Mitochondria shed their outer membrane in response to infection-induced stress

Li, Xianhe; Straub, Julian; Medeiros, Tania; Mehra, Chahat; Brave, Fabian den; Peker, Esra; Atanassov, Ilian; Stillger, Katharina; Michaelis, Jonas B.; Burbridge, Emma; Adrain, Colin; Münch, Christian; Riemer, Jan; Becker, Thomas; Pernas, Lena

doi:10.1126/science.abi4343

Cited by 71 publications

(48 citation statements)

References 60 publications

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“…Loss of HSPA9 led to the accumulation of full-length PINK1 (Supplementary Fig. 2c), while PINK1 knock-out cells 28 exhibited a significantly reduced mitophagic flux, demonstrating that HSPA9 depletion triggered a PINK1-dependent mitophagy pathway (Fig. 2c).…”

Section: Decreased Mitochondrial Protein Import Induces Mitophagy Wit...mentioning

confidence: 91%

Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy

et al. 2022

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Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the mitochondrial outer membrane. Strikingly, a number of conditions, including mitochondrial protein misfolding, can induce mitophagy without a loss in membrane potential. The underlying molecular details remain unclear. Here, we report that a loss of mitochondrial protein import, mediated by the pre-sequence translocase-associated motor complex PAM, is sufficient to induce mitophagy in polarized mitochondria. A genome-wide CRISPR/Cas9 screen for mitophagy inducers identifies components of the PAM complex. Protein import defects are able to induce mitophagy without a need for depolarization. Upon mitochondrial protein misfolding, PAM dissociates from the import machinery resulting in decreased protein import and mitophagy induction. Our findings extend the current mitophagy model to explain mitophagy induction upon conditions that do not affect membrane polarization, such as mitochondrial protein misfolding.

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Section: Decreased Mitochondrial Protein Import Induces Mitophagy Wit...mentioning

confidence: 91%

Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy

et al. 2022

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“…Of note, mitochondrial outer membrane shedding has been reported in response to infection-induced stress. It has also been discussed as a potential mechanism for DNA damage induction in SARS-CoV-2-infected cells, where the viral protein Orf9b is thought to inhibit the translocase of the mitochondrial outer membrane complex 53 , 54 . Collectively, these observations indicate that ROS levels appear to play a crucial role in triggering VIS in the context of SARS-CoV-2 infection.…”

Section: Virus-evoked Cellular Stressmentioning

confidence: 99%

COVID-19 and cellular senescence

et al. 2022

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The clinical severity of coronavirus disease 2019 (COVID-19) is largely determined by host factors. Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a critical regulator of SARS-CoV-2-evoked hyperinflammation. SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP), which is comprised largely of pro-inflammatory, extracellular matrix-degrading, complement-activating and pro-coagulatory factors secreted by senescent cells. These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues. SASP factors can contribute to a ‘cytokine storm’, tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis. SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion and can further amplify the SASP by increasing the burden of senescent cells. Preclinical and early clinical studies indicate that targeted elimination of senescent cells may offer a novel therapeutic opportunity to attenuate clinical deterioration in COVID-19 and improve resilience following infection with SARS-CoV-2 or other pathogens.

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“…Photodynamic therapy (PDT) involves the exploration of tumor-localized photosensitizers (PSs), which can absorb a laser with a specific wavelength and generate a large number of cytotoxic reactive oxygen species (ROS), especially singlet oxygen species (SO) as the main ROS, thus causing the destruction of cancer cells and blood vessels. − For effective PDT, polymeric drug delivery nanoparticles (NPs) are widely used to realize the tumor-targeted delivery of PSs, because the nonspecific activation of PSs could also induce SO generation in normal tissues upon exposure to light. − In addition, owing to the short life span (<0.1 ms) and low diffusion radius of ROS (<20 nm) in biological systems, it would be ideal to deliver PSs not only into tumor cells but also to those critical subcellular organelles that are most vulnerable to ROS . Mitochondrion, acting as a cell energy house, such as aerobic respiration and ATP synthesis, has a tight relationship with apoptosis. , Mitochondria-targeting phototherapy that directs the photo-absorbed agents to the mitochondria of cancerous cells has been proposed to improve PDT efficacy . Decorated NPs with mitochondrial-targeting anchors, in which the case in point was the lipophilic cationic ligand triphenylphosphonium (TPP), have been accepted as effective methods to deliver PSs into mitochondria. , However, the highly positive charge of TPP in NPs could cause a severe aggregation in blood circulation.…”

Section: Introductionmentioning

confidence: 99%

Light-Activated Reactive Oxygen Species-Responsive Nanocarriers for Enhanced Photodynamic Immunotherapy of Cancer

Peng

et al. 2022

Langmuir

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Exploring polymeric nanoplatforms combined with reactive oxygen species (ROS) responsiveness with mitochondria targeting has emerged as an effective strategy for enhanced photodynamic therapy (PDT). Amphiphilic copolymers were synthesized by reacting acrylamide thioketal (TK) linkers with amino-terminated triphenylphosphonium-polyethylene glycol and dodecylamine for encapsulating chlorin e6 (Ce6) via self-assembly. Then, anionic cladding with tumor targeting deshelled in tumor acidic microenvironments was surface-anchored by electrostatic forces (BioPEGDMA@RM). After sequential targeting to the mitochondria of cancerous cells, BioPEGDMA@RM could be light-activated with Ce6 released upon ROS cleavage of TK linkages. It was found that Ce6-loaded BioPEGDMA@RM exhibited higher cytotoxicity on CT26 cells and performed stronger ability on the production of ROS than that without TK linkers. Moreover, a minimum illumination of 3 and 5 min could be required for achieving the maximum release of Ce6 and high in vitro cytotoxicity for Ce6-loaded BioPEGDMA@RM, respectively. Furthermore, Ce6-loaded BioPEGDMA@RM showed 1.29-fold and 1.21-fold higher tumor inhibition on BALB/c nude mice and Kunming mice and stimulated immunologic reactions with more generation of IFN-γ and TNF-α and activation of CD3 + , CD4 + , and CD8 + T-lymphocytes and DCs than that of Ce6-loaded nanoparticles without TK bonds. This work provided an academic reference for the development of ROS-responsive drug delivery systems for advanced PDT efficiency.

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Mitochondria shed their outer membrane in response to infection-induced stress

Cited by 71 publications

References 60 publications

Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy

Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy

COVID-19 and cellular senescence

Light-Activated Reactive Oxygen Species-Responsive Nanocarriers for Enhanced Photodynamic Immunotherapy of Cancer

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