bims-tofagi 2026-08-23 papers

Issue of 2026–08–23
six papers selected by
Michele Frison, University of Cambridge

Alzheimers Dement. 2026 Aug;22(8): e71680

A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.

Sofie Lautrup, Shu-Qin Cao, Xi Long, Bonnie Hei Man Liu, Beatriz Escobar-Doncel, Aristide Ferrante, Johannes Frank, Tomas Schmauck-Medina, Geoffrey Ho Duen Leung, Kristina Xiao Liang, Ning Lu, Katerina Veverova, Martin Vyhnalek, Frank W Pun, Alex Zhavoronkov, Evandro Fei Fang.

INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD+) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD+-mitophagy axis contributes to brain aging and neurodegeneration.
METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD+-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.
RESULTS: The NAD+-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.
DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD+-mitophagy axis as a central player in brain aging and AD.

Keywords: AD; ALS; HD; NAD+; PD; PandaOmics; aging; artificial intelligence; machine learning; mitophagy

DOI: https://doi.org/10.1002/alz.71680

EMBO J. 2026 Aug 15.

FAF1 and FAF2 enhance unfolding by p97-UFD1-NPL4 complex enabling rational design of p97 activators.

Pritha Dasgupta, Ian R Kelsall, Gaurav Anand, Anna Pérez-Ràfols, Thomas A Jowitt, Axel Knebel, Robert Gourlay, Glenn R Masson, Yogesh Kulathu.

VCP/p97 is an AAA+ ATPase that, together with its cofactors UFD1-NPL4 (p97-UN), unfolds ubiquitylated substrates to maintain cellular homeostasis. The human p97-UN complex associates with additional cofactors, but how these cofactors modulate p97-UN activity is not fully understood. Here, we screen cofactors and identify FAF2 to potently enhance substrate unfolding by p97-UN. Using biochemical and structural approaches, we show how FAF2 engages p97-UN and polyubiquitin to promote unfolding. We define a conserved activation motif in FAF2 that contacts both UFD1 and the ubiquitin proximal to the initiator, thereby stabilizing and supporting the unfolding of the initiator ubiquitin in a UFD1-dependent manner. We leverage the features of the FAF2 activation motif to engineer de novo proteins that potently enhance unfolding, providing a rational strategy to boost p97 activity. Our findings reveal how cofactors can provide additional adaptive control, fine-tuning human p97 activity to unfold challenging substrates and those modified with short ubiquitin chains.

DOI: https://doi.org/10.1038/s44318-026-00894-x

J Am Chem Soc. 2026 Aug 19. 148(32): 34311-34319

De Novo-Designed Bifunctional Proteins for Targeted Protein Degradation.

Bram Mylemans, Boguslawa Korona, Amanda M Acevedo-Jake, Ailsa MacRae, Thomas A Edwards, Danny T Huang, Andrew J Wilson, Laura S Itzhaki, Derek N Woolfson.

In targeted protein degradation (TPD), specific subcellular proteins are removed by routing them to the ubiquitin-proteasome, autophagy, or lysosome machinery. For instance, proteolysis-targeting chimeras (PROTACs) are synthetic heterobifunctional small molecules that simultaneously bind the target and an E3 ubiquitin ligase to drive ubiquitination and degradation by the proteasome. Despite considerable success, designing such molecules is challenging, and the number of currently addressable ubiquitin E3 ligases is limited. Here, we design a heterobifunctional de novo protein to trigger the degradation of a common cancer target, resulting in a desired phenotypic output. First, we developed a highly stable and adaptable helix-turn-helix scaffold for presenting multiple binding sites. Next, we use computational protein design to incorporate and embellish hot-spot-binding sites to target the antiapoptotic mediators BCL-xL and MCL-1. We show a 75% success rate for creating submicromolar binders against these targets. Crystal structures of the complexes confirmed the designed binding poses. Then, we designed short linear motifs (SLiMs) into the loop of the scaffold to recruit KLHL20 and the ubiquitin ligase machinery. These designs have low micromolar affinity for KLHL20 comparable to that of the natural SLiMs. Moreover, the bifunctionalized proteins degrade BCL-xL in cells, leading to apoptosis.

