bims-nenemi 2025-03-23 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–03–23
eight papers selected by
Marco Tigano, Thomas Jefferson University

VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.
Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
Optogenetic tools for inducing organelle membrane rupture.
Definition of the human mitochondrial TOM interactome reveals TRABD as new interacting protein.
Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.
Retinal Pigment Epithelium and Monocytes' Mitochondrial Control of Ferroptosis and its Relevance to Age-Related Macular Degeneration.
In-cell architecture of the mitochondrial respiratory chain.
DNA damage response regulator ATR licenses PINK1-mediated mitophagy.

Nature. 2025 Mar 19.

VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.

Sujing Yuan, Renqiang Sun, Hao Shi, Nicole M Chapman, Haoran Hu, Cliff Guy, Sherri Rankin, Anil Kc, Gustavo Palacios, Xiaoxi Meng, Xiang Sun, Peipei Zhou, Xiaoyang Yang, Stephen Gottschalk, Hongbo Chi.

Tumour cells often evade immune pressure exerted by CD8+ T cells or immunotherapies through mechanisms that are largely unclear1,2. Here, using complementary in vivo and in vitro CRISPR-Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 (VDAC2) as an immune signal-dependent checkpoint that curtails interferon-γ (IFNγ)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS-STING activation, and markedly improved anti-tumour effects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identified BAK as the mediator of VDAC2-deficiency-induced effects. Mechanistically, IFNγ stimulation increased BIM, BID and BAK expression, with VDAC2 deficiency eliciting uncontrolled IFNγ-induced BAK activation and mitochondrial damage. Consequently, mitochondrial DNA was aberrantly released into the cytosol and triggered robust activation of cGAS-STING signalling and type I IFN response. Importantly, co-deletion of STING signalling components dampened the therapeutic effects of VDAC2 depletion in tumour cells, suggesting that targeting VDAC2 integrates CD8+ T cell- and IFNγ-mediated adaptive immunity with a tumour-intrinsic innate immune-like response. Together, our findings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and inflaming tumours to enable efficacious cancer immunotherapy.

DOI: https://doi.org/10.1038/s41586-025-08732-6
Nat Commun. 2025 Mar 19. 16(1): 2685

Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.

Joshua G Pemberton, Krishnendu Roy, Yeun Ju Kim, Tara D Fischer, Vijay Joshi, Elizabeth Ferrer, Richard J Youle, Thomas J Pucadyil, Tamas Balla.

Mitochondrial dynamics are orchestrated by protein assemblies that directly remodel membrane structure, however the influence of specific lipids on these processes remains poorly understood. Here, using an inducible heterodimerization system to selectively modulate the lipid composition of the outer mitochondrial membrane (OMM), we show that local production of diacylglycerol (DAG) directly leads to transient tubulation and rapid fragmentation of the mitochondrial network, which are mediated by isoforms of endophilin B (EndoB) and dynamin-related protein 1 (Drp1), respectively. Reconstitution experiments on cardiolipin-containing membrane templates mimicking the planar and constricted OMM topologies reveal that DAG facilitates the membrane binding and remodeling activities of both EndoB and Drp1, thereby independently potentiating membrane tubulation and fission events. EndoB and Drp1 do not directly interact with each other, suggesting that DAG production activates multiple pathways for membrane remodeling in parallel. Together, our data emphasizes the importance of OMM lipid composition in regulating mitochondrial dynamics.

DOI: https://doi.org/10.1038/s41467-025-57439-9
J Biol Chem. 2025 Mar 18. pii: S0021-9258(25)00270-4. [Epub ahead of print] 108421

Optogenetic tools for inducing organelle membrane rupture.

Yuto Nagashima, Tomoya Eguchi, Ikuko Koyama-Honda, Noboru Mizushima.

  Disintegration of organelle membranes induces various cellular responses and has pathological consequences, including autoinflammatory diseases and neurodegeneration. Establishing methods to induce membrane rupture of specific organelles is essential to analyze the downstream effects of membrane rupture; however, the spatiotemporal induction of organelle membrane rupture remains challenging. Here, we develop a series of optogenetic tools to induce organelle membrane rupture by using engineered Bcl-2-associated X protein (BAX), which primarily functions to form membrane pores in the outer mitochondrial membrane (OMM) during apoptosis. When BAX is forced to target mitochondria, lysosomes, or the endoplasmic reticulum (ER) by replacing its C-terminal transmembrane domain (TMD) with organelle-targeting sequences, the BAX mutants rupture their targeted membranes. To regulate the activity of organelle-targeted BAX, the photosensitive light-oxygen-voltage-sensing 2 (LOV2) domain is fused to the N-terminus of BAX. The resulting LOV2-BAX fusion protein exhibits blue light-dependent membrane-rupture activity on various organelles, including mitochondria, the ER, and lysosomes. Thus, LOV2-BAX enables spatiotemporal induction of membrane rupture across a broad range of organelles, expanding research opportunities on the consequences of organelle membrane disruption.

