bims-nenemi 2025-10-12 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–10–12
fifteen papers selected by
Marco Tigano, Thomas Jefferson University

Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.
A bioinformatics pipeline for identifying homoplasmic and heteroplasmic mitochondrial DNA SNVs in single-cell RNA-Seq datasets.
Targeting mitochondrial translation and OXPHOS in high-grade serous ovarian carcinoma eliminates stem-like cells.
The biophysical mechanism of mitochondrial pearling.
Mycobacterium bovis induces macrophage mitochondrial release of hexokinase 2 to enhance intracellular survival.
Advances in mitochondria-nucleus crosstalk in septic cardiomyopathy.
PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.
PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.
Acidosis orchestrates adaptations of energy metabolism in tumors.
Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke.
Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
Multifaceted mitochondria in innate immunity.

Science. 2025 Oct 09. 390(6769): 156-163

Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.

Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.

Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.

DOI: https://doi.org/10.1126/science.adr5438
Cell Death Dis. 2025 Oct 06. 16(1): 693

The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.

Jule Gerlach, Paola Pireddu, Xiaoqun Zhang, Simon Wetzel, Mara Mennuni, Dusanka Milenkovic, Hendrik Nolte, Fernanda da Silva Rodrigues, Niclas Branzell, Ibrahim Kaya, Rodolfo Garcia Villegas, Diana Rubalcava-Gracia, David Alsina, Regina Feederle, Per E Andrén, Thomas Langer, Per Svenningsson, Roberta Filograna.

The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the genes encoding these proteins have been linked to severe disorders, including Parkinson's disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increase, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.

DOI: https://doi.org/10.1038/s41419-025-08030-z
Genomics. 2025 Oct 06. pii: S0888-7543(25)00138-7. [Epub ahead of print] 111122

A bioinformatics pipeline for identifying homoplasmic and heteroplasmic mitochondrial DNA SNVs in single-cell RNA-Seq datasets.

Zhiling Guan, Patrick Lindsey, Rick Kamps, Hubert J M Smeets.

  Mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) are associated with various pathologies, predominantly in energy-demanding tissues like muscles and brain. Characterizing these SNVs at the single-cell level is crucial for understanding their mechanism and clinical manifestation. Publicly available single-cell RNA sequencing (scRNA-seq) data could be an invaluable resource, but existing pipelines fall short in reliable detection of mtDNA SNVs from scRNA-seq data. Therefore, we developed a novel bioinformatics pipeline, that includes quality control, alignment to the mitochondrial genome, SNV calling, and annotation, and that filters-out sequencing errors. Coverage-dependent thresholds are customizable for detecting heteroplasmic SNVs. Duplicate reads can be retained as the majority were valid biological duplicates. Strand bias errors, exceeding a 1:3 ratio, RNA modification-induced errors, identified by the presence of multiple alternative alleles at the same position, and overrepresented SNVs were removed. Our data demonstrated that this pipeline effectively detects homoplasmic and heteroplasmic mtDNA SNVs in scRNA-Seq data.

Keywords:  Mitochondrial DNA; SNVs calling; Single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.ygeno.2025.111122
Cell Death Dis. 2025 Oct 06. 16(1): 676

Targeting mitochondrial translation and OXPHOS in high-grade serous ovarian carcinoma eliminates stem-like cells.

Aravindan Narayanan, Souvik Guha, Avinash Mali, Sharmila A Bapat.