DOI: https://doi.org/10.1021/jacs.6c07593

Cell Chem Biol. 2026 Aug 20. pii: S2451-9456(26)00283-7. [Epub ahead of print]33(8): 1071-1073

Allosteric rewiring of mitochondrial stress signaling through Miro1.

Layla Drwesh, Julia C Fitzgerald.

In this issue of Cell Chemical Biology, Chandra and colleagues1 demonstrate that allosteric modulation of the mitochondrial protein Miro1 can selectively reprogram mitochondrial stress signaling. Chemical targeting of a single molecular hub can produce distinct responses in disease-relevant cell types, despite acting within a broadly conserved stress pathway.

DOI: https://doi.org/10.1016/j.chembiol.2026.07.011

Autophagy. 2026 Aug 21. 1-10

Dealing with membrane stress through CASM.

Håvard Styrkestad Haukaas, Sven R Carlsson, Alf Håkon Lystad.

Compartments of the endolysosomal and secretory pathways encounter diverse insults - from loss of ion gradients and osmotic imbalance to physical membrane disruption - creating a need for rapid, localized surveillance and response systems. Recent work demonstrates that conjugation of ATG8 to single membranes (CASM) provides such specificity via stress-responsive targeting mechanisms that recruit the ATG8 conjugation machinery through pathways distinct from macroautophagy/autophagy. Here, we review recent advances in how membrane stress is sensed, coupled to CASM initiation, and converted into downstream cellular responses.

Keywords: ATG16L1; ATG16L2; ATG8; STIL; TECPR1; VAIL

DOI: https://doi.org/10.1080/15548627.2026.2717033

Life Sci. 2026 Aug 20. pii: S0024-3205(26)00451-0. [Epub ahead of print]403 124642

Redox-sensitive coordination of mitochondrial quality control: Integrating ROS, NAD+, and Ca2+ signaling in disease.

Ilitch A Marcondes-de-Castro, Thamyres Alves Sales, Thatiany Souza Marinho, Marcia Barbosa Aguila, Carlos A Mandarim-de-Lacerda.

Mitochondrial quality control (QC) preserves cellular homeostasis by coordinating mitochondrial structure, turnover, and bioenergetic function. Rather than operating through isolated pathways, QC is increasingly recognized as an integrated, redox-sensitive network in which reactive oxygen species (ROS), nicotinamide adenine dinucleotide (NAD+), and calcium (Ca2+) signaling regulate mitochondrial dynamics, mitophagy, biogenesis, and, ultimately, cell fate. In this narrative review, we propose a hierarchical framework in which these signaling systems function as interconnected sensors and transducers that determine whether mitochondria undergo repair, adaptive remodeling, or elimination. Under physiological conditions, controlled ROS production, adequate NAD+ availability, and tightly regulated Ca2+ flux promote a balanced mitochondrial fusion and fission, efficient mitophagic turnover, and mitochondrial biogenesis, thereby preserving bioenergetic competence and metabolic flexibility. Mitochondria-associated membranes (MAMs) emerge as key spatial platforms that integrate redox signaling, Ca2+ transfer, and lipid exchange, synchronizing communication between the endoplasmic reticulum and mitochondria. Conversely, persistent redox imbalance, characterized by excessive ROS, NAD+ depletion, and Ca2+ dysregulation, disrupts the coordination of QC pathways, resulting in mitochondrial fragmentation, defective turnover, impaired biogenesis, bioenergetic failure, and activation of apoptotic signaling. We critically discuss the mechanistic interplay among these pathways across metabolic disorders, cardiovascular disease, neurodegeneration, cancer, and aging, highlighting context-dependent adaptive and maladaptive responses. Finally, we identify unresolved questions regarding the spatiotemporal integration of redox signals, tissue-specific regulation of mitochondrial QC, and therapeutic targeting of network-level regulatory nodes. This framework provides a systems-level perspective for understanding how coordinated redox signaling governs mitochondrial adaptation and contributes to disease pathogenesis.

Keywords: Mitochondria-associated membranes; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Redox signaling

DOI: https://doi.org/10.1016/j.lfs.2026.124642