Keywords:  Bcl-2-associated X protein (BAX); Membrane rupture; light-oxygen-voltage-sensing 2 (LOV2) domain; lysosomal membrane permeabilization (LMP); mitochondrial outer membrane permeabilization (MOMP); optogenetics

DOI:  https://doi.org/10.1016/j.jbc.2025.108421
J Cell Sci. 2025 Mar 19. pii: jcs.263576. [Epub ahead of print]

Definition of the human mitochondrial TOM interactome reveals TRABD as new interacting protein.

Metin Özdemir, Silke Oeljeklaus, Schendzielorz Alexander, Marcel Morgenstern, Anusha Valpadashi, Roya Yousefi, Bettina Warscheid, Sven Dennerlein.

  The mitochondrial proteome arises from dual genetic origin. Nuclear-encoded proteins need to be transported across or inserted into two distinguished membranes, and the TOM complex represents the main translocase in the outer mitochondrial membrane. Its composition and regulations have been extensively investigated within yeast cells. However, we have little knowledge of the TOM complex composition within human cells. Here, we have defined the TOM interactome in a comprehensive manner using biochemical approaches to isolate the TOM complex in combination with quantitative mass spectrometry analyses. Within these studies, we defined the pleiotropic nature of the human TOM complex, including new interactors, such as TRABD. Our studies provide a framework to understand the various biogenesis pathways that merge at the TOM complex within human cells.

Keywords:  Mitochondria; Mitochondrial Biogenesis; Mitochondrial protein import; Mitochondrial quality control; Protein transport; TOM complex

DOI:  https://doi.org/10.1242/jcs.263576
Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00201-3. [Epub ahead of print]44(3): 115430

Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.

Beibei Wu, Jin Seok Woo, Spyridon Hasiakos, Calvin Pan, Shawn Cokus, Cristiane Benincá, Linsey Stiles, Zuoming Sun, Matteo Pellegrini, Orian S Shirihai, Aldon J Lusis, Sonal Srikanth, Yousang Gwack.

  Genetic and environmental factors shape an individual's susceptibility to autoimmunity. To identify genetic variations regulating effector T cell functions, we used a forward genetics screen of inbred mouse strains and uncovered genomic loci linked to cytokine expression. Among the candidate genes, we characterized a mitochondrial inner membrane protein, TMEM11, as an important determinant of Th1 responses. Loss of TMEM11 selectively impairs Th1 cell functions, reducing autoimmune symptoms in mice. Mechanistically, Tmem11-/- Th1 cells exhibit altered cristae architecture, impaired respiration, and increased mitochondrial reactive oxygen species (mtROS) production. Elevated mtROS hindered histone acetylation while promoting neutral lipid accumulation. Further experiments using genetic, biochemical, and pharmacological tools revealed that mtROS regulate acetyl-CoA flux between histone acetylation and fatty acid synthesis. Our findings highlight the role of mitochondrial cristae integrity in directing metabolic pathways that influence chromatin modifications and lipid biosynthesis in Th1 cells, providing new insights into immune cell metabolism.

Keywords:  CP: Immunology; CP: Metabolism; EAE; MICOS complex; Th1 cells; cytokine production; histone acetylation; mitochondria; mitochondrial cristae architecture; neutral lipids; reactive oxygen species

DOI:  https://doi.org/10.1016/j.celrep.2025.115430
Mol Neurobiol. 2025 Mar 18.

Retinal Pigment Epithelium and Monocytes' Mitochondrial Control of Ferroptosis and its Relevance to Age-Related Macular Degeneration.

Mithalesh Kumar Singh, Lata Singh, Shari Atilano, Marilyn Chwa, Nasim Salimiaghdam, M Cristina Kenney.

