivo. Analysis of NSCLC clinical specimens showed that the protein levels of USP7, CREBBP, and PINK1 were positively correlated, and their high expression was associated with poor patient prognosis. Collectively, our findings establish the CREBBP-USP7-PINK1 axis as a promising therapeutic target for NSCLC treatment.Abbreviations: CHX: cycloheximide; CREBBP/CBP: CREB binding lysine acetyltransferase; DUB: deubiquitinating enzyme; IHC: immunohistochemistry; IP: immunoprecipitation; KO: knockout; LDHA: lactate dehydrogenase A; MS: mass spectrometry; NALA: L-sodium lactate; NSCLC: non-small cell lung cancer; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PINK1: PTEN induced kinase 1; PLA: proximity ligation assay; ROS: reactive oxygen species; shRNA: short hairpin RNA; TEM: transmission electron microscopy; TUBE: tandem ubiquitin binding entity; UPS: ubiquitin-proteasome system; USP7: ubiquitin specific peptidase 7; WT: wild type.

Keywords: CREBBP; deubiquitination; lung cancer; mitochondrial quality control; post-translational modification

DOI: https://doi.org/10.1080/15548627.2026.2728617

Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2537797123

Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.

Sneha P Rath, Zhu Li, Arkajit Guha, Fangcong Dong, Ruma Banerjee, Vamsi K Mootha.

Of the ~1,100 mitochondrial proteins, only a handful like PINK1 and ATFS-1 are known to stabilize and relocalize upon collapse of the proton motive force (PMF) to execute signaling roles. To systematically identify genes that increase exclusively at the protein level upon PMF collapse, we performed a joint proteomic and RNA-seq screen. The screen revealed 10 candidates (six mitochondrial), including two genes in vitamin B12 metabolism - the B12 chaperone MMADHC and cytosolic B12-dependent 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). MMADHC is short-lived across cell types and we show that its levels increase with PMF collapse. MMADHC stabilization precedes PINK1 activation in a time course of increasing mtDNA depletion, suggesting greater sensitivity to PMF collapse. MMADHC accumulates in mitochondria with LONP1 inhibition but in the cytosol upon PMF collapse, likely due to mitochondrial import failure. Cytosol-stabilized MMADHC increases MTR levels and activity. Altogether, the mitochondrial PMF regulates the cytosolic B12-dependent MTR, integral to one-carbon metabolism, by controlling the stability and compartmentalization of the B12 chaperone MMADHC.

Keywords: MMADHC; methionine synthase; mitochondria; proton motive force; vitamin B12

DOI: https://doi.org/10.1073/pnas.2537797123

Autophagy. 2026 Sep 09.

Spatiotemporal control of Atg9 vesicle fusion in autophagosome formation.

Takumi Kimura, Tetsuya Kotani, Hitoshi Nakatogawa.

Atg9 vesicles serve as membrane seeds for autophagosome formation. These vesicles are derived from the Golgi/endosomes and localized to the pre-autophagosomal structure or phagophore assembly site (PAS) upon autophagy induction. How these vesicles are maintained as discrete membrane carriers while diffusing through the cytoplasm and subsequently become competent for downstream events at the PAS has remained unknown. Here, we show that the Atg9-interacting protein Atg23 remains associated with Atg9 vesicles following their formation and protects them from inappropriate fusion with endomembranes during their movement through the cytoplasm. Upon arrival at the PAS, Atg1-mediated phosphorylation of Atg9 triggers the dissociation of Atg23, thereby enabling efficient recruitment of the lipid-transfer protein Atg2. Collectively, these findings define a spatiotemporally regulated mechanism in which Atg23 preserves Atg9 vesicles during cytoplasmic transport, whereas its dissociation enables their productive utilization in autophagosome formation.

Keywords: Atg9; Phosphorylation-dependent regulation; autophagosome; membrane trafficking; vesicle coating; yeast

DOI: https://doi.org/10.1080/15548627.2026.2730073

Autophagy. 2026 Sep 08.

α-ketoglutarate ameliorates spinal motor neuron ferroptosis after sacral plexus transection via enhancing PINK1 O‑GlcNAcylation and mitophagy.

Hui Han, Sheng Wang, Jiajia Lu, Jing Li, Jinlong Zheng, Yongchuan Li, Hongtao Lu, Aimin Chen.

Sacral plexus transection (SPT), mostly caused by high‑energy trauma, induces secondary death of spinal motor neurons in the lumbosacral segments and contributes to poor clinical outcomes after nerve repair. This study aimed to investigate the protective effect of α‑ketoglutarate (AKG) against ferroptosis in spinal motor neurons following SPT and the underlying molecular mechanism. Our results showed that endogenous AKG levels were significantly decreased in the spinal cord of SPT rats and in oxidative stress‑injured motor neurons, accompanied by abnormal expression of core ferroptosis‑related proteins, including downregulated glutathione peroxidase 4 and solute carrier family 7 member 11, upregulated acyl-CoA synthetase long-chain family member 4, as well as Fe2+ overload, malondialdehyde accumulation, and glutathione depletion. Exogenous AKG supplementation markedly reversed these anomalies, suppressed ferroptosis, and improved neuronal survival. Mechanistically, AKG specifically enhanced O-GlcNAcylation at the Thr177 site of PTEN‑induced kinase 1 (PINK1) and suppressed its ubiquitin-mediated degradation, which in turn selectively activated PINK1-PRKN-dependent mitophagy to eliminate damaged mitochondria and sustain mitochondrial homeostasis. Furthermore, downregulation of isocitrate dehydrogenase 1 (IDH1) after SPT was identified as a critical upstream event leading to endogenous AKG depletion. This study systematically elucidates the key role of the IDH1‑AKG‑PINK1 O‑GlcNAcylation ‑mitophagy axis in regulating SPT‑induced ferroptosis in spinal motor neurons, providing novel targets and experimental evidence for neuroprotective therapy of sacral plexus injury.

Keywords: Ferroptosis; O-GlcNAcylation; mitophagy; sacral plexus transection; α-ketoglutarate

DOI: https://doi.org/10.1080/15548627.2026.2730071