Ex vivo stem cell self-renewal and maintenance is supported by absence of serum-derived mitogens. In the present study, we sought to elucidate the proteomes of stem-like cells grown in serum-free media across a panel of high-grade serous ovarian cancer cell lines, which encompass a gradient from epithelial, intermediate and mesenchymal cell phenotypes to recapitulate the heterogeneity of the disease. MaxQuant-based label-free quantification of proteins identified that despite their different cellular and molecular architectures, all phenotypes exhibited mitochondria- and stemness-related pathways under conditions of serum starvation, although the specific proteins involved were discrete to each phenotype. This suggests that common cellular programs in a disease can be mediated through variable biological networks that generates molecular heterogeneity. We further explored if these pathways are inter-related, co-regulated or just incidentally associated in response to an environment depleted of growth factors and mitogens. Irrespective of their phenotype, cell lines on serum-starvation displayed an increased amount of mitochondrial DNA, mitochondrial biogenesis and mitochondrial activity with a switch from glycolysis to oxidative phosphorylation fuelled by the fatty acid oxidation. Ultra-structural studies implicated this metabolic fluctuation was regulated by dynamic mitochondrial remodelling. This also led us to explore a possible therapeutic strategy of targeting mitochondrial function to restrict tumor regenerative potential and disease recurrence. Conclusively, these new avenues contribute to a more comprehensive understanding of ovarian cancer.

DOI: https://doi.org/10.1038/s41419-025-07987-1
Mol Biol Cell. 2025 Oct 08. mbcE25060302

The biophysical mechanism of mitochondrial pearling.

Gabriel Sturm, Kayley Hake, Austin E Y T Lefebvre, Caleb J Rux, Daria Ivanova, Alfred Millett-Sikking, Kevin M Tharp, Beiduo Rao, Michael Closser, Adam James Waite, Magdalena Precido-Lopez, Alex T Ritter, Sophie Dumont, Wen Lu, Suliana Manley, Juan C Landoni, Wallace F Marshall.

Mitochondrial networks exhibit remarkable dynamics that are driven in part by fission and fusion events. However, there are other reorganizations of the network that do not involve fission and fusion. One such exception is the elusive, "beads-on-a-string" morphological transition of mitochondria. During such transitions, the cylindrical tubes of the mitochondrial membrane transiently undergo shape changes to a string of "pearls" connected along thin tubes. These dynamics have been observed in many contexts and given disparate explanations. Here we unify these observations by proposing a common underlying mechanism based on the biophysical properties of tubular fluid membranes for which it is known that, under particular regimes of tension and pressure, membranes reach an instability and undergo a shape transition to a string of connected pearls. First, we use high-speed light-sheet microscopy to show that transient, short-lived pearling events occur spontaneously in the mitochondrial network in every cell type we have examined, including during T cell activation, neuronal firing, and replicative senescence. This high-temporal data reveals two distinct classes of spontaneous pearling, triggered either by ionic flux or cytoskeleton tension. We then induce pearling with chemical, genetic, and mechanical perturbations and establish three main physical causes of mitochondrial pearling, i) ionic flux producing internal osmotic pressure, ii) membrane packing lowering bending elasticity, and iii) external mechanical force increasing membrane tension. Pearling dynamics thereby reveal a fundamental biophysical facet of mitochondrial biology. We suggest that pearling should take its place beside fission and fusion as a key process of mitochondrial dynamics, with implications for physiology, disease, and aging.

DOI: https://doi.org/10.1091/mbc.E25-06-0302
Cell Rep. 2025 Oct 08. pii: S2211-1247(25)01192-1. [Epub ahead of print]44(10): 116421

Mycobacterium bovis induces macrophage mitochondrial release of hexokinase 2 to enhance intracellular survival.

Lin Li, Yulan Chen, Yuanzhi Wang, Yuhui Dong, Haoran Wang, Ziyi Liu, Xin Ge, Puxiu Shen, Yue Li, Dingpu Liu, Xiangmei Zhou.

  Hexokinases (HKs) are essential enzymes in sugar metabolism, but their mitochondrial release also reflects cellular status in disease. Mycobacterium bovis (M. bovis), the causative agent of bovine and human tuberculosis, infects macrophages and induces mitophagy, yet the role of HKs in this process remains unclear. We find that M. bovis infection induces the release of HK2 from mitochondria, where it dissociates from voltage-dependent anion channel (VDAC). This dissociation promotes VDAC oligomerization, pore formation in the outer mitochondrial membrane, and mitochondrial damage. Damaged mitochondria subsequently undergo mitophagy, which enhances the intracellular survival of M. bovis. Consistent with this mechanism, we show that ESAT6-mediated phagosome membrane rupture is critical for HK2 release and subsequent mitochondrial events. Our study identifies a pathway by which M. bovis manipulates host cell processes to promote survival, providing insights into the host-pathogen interaction and potential avenues for tuberculosis prevention and therapy.