  Age-related macular degeneration (AMD) is the leading cause of vision impairment among older aged people. Recent studies have indicated that focusing on the underlying mechanism of ferroptosis (a form of iron-dependent cell death) could be crucial in understanding the progression of AMD, as it is strongly linked with inflammation. However, the specific dependence of ferroptosis on the mitochondria in the retinal pigment epithelium (RPE) and its surrounding immune cells remains unclear. In this study, we showed that mitochondria were required for the proliferation and maintenance of the RPE by regulating the expression of genes implicated in both pro- and antiferroptosis activities. Under chemically induced hypoxic conditions, Wt-ARPE-19 cells (basal mitochondrial level) increased the expression of genes linked with antiferroptotic activity. In contrast, rho0-ARPE-19 cells (mitochondria depleted) did not stimulate either pro- or antiferroptosis gene expression. However, diff-ARPE-19 cells (abundant in mitochondria) presented an improved proferroptotic activity. Furthermore, we demonstrated that mitochondria regulated monocyte differentiation into macrophages, resulting in differential expression of pro- and antiferroptotic factors. Through a direct coculture approach, the absence of mitochondria in ARPE-19 cells was shown to influences monocyte differentiation toward an inflammatory phenotype. This differentiation might increase ferroptosis activity. Transmitochondrial cybrids derived from patients with dry AMD and age-matched controls without dry AMD presented elevated mtDNA copy numbers, leading to increased ferritinophagy and increased levels of polyunsaturated fatty acids. These data highlighted that ferroptosis was partly regulated by mitochondria and that understanding the mechanisms governing the relationship between mitochondria and ferroptosis may open new potential avenues for managing dry AMD.

Keywords:   rho0 ; Cybrids; Differentiated ARPE-19; Dry-age macular degeneration; Ferroptosis; Mitochondria; Monocytes

DOI:  https://doi.org/10.1007/s12035-025-04832-6
Science. 2025 Mar 21. 387(6740): 1296-1301

In-cell architecture of the mitochondrial respiratory chain.

Florent Waltz, Ricardo D Righetto, Lorenz Lamm, Thalia Salinas-Giegé, Ron Kelley, Xianjun Zhang, Martin Obr, Sagar Khavnekar, Abhay Kotecha, Benjamin D Engel.

Mitochondria regenerate adenosine triphosphate (ATP) through oxidative phosphorylation. This process is carried out by five membrane-bound complexes collectively known as the respiratory chain, working in concert to transfer electrons and pump protons. The precise organization of these complexes in native cells is debated. We used in situ cryo-electron tomography to visualize the native structures and organization of several major mitochondrial complexes in Chlamydomonas reinhardtii cells. ATP synthases and respiratory complexes segregate into curved and flat crista membrane domains, respectively. Respiratory complexes I, III, and IV assemble into a respirasome supercomplex, from which we determined a native 5-angstrom (Å) resolution structure showing binding of electron carrier cytochrome c. Combined with single-particle cryo-electron microscopy at 2.4-Å resolution, we model how the respiratory complexes organize inside native mitochondria.

DOI: https://doi.org/10.1126/science.ads8738
Nucleic Acids Res. 2025 Feb 27. pii: gkaf178. [Epub ahead of print]53(5):

DNA damage response regulator ATR licenses PINK1-mediated mitophagy.

Christian Marx, Xiaobing Qing, Yamin Gong, Joanna Kirkpatrick, Kanstantsin Siniuk, Galina V Beznoussenko, Gururaj Rao Kidiyoor, Murat Kirtay, Katrin Buder, Philipp Koch, Martin Westermann, Christopher Bruhn, Eric J Brown, Xingzhi Xu, Marco Foiani, Zhao-Qi Wang.

Defective DNA damage response (DDR) and mitochondrial dysfunction are a major etiology of tissue impairment and aging. Mitochondrial autophagy (mitophagy) is a mitochondrial quality control (MQC) mechanism to selectively eliminate dysfunctional mitochondria. ATR (ataxia-telangiectasia and Rad3-related) is a key DDR regulator playing a pivotal role in DNA replication stress response and genomic stability. Paradoxically, the human Seckel syndrome caused by ATR mutations exhibits premature aging and neuropathies, suggesting a role of ATR in nonreplicating tissues. Here, we report a previously unknown yet direct role of ATR at mitochondria. We find that ATR and PINK1 (PTEN-induced kinase 1) dock at the mitochondrial translocase TOM/TIM complex, where ATR interacts directly with and thereby stabilizes PINK1. ATR deletion silences mitophagy initiation thereby altering oxidative phosphorylation functionality resulting in reactive oxygen species overproduction that attack cytosolic macromolecules, in both cells and brain tissues, prior to nuclear DNA. This study discloses ATR as an integrated component of the PINK1-mediated MQC program to ensure mitochondrial fitness. Together with its DDR function, ATR safeguards mitochondrial and genomic integrity under physiological and genotoxic conditions.

DOI: https://doi.org/10.1093/nar/gkaf178