bims-tofagi 2026-03-15 papers

Issue of 2026–03–15
five papers selected by
Michele Frison, University of Cambridge

Autophagy. 2026 Mar 08. 1-17

FUNDC1-dependent mitophagy determines axon regeneration capacity.

Wenlei Li, Yujiao Liu, Ruixuan Liu, Yuyuan Fan, Jinming Liu, Yingjie Guo, Zeping Hu, Lei Liu, Quan Chen, Bing Zhou.

Neuronal axon regeneration is a complex and coordinated reorganization process that requires the involvement of mitochondria. Here, we demonstrated that FUNDC1 (FUN14 domain containing 1)-mediated mitophagy played a crucial role in determining the intrinsic capacity for axonal regrowth and peripheral nerve recovery. We found that acute nerve injury resulted in the accumulation of impaired mitochondria at the axonal injury site, accompanied by an increase in the expression of the mitophagy receptor FUNDC1. Strikingly, overexpression of FUNDC1 enhanced axonal regeneration both in vitro and in vivo, likely by maintaining a healthy mitochondrial population through mitophagy. Similarly, treatment with urolithin A (UA), a natural mitophagy inducer, promoted axon regrowth after injury. Conversely, fundc1 deletion impaired regeneration, an effect reversed by reintroducing wild type (WT) FUNDC1 in neurons but not an MAP1LC3B/LC3 (microtubule associated protein 1 light chain 3 beta)-interacting region (LIR) mutant. Metabolic profiling further demonstrated that FUNDC1-mediated mitophagy drives dorsal root ganglion (DRG) neurons regeneration through enhanced carnosine biosynthesis. Mechanistically, sciatic nerve injury (SNI) in Fundc1 transgenic (TG) mice upregulated NRF1 (nuclear respiratory factor 1) and PPARGC1A/PGC-1α (PPARG coactivator 1 alpha), which stimulated mitochondrial biogenesis and activated Carns1 (carnosine synthase 1) transcription. This increased carnosine biosynthesis, aiding peripheral nerve recovery through its antioxidant effects. Our findings highlighted FUNDC1-mediated mitophagy as a key mechanism in nerve regeneration, linking mitochondrial quality control, metabolic adaptation, and nerve regeneration.Abbreviations: Δψm: mitochondrial membrane potential; DIV: days in vitro; DRG: dorsal root ganglion; KO: knockout; LIR: LC3-interacting region; P60: postnatal day 60; PNS: peripheral nervous system; PSI: post sciatic nerve injury; ROS: reactive oxygen species; SD: standard deviation; SNI: sciatic nerve injury; TEM: transmission electron microscopy; TG: transgenic; TMRE: tetramethylrhodamine ethylester; UA: urolithin A; WT: wild type.

Keywords: Axon regeneration; FUNDC1; NRF1; carnosine; mitochondrial quality; mitophagy

DOI: https://doi.org/10.1080/15548627.2026.2629721

Neuron. 2026 Mar 11. pii: S0896-6273(26)00086-3. [Epub ahead of print]

Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes.

Zhilong Zheng, Wangju Yang, Zhen Chen, Panpan Chen, Mengdan Tao, Shengda Wang, Bowei Cui, Zeyue Yang, Yanqing Yan, Xiao Han, Yongjie Zhang, Zijian Ren, Xiaoxin Yan, Yueqing Jiang, Jing Wang, Tingyou Li, Yan Liu, Xing Guo.

Amyotrophic lateral sclerosis (ALS) is genetically and clinically heterogeneous, yet convergent pathogenic mechanisms remain poorly defined. A CRISPR-Cas9 screen identified phosphoglycerate mutase-5 (PGAM5) as a common mediator of ALS pathogenesis. PGAM5 activates the mitochondrial integrated stress response (mtISR) via dephosphorylation of metallopeptidase OMA1 at Ser223 and Ser237, thereby driving neuromuscular junction disruption and motor deficits. We show that PGAM5 is a substrate of valosin-containing protein (VCP) and is consistently elevated in spinal cords from sporadic ALS patients, in human spinal cord organoids derived from sporadic or familial ALS, and in ALS mouse models. The disruption of PGAM5-OMA1 interaction by a selective inhibitor (TAT-PO1) or pharmacological inhibition of PGAM5 with telmisartan suppresses mtISR activation and ameliorates ALS-related phenotypes by reshaping mtISR outputs in a manner distinct from those elicited by activation of translation initiation factor 2B (eIF2B). These findings establish PGAM5 as a convergent and actionable therapeutic target across ALS subtypes.

