bims-tofagi 2025-03-09 papers

Issue of 2025–03–09
five papers selected by
Michele Frison, University of Cambridge

Nat Neurosci. 2025 Mar 03.

CLEC16A in astrocytes promotes mitophagy and limits pathology in a multiple sclerosis mouse model.

Astrocytes promote neuroinflammation and neurodegeneration in multiple sclerosis (MS) through cell-intrinsic activities and their ability to recruit and activate other cell types. In a genome-wide CRISPR-based forward genetic screen investigating regulators of astrocyte proinflammatory responses, we identified the C-type lectin domain-containing 16A gene (CLEC16A), linked to MS susceptibility, as a suppressor of nuclear factor-κB (NF-κB) signaling. Gene and small-molecule perturbation studies in mouse primary and human embryonic stem cell-derived astrocytes in combination with multiomic analyses established that CLEC16A promotes mitophagy, limiting mitochondrial dysfunction and the accumulation of mitochondrial products that activate NF-κB, the NLRP3 inflammasome and gasdermin D. Astrocyte-specific Clec16a inactivation increased NF-κB, NLRP3 and gasdermin D activation in vivo, worsening experimental autoimmune encephalomyelitis, a mouse model of MS. Moreover, we detected disrupted mitophagic capacity and gasdermin D activation in astrocytes in samples from individuals with MS. These findings identify CLEC16A as a suppressor of astrocyte pathological responses and a candidate therapeutic target in MS.

DOI: https://doi.org/10.1038/s41593-025-01875-9

J Cell Biol. 2025 May 05. pii: e202404009. [Epub ahead of print]224(5):

SNX10 functions as a modulator of piecemeal mitophagy and mitochondrial bioenergetics.

Laura Trachsel-Moncho, Chiara Veroni, Benan John Mathai, Ana Lapao, Sakshi Singh, Nagham Theres Asp, Sebastian W Schultz, Serhiy Pankiv, Anne Simonsen.

We here identify the endosomal protein SNX10 as a negative regulator of piecemeal mitophagy of OXPHOS machinery components. In control conditions, SNX10 localizes to early endocytic compartments in a PtdIns3P-dependent manner and modulates endosomal trafficking but also shows dynamic connections with mitochondria. Upon hypoxia-mimicking conditions, SNX10 localizes to late endosomal structures containing selected mitochondrial proteins, including COX-IV and SAMM50, and the autophagy proteins SQSTM1/p62 and LC3B. The turnover of COX-IV was enhanced in SNX10-depleted cells, with a corresponding reduced mitochondrial respiration and citrate synthase activity. Importantly, zebrafish larvae lacking Snx10 show reduced levels of Cox-IV, as well as elevated ROS levels and ROS-mediated cell death in the brain, demonstrating the in vivo relevance of SNX10-mediated modulation of mitochondrial bioenergetics.

DOI: https://doi.org/10.1083/jcb.202404009

Sci Adv. 2025 Feb 28. 11(9): eadr1938

A long-lived pool of PINK1 imparts a molecular memory of depolarization-induced activity.

Liam Pollock, Ioanna Ch Georgiou, Emma V Rusilowicz-Jones, Michael J Clague, Sylvie Urbé.

The Parkinson's disease-linked kinase, PINK1, is a short-lived protein that undergoes cleavage upon mitochondrial import leading to its proteasomal degradation. Under depolarizing conditions, it accumulates on mitochondria where it becomes activated, phosphorylating both ubiquitin and the ubiquitin E3 ligase Parkin, at Ser65. Our experiments reveal that in retinal pigment epithelial cells, only a fraction of PINK1 becomes stabilized after depolarization by electron transport chain inhibitors. Furthermore, the observed accrual of PINK1 cannot be completely accounted for without an accompanying increase in biosynthesis. We have used a ubiquitylation inhibitor TAK-243 to accumulate cleaved PINK1. Under these conditions, generation of unconjugated "free" phospho-ubiquitin serves as a proxy readout for PINK1 activity. This has enabled us to find a preconditioning phenomenon, whereby an initial depolarizing treatment leaves a residual pool of active PINK1 that remains competent to seed the activation of nascent cleaved PINK1 following a 16-hour recovery period.

DOI: https://doi.org/10.1126/sciadv.adr1938

Cell Death Dis. 2025 Mar 01. 16(1): 145

PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.

Xiayun Xu, Yingji Chen, Siqi Fei, Xinyue Jiang, Xiaoting Zhou, Yimeng Xue, Yao Li, Shi-Min Zhao, Yan Huang, Chenji Wang.

Mitophagy is a selective process that targets the damaged, dysfunctional, or superfluous mitochondria for degradation through autophagy. The SCFFBXL4 E3 ubiquitin ligase complex suppresses basal mitophagy by targeting BNIP3 and BNIP3L, two key mitophagy cargo receptors, for ubiquitin-proteasomal degradation. FBXL4 loss-of-function mutations lead to excessive BNIP3/3L-dependent mitophagy, thereby causing a devastating multi-system disorder called mitochondrial DNA depletion syndrome, type 13 (MTDPS13). PPTC7, a mitochondrial matrix phosphatase, is essential for proper mitochondrial function and biogenesis. Here, we show that a proportion of PPTC7 is located on the outer mitochondrial membrane, where it interacts with FBXL4 and BNIP3/3L. PPTC7 decreases BNIP3/3L protein stability in a protein phosphatase activity-independent manner. Using in vitro cell culture and Pptc7 knockout mouse model, we demonstrate that PPTC7 deficiency activates high levels of basal mitophagy in a BNIP3/3L-dependent manner. Mechanistically, PPTC7 facilitates SCFFBXL4-mediated ubiquitin-proteasomal degradation of BNIP3/3L. Overall, these findings establish PPTC7 as an essential co-factor of the SCFFBXL4 complex and a suppressor of BNIP3/3L-dependent mitophagy.

DOI: https://doi.org/10.1038/s41419-025-07463-w

iScience. 2025 Feb 21. 28(2): 111814

Urolithin A provides cardioprotection and mitochondrial quality enhancement preclinically and improves human cardiovascular health biomarkers.

Sophia Liu, Julie Faitg, Charlotte Tissot, Dimitris Konstantopoulos, Ross Laws, Guillaume Bourdier, Pénélope A Andreux, Tracey Davey, Hector Gallart-Ayala, Julijana Ivanisevic, Anurag Singh, Chris Rinsch, David J Marcinek, Davide D'Amico.

Cardiovascular diseases (CVDs) remain the primary cause of global mortality. Nutritional interventions hold promise to reduce CVD risks in an increasingly aging population. However, few nutritional interventions are proven to support heart health and act mostly on blood lipid homeostasis rather than at cardiac cell level. Here, we show that mitochondrial quality dysfunctions are common hallmarks in human cardiomyocytes upon heart aging and in chronic conditions. Preclinically, the post-biotic and mitophagy activator, urolithin A (UA), reduced both systolic and diastolic cardiac dysfunction in models of natural aging and heart failure. At a cellular level, this was associated with a recovery of mitochondrial ultrastructural defects and mitophagy. In humans, UA supplementation for 4 months in healthy older adults significantly reduced plasma ceramides clinically validated to predict CVD risks. These findings extend and translate UA's benefits to heart health, making UA a promising nutritional intervention to support cardiovascular function as we age.

Keywords: Biological sciences; Cardiovascular medicine; Health sciences; Internal medicine; Medical specialty; Medicine; Natural sciences; Physiology

DOI: https://doi.org/10.1016/j.isci.2025.111814