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Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity

ABSTRACT: Virus-infected cells often exhibit dramatic cellular changes accompanied by altered mitochondrial function. The contribution of factors shaping the inner mitochondrial membrane (IMM) and cristae architecture on viral replication is insufficiently understood. Single cell transcriptomics applying vesicular stomatitis virus (VSV) infection suggests involvement of factors determining IMM architecture following infection. Consistently, inhibition of the F1Fo ATP synthase reduces viral replication which is associated with oligomerization of the complex and altered IMM structure. Moreover, deletion of mitochondrial contact site and cristae organizing system (MICOS) complex by targeting MIC60 results in reduced viral replication. Generation of Mic60inv/inv CD11c-Cre+ mice uncovers reduced crista junctions and viral replication in bone marrow-derived dendritic cells. Consequently, reduced viral replication in CD11c-expressing cells limits prolonged immune activation. Altogether, by linking the F1Fo ATP synthase and the MICOS complex to viral replication and immune activation, we describe links between the mitochondrial structure-metabolism and the immune response against viral infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297187 | GEO | 2025/05/14

REPOSITORIES: GEO

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MICOS and F1FO-ATP synthase crosstalk is a fundamental property of mitochondrial cristae

Project description:Mitochondrial cristae are polymorphic invaginations of the inner membrane that are the fabric of cellular respiration. Both the Mitochondrial Contact Site and Cristae Organization System (MICOS) and the F1FO-ATP synthase are vital for sculpting cristae by opposing membrane bending forces. While MICOS promotes negative curvature at cristae junctions, dimeric F1FO-ATP synthase is crucial for positive curvature at cristae rims. Crosstalk between these two complexes has been observed in baker’s yeast, the model organism of the Opisthokonta supergroup. Here, we report that this property is conserved in Trypanosoma brucei, a member of the Discoba supergroup that separated from Opisthokonta ~2 billion years ago. Specifically, one of the paralogs of the core MICOS subunit Mic10 interacts with dimeric F1FO-ATP synthase, whereas the other core Mic60 subunit has a counteractive effect on F1FO-ATP synthase oligomerization. This is evocative of the nature of MICOS-F1FO-ATP synthase crosstalk in yeast, which is remarkable given the diversification these two complexes have undergone during almost 2 eons of independent evolution. Furthermore, we identified a highly diverged trypanosome homolog of subunit e, which is essential for the stability of F1FO-ATP synthase dimers in yeast. Just like subunit e, it is preferentially associated with dimers, interacts with Mic10 and its silencing results in severe defects to cristae and disintegration of F1FO-ATP synthase dimers. Our findings indicate that crosstalk between MICOS and dimeric F1FO-ATP synthase is a fundamental property impacting cristae shape throughout eukaryotes.

2021-06-15 | PXD025109 | Pride

Mitochondrial cristae architecture protects against mtDNA release and inflammation

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Project description:Mitochondria are the metabolic center and powerhouses of cells by coordinating the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS) and electron transport to generate ATP, which provide energy for cell survival and functional maintenance. This is attributed to the key structure of mitochondria cristae, which are formed by the inward folding of inner mitochondrial membranes. Numerous studies have demonstrated that RNA-binding proteins play an important role in maintaining the normal structure and function of mitochondria. However, the relevant mechanism remains unclear. Here, we report that the RNA-binding protein LARP-1 affects the structure and function of mitochondria by disrupting crista-related proteins, including the MICOS complex, respiratory chain complexes, and the proton-transporting ATP synthase complex. Using APEX-based proximity labeling assays, we pulled down mRNAs associated with LARP-1::APEX2, and determined the identities of mRNAs by sequencing. Among the 653 LARP-1::APEX2-enriched mRNAs, 37.5% (245/653) encode mitochondrial proteins, of which 71.8% (176/245) were identified to be down-regulated in larp-1 mutants by LC-MS analysis of purified mitochondria. In addition, mRNAs encoding components of the MICOS complex, respiratory chain complexes, and ATP synthase complex were strongly enriched, suggesting that they were associated with LARP-1.

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Diverged Trypanosome MICOS as a Hub for Mitochondrial Cristae Shaping and Protein Import

Project description:The mitochondrial contact site and cristae organization system (MICOS) is a complex responsible for proper cristae formation. Empirical data about this ubiquitous complex is limited to opisthokont models (e.g. yeast), impeding understanding of its core properties and adaptation potential to diverse cellular milieus. To close this knowledge gap, we characterized MICOS from the diverged excavate Trypanosoma brucei. These results allow the definition of fundamental MICOS properties, such as its role in maintaining both cristae and contacts between the inner and outer membranes plus its extrusion into the intermembrane space. Yet, surprising differences with opisthokonts indicate that MICOS can assume different forms. T. brucei MICOS contains a novel subunit involved in the import of intermembrane space proteins, including respiratory chain complex assembly factors. We propose an evidence-based hypothesis that T. brucei MICOS populates cristae membranes with proteins needed for respiration, supported by the complex's even distribution in cristae

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Project description:Description: MIC13 is a subunit of the mitochondrial contact site and cristae organizing system (MICOS) and essential for mitochondrial cristae structure. Here we enriched Mic13 by co-Immunoprecipitation and identified interacting proteins.

2025-01-02 | PXD044968 | Pride

Listeria monocytogenes exploits the MICOS complex subunit Mic10 to promote mitochondrial fragmentation and cellular infection

Project description:Mitochondrial function adapts to cellular demands and is affected by the ability of the organelle to undergo fusion and fission in response to physiological and non-physiological cues. We previously showed that infection with the human bacterial pathogen Listeria monocytogenes elicits transient mitochondrial fission and a drop in mitochondrial -dependent energy production through a mechanism requiring the bacterial pore-forming toxin listeriolysin O (LLO). Here, we performed quantitative mitochondrial proteomics to search for host factors involved in L. monocytogenes-induced mitochondrial fission. We found that Mic10, a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex, is significantly enriched in mitochondria isolated from cells infected with wild-type but not with LLO-deficient L. monocytogenes. Increased mitochondrial Mic10 levels did not correlate with upregulated transcription, suggesting a post-transcriptional regulation. We showed that Mic10 is necessary for L. monocytogenes-induced mitochondrial network fragmentation, and that it contributes to L. monocytogenes cellular infection independently of MICOS proteins Mic13, Mic26 and Mic27. Together, L. monocytogenes infection allowed us to uncover a role for Mic10 in mitochondrial fission.

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Project description:Here we analysed the impact of two subunits of the mitochondrial contact site and cristae organizing system (MICOS) complex, MIC26 and MIC27, on the assembly and stability of mitochondrial complexes of the oxidative phosphorylation system (OXPHOS).

2020-07-28 | PXD016733 | Pride

Project description:Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity

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