Keywords: ALS; NMJ; PGAM5; VCP; amyotrophic lateral sclerosis; mitochondrial integrated stress response; mitochondrial phosphatase phosphoglycerate mutase 5; mtISR; neuromuscular junction; valosin-containing protein

DOI: https://doi.org/10.1016/j.neuron.2026.02.003

Autophagy Rep. 2026 ;5(1): 2638025

Kenny is the adaptor protein for ubiquitin-dependent mitophagy in Drosophila melanogaster.

Hubert Osei Acheampong, Ryan Insolera.

Mitophagy is the selective degradation program for damaged and unnecessary mitochondria to maintain cellular mitostasis and survival. Specific mutations in the mediators for the canonical ubiquitin (ub)-dependent mitophagy pathway have been identified with unique neurological diseases like Parkinson disease and ALS (amyotrophic lateral sclerosis), metabolic diseases, and cancer. Mammalian OPTN (optineurin) has been shown as a SAR (selective autophagy receptor) for ub-dependent mitophagy in vitro with direct connections of its mutations with glaucoma and ALS. Despite the in vitro demonstration of OPTN's role in mitophagy, the in vivo physiological characterization of OPTN's mitophagy function is largely unexplored. In our recent study, we provide in vivo evidence that the Drosophila melanogaster (Dm) protein, Kenny, directly mediates the sequestration of target mitochondria for the progression and completion of ub-dependent mitophagy. This result establishes Kenny as the Dm homolog of OPTN. Previously, Kenny had only been characterized for its role in innate immune activation and modulation. The conclusion from this study provides avenues for further understanding the in vivo signaling regulating Kenny's role in mitophagy and investigating homologous disease-relevant mutations of OPTN in Dm.

Keywords: ALS; Kenny; VPS13D; autophagosome; autophagy; mitochondria; mitophagy adaptor; optineurin; phagophore; ubiquitin

DOI: https://doi.org/10.1080/27694127.2026.2638025

Mol Biol Cell. 2026 Mar 11. mbcE25070334

ATG9B Regulates Mitochondrial Integrity and Apoptotic Tumor Cell Death.

Hong Cao, Lixia Guo, Jing Chen, Eugene Krueger, Gina Razidlo, Mark A McNiven.

It is well established that many tumor types possess defective autophagic pathways. Several studies have reported that the transmembrane, autophagic lipid scramblase ATG9B is altered in multiple cancers, suggesting that this dysregulation could contribute to oncogenesis. Therefore, the goal of this study was to define the cellular distribution of ATG9B in two different tumor cell types and to provide insights into its cellular function. Surprisingly, we found that ATG9B shows a modest association with autophagic structures and exhibits a unique and prominent localization to mitochondria, in contrast to its related form ATG9A. Upon expression of tagged ATG9B forms, this mitochondrial distribution was accompanied by aberrant changes in mitochondrial morphology as well as a reduction in the mitochondrial membrane potential and the release of mtDNA. Few indicators for ATG9B-dependent mitophagy were noted. Instead, ATG9B overexpression led to pronounced apoptotic cell death as assessed by a variety of indicators. Further, we find that the N-terminal sequence of ATG9B acts as a mitochondrial targeting domain and that expression of this peptide alone can induce apoptotic cell death. These findings provide new insights into a putative cellular localization and function for ATG9B. [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-07-0334

Exp Mol Med. 2026 Mar 13.

TANK-binding kinase 1 protects against MASH progression via mitochondrial quality control.

Sung-Min An, Jun Hee Jang, Jin Hyun Sung, Ji Won Myung, Yong Geun Jeon, Won Taek Lee, Jin Won Jeon, Kyung Min Yim, Jae-Ho Lee, Bichen Zhang, Jong Bae Seo, Seung Soon Im, Jae Bum Kim, Alan R Saltiel, Jin Young Huh.

Mitochondrial dysfunction is a critical driver of metabolic dysfunction-associated steatotic liver disease progression to steatohepatitis (MASH), yet the mechanisms governing mitochondrial quality control in hepatocytes remain poorly defined. Here we identify TANK-binding kinase 1 (TBK1) as an essential regulator of hepatic mitophagy and lysosomal activity. Using TBK1-deficient hepatocytes and liver-specific TBK1-knockout mice, we show that TBK1 loss leads to the accumulation of depolarized, reactive oxygen species-producing mitochondria due to impaired mitophagy flux, including defective lysosomal degradation. Mechanistically, TBK1 is required for p62 phosphorylation at Ser403 and partially modulates mTOR signaling to preserve lysosomal activity. Notably, both human samples and murine steatohepatitis models exhibited a substantial decline in TBK1 kinase activity. Therapeutic restoration of TBK1 expression via AAV8 delivery in MASH mouse model enhanced mitophagy, reduced mitochondrial burden and ameliorated liver fibrosis. Collectively, these findings establish TBK1 as a critical guardian of mitochondrial and lysosomal homeostasis in MASH.

DOI: https://doi.org/10.1038/s12276-026-01672-9