Keywords:  CP: Microbiology; Mycobacterium bovis; VDAC; autophagy; hexokinase; macrophage; mitochondria; mitophagy; tuberculosis

DOI:  https://doi.org/10.1016/j.celrep.2025.116421
Cell Biol Toxicol. 2025 Oct 06. 41(1): 136

Advances in mitochondria-nucleus crosstalk in septic cardiomyopathy.

Wei Chen, Zeze Zhao, Zhengguang Geng, Han Zhang, Xiaoyun Fu.

  Sepsis-induced cardiomyopathy (SICM), a critical contributor to the high mortality rate associated with sepsis, involves complex pathophysiological mechanisms that remain incompletely elucidated. In recent years, dysregulation of bidirectional signaling communication between mitochondria and the nucleus has been recognized as a pivotal factor in the pathogenesis of SICM. The anterograde signaling pathways-including the PGC-1α/NRF1/NRF2 axis, SIRT3-mediated deacetylation, and TFAM-dependent mitochondrial DNA (mtDNA) maintenance-are suppressed by inflammation and metabolic disturbances. This suppression leads to impaired mitochondrial biogenesis and disrupted energy metabolism. Concurrently, within retrograde signaling pathways, molecular mediators such as reactive oxygen species (ROS), mtDNA, and calcium signaling activate pro-inflammatory and apoptotic pathways, notably NF-κB and cGAS-STING. This activation establishes a vicious cycle perpetuating inflammation and cellular damage. Although current targeted interventions aimed at modulating mitochondrial-nuclear crosstalk have demonstrated some efficacy in animal models, their clinical translation faces significant challenges. These include the dynamic nature of the disease, substantial interindividual variability, and difficulties in achieving targeted delivery. This review summarizes the mechanisms of mitochondrial-nuclear bidirectional signaling in SICM and explores potential therapeutic targets, aiming to provide novel insights for SICM treatment strategies.

Keywords:  Anterograde signaling; Mitochondrial dysfunction; Mitochondria–nucleus crosstalk; Retrograde signaling; Sepsis-induced cardiomyopathy

DOI:  https://doi.org/10.1007/s10565-025-10090-y
Cell Death Dis. 2025 Oct 06. 16(1): 700

PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.

Shiyi Yin, Yibo Zhai, Run Song, Jiannan Wu, Yongjiang Zhang, Miao Yu, Hongxia Ma, Mengmeng Shen, Xiaoyi Lai, Weina Jin, Yunqi Xu, Junqiang Yan.

