bims-mitpro 2024-03-31 papers

bims-mitpro

Biomed News

on Mitochondrial Proteostasis

Issue of 2024‒03‒31
six papers selected by
Andreas Kohler, Umeå University

Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.
Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.
OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization.
Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species.
ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor.
A pH-response-based fluorescent probe for detecting the mitophagy process by tracing changes in colocalization coefficients.

Mol Biol Cell. 2024 Mar 27. mbcE24010041

Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.

Nicole Madrazo, Zinia Khattar, Evan T Powers, Jessica D Rosarda, R Luke Wiseman.

Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically-diverse diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria in response to mitochondrial stress. Numerous stress-responsive signaling pathways have been suggested to regulate mitochondria in response to proteotoxic stress. These include the integrated stress response (ISR), the heat shock response (HSR), and the oxidative stress response (OSR). Here, we define the stress signaling pathways activated in response to chronic mitochondrial proteostasis perturbations by monitoring the expression of sets of genes regulated downstream of each of these signaling pathways in published Perturb-seq datasets from K562 cells CRISPRi-depleted of mitochondrial proteostasis factors. Interestingly, we find that the ISR is preferentially activated in response to chronic, genetically-induced mitochondrial proteostasis stress, with no other pathway showing significant activation. Further, we demonstrate that CRISPRi depletion of other mitochondria-localized proteins similarly shows preferential activation of the ISR relative to other stress-responsive signaling pathways. These results both establish our gene set profiling approach as a viable strategy to probe stress responsive signaling pathways induced by perturbations to specific organelles and identify the ISR as the predominant stress-responsive signaling pathway activated in response to chronically disrupted of mitochondrial proteostasis.

DOI: https://doi.org/10.1091/mbc.E24-01-0041
Cell Rep. 2024 Mar 28. pii: S2211-1247(24)00346-2. [Epub ahead of print]43(4): 114018

Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.

Lea Bertgen, Jan-Eric Bökenkamp, Tim Schneckmann, Christian Koch, Markus Räschle, Zuzana Storchová, Johannes M Herrmann.

  Mitochondria consist of hundreds of proteins, most of which are inaccessible to the proteasomal quality control system of the cytosol. How cells stabilize the mitochondrial proteome during challenging conditions remains poorly understood. Here, we show that mitochondria form spatially defined protein aggregates as a stress-protecting mechanism. Two different types of intramitochondrial protein aggregates can be distinguished. The mitoribosomal protein Var1 (uS3m) undergoes a stress-induced transition from a soluble, chaperone-stabilized protein that is prevalent under benign conditions to an insoluble, aggregated form upon acute stress. The formation of Var1 bodies stabilizes mitochondrial proteostasis, presumably by sequestration of aggregation-prone proteins. The AAA chaperone Hsp78 is part of a second type of intramitochondrial aggregate that transiently sequesters proteins and promotes their folding or Pim1-mediated degradation. Thus, mitochondrial proteins actively control the formation of distinct types of intramitochondrial protein aggregates, which cooperate to stabilize the mitochondrial proteome during proteotoxic stress conditions.

Keywords:  CP: Cell biology; CP: Molecular biology; Hsp78; MitoStores; Pim1 protease; Var1 bodies; aggregates; chaperones; mitochondria; mitoribosome; protein folding; protein import

DOI:  https://doi.org/10.1016/j.celrep.2024.114018
J Cell Biol. 2024 May 06. pii: e202306051. [Epub ahead of print]223(5):

OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization.

Magda Krakowczyk, Anna M Lenkiewicz, Tomasz Sitarz, Dominika Malinska, Mayra Borrero, Ben Hur Marins Mussulini, Vanessa Linke, Andrzej A Szczepankiewicz, Joanna M Biazik, Agata Wydrych, Hanna Nieznanska, Remigiusz A Serwa, Agnieszka Chacinska, Piotr Bragoszewski.

Most mitochondrial proteins originate from the cytosol and require transport into the organelle. Such precursor proteins must be unfolded to pass through translocation channels in mitochondrial membranes. Misfolding of transported proteins can result in their arrest and translocation failure. Arrested proteins block further import, disturbing mitochondrial functions