Parkinson's disease (PD) involves both mitochondrial dysfunction and Lewy body pathology. However molecular links between these features remain unclear. Here, we identify Presenilin-associated rhomboid-like protein (PARL) as a Lewy body component, RARL regulates mitochondrial apoptosis via interacting with orphan nuclear receptor Nur77. Clinical profiling revealed reduced plasma PARL levels in 71 PD patients versus controls (p < 0.001), which correlated with disease severity. In MPP+/MPTP models, PARL depletion amplified BAX activation and caspase-3 cleavage, driving neuronal death. Mechanistically, mitochondrial translocation of Nur77 stabilized PARL-BCL-2 complexes, suppressing apoptosis. AlphaFold2-guided structural modeling uncovered a PARL α-helix essential for Nur77 binding. Disrupting this interface abolished BCL-2 stabilization. Parl knockdown exacerbated motor/cognitive deficits in MPTP mice, rescued by Nur77 overexpression. Subcellular tracking demonstrated Nur77 nuclear-cytoplasmic shuttling dynamically regulates PARL-BCL-2 assembly, while co-immunoprecipitation confirmed Nur77 knockdown dissociates this complex. Our findings define the Nur77-PARL axis as a critical mitochondrial gatekeeper in PD, where PARL serves dual roles as a Lewy body constituent and apoptosis regulator. Reduced circulating PARL levels may reflect disease progression, while the Nur77-PARL structural interface offers a therapeutic target for neuroprotection. This study bridges Lewy body biology with mitochondrial apoptosis. It proposes biomarker-driven strategies to modulate BCL-2-dependent neuronal survival in PD. Schematic summary. In normal neuronal cells, PARL can inhibit the release of apoptotic signals by interacting with Nur77. In the MPP+-induced PD model, PARL expression is reduced inhibits the apoptosis of dopaminergic neurons, and reduces cell viability. Mechanistic schema: Normal state: PARL-Nur77 complex stabilizes mitochondrial membrane integrity, inhibiting BCL-2 ubiquitination. MPP+ injury: PARL downregulation disrupts Nur77 binding, triggering BAX oligomerization and caspase-3 activation. Therapeutic rescue: Nur77 overexpression restores PARL-mediated anti-apoptotic signaling.

DOI: https://doi.org/10.1038/s41419-025-08035-8
J Cell Sci. 2025 Oct 09. pii: jcs.263903. [Epub ahead of print]

PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.

Sudeshna Nag, Kaitlin Szederkenyi, Christopher M Yip, G Angus McQuibban.

  Mitochondrial dynamics relies on the function of dynamin family GTPase proteins including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and dynamin-related protein 1 (DRP1). The mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) protein can regulate the phosphorylation levels and the function of both MFN2 and DRP1, however, the precise regulation of PGAM5 activity is unknown. We show that PGAM5 oligomerization and localization controls its function. Under depolarization and/or metabolic stress PGAM5 changes its association from dodecamers to dimers. These PGAM5 oligomers have differential affinity towards MFN2 and DRP1. Simultaneously, PGAM5 is cleaved by the inner mitochondrial membrane resident proteases PARL and OMA1 and a fraction of the cleaved PGAM5 translocates to the cytosol. These two events play an important role in regulating mitochondrial dynamics under depolarization and/or metabolic stress. Taken together, our results identify PGAM5 oligomerization and cleavage-induced relocalization as critical regulators of its function.

Keywords:  DRP1; Glucose-Starvation; MFN2; Mitochondrial morphology; PGAM5

DOI:  https://doi.org/10.1242/jcs.263903
Science. 2025 Oct 09. 390(6769): eadp7603

Acidosis orchestrates adaptations of energy metabolism in tumors.

Sven Groessl, Robert Kalis, Marteinn T Snaebjornsson, Leon Wambach, Jakob Haider, Florian Andersch, Almut Schulze, Wilhelm Palm, Johannes Zuber.

Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal-regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.

DOI: https://doi.org/10.1126/science.adp7603
Neurosci Lett. 2025 Oct 06. pii: S0304-3940(25)00299-X. [Epub ahead of print]868 138410

Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke.

Pallab Bhattacharya, Shailendra Saraf, Anirban Barik, Bijoyani Ghosh, Aishika Datta, Davendra Singh Malik.

  The crucial influence of mitochondria in ischemic stroke pathophysiology presents many unexplored yet promising avenues for therapeutic strategies and clinical outcomes. Post-stroke mitochondrial dysfunction contributes to aggravated levels of calcium overload and apoptosis. This dysfunction is signified by disruption of the mitochondrial lipids such as cardiolipin, along with mitochondrial DNA mutation, leading to an imbalance in mitophagy. Calcium overload-mediated calcineurin overexpression has been reported to exacerbate mitochondrial damage and further contribute to neuronal apoptosis. In our study, we explored the alterations in the mitochondrial function following inhibition of the calcium-mediated calcineurin levels in post-stroke condition. In a rodent model of middle cerebral artery occlusion (MCAo), we observed that the inhibition of the calcium channels in post-stroke condition led to restored neuronal histology and viability following upregulation of the antioxidant levels. At the mitochondrial level, calcium channel inhibition downregulated calcineurin activation and normalized cardiolipin concentration, mitochondrial membrane potential, and respiratory control ratio in post-stroke condition. This inhibition also balanced the mitochondrial dynamics proteins and mitophagy towards neuronal recovery following ischemic stress. Moreover, it also normalized the expression of TERT, a key marker of mitochondrial health and aging. These findings highlight the role of calcium-mediated calcineurin in influencing mitochondrial dysfunction and aging in ischemic stroke. Thus, calcium channel inhibition offers a promising therapeutic strategy by preserving mitochondrial integrity and promoting neuroprotection following stroke.

Keywords:  Calcineurin; Calcium signaling; Cardiolipin; Mitochondrial aging; Stroke

DOI:  https://doi.org/10.1016/j.neulet.2025.138410
Nat Commun. 2025 Oct 10. 16(1): 9053

Quantitative cellular characterization of extracellular mitochondria uptake and delivery.

Zahra Al Amir Dache, Maud Chevé, Julia Dancourt, Grégory Lavieu.

Mitochondria are essential intracellular organelles responsible for energy production. Over the past two decades, unconventional intercellular mitochondrial transfer has been reported, but the nature of the transport intermediates, the efficiency of the process, and the cellular mechanisms involved in their uptake and putative integration by acceptor cells remain poorly understood. This gap in knowledge is especially significant given the potential therapeutic applications of mitochondrial transplantation. In this study, we use quantifiable cell biology and biochemical approaches to assess intercellular mitochondria exchange. Our findings suggest that low amount of free mitochondria can be released into conditioned media and subsequently internalized by recipient cells, primarily via fluid-phase uptake, although alternative or concurrent endocytic pathways may also contribute. Notably, we show that a subset of internalized mitochondria escapes the endosomal compartment, reaches the cytosol, and may integrate into the host cell's pre-existing mitochondrial network.

DOI: https://doi.org/10.1038/s41467-025-64147-x
Nat Commun. 2025 Oct 08. 16(1): 8952

Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.

Vidhi Pareek, Stephen Benkovic.

Cancer cells have the unique capability to upregulate the de novo nucleotide biosynthesis supporting cell survival under nucleotide deprivation. We probe the role of metabolic channeling and membrane-less metabolic compartmentalization by mitochondria-proximal dynamic de novo pyrimidine and purine biosynthesis metabolons, the pyrimidinosome and the purinosome, respectively. We designed in-cell stable isotope label incorporation assays (13C6 glucose, 15N2 glutamine) for detection of metabolic channeling, revealing the function and enzymatic composition of these complexes. Moreover, we discovered that the mitochondrially compartmentalized GOT2 dependent generation of aspartic acid feeds the channeled nucleotide synthesis instead of the bulk cytosolic pool or the GOT1 activity. While a low flux diffusive pathway generates the pathway intermediates in an accumulative process, it's the channeled pathway that successfully generates the end product nucleotides. Our results demonstrate how metabolic channeling and efficient de novo nucleotide biosynthesis is fueled by coordination of mitochondrially compartmentalized metabolic events with cytosolic metabolons in cancer cells.

DOI: https://doi.org/10.1038/s41467-025-64013-w
Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2508809122

STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.

Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.

  The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.

Keywords:  cholesterol; intermembrane space; lipoid congenital adrenal hyperplasia; mitochondria; steroidogenesis

DOI:  https://doi.org/10.1073/pnas.2508809122
NPJ Metab Health Dis. 2024 May 27. 2(1): 6

Multifaceted mitochondria in innate immunity.

Eloïse Marques, Robbin Kramer, Dylan G Ryan.

The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.

DOI: https://doi.org/10.1038/s44324-024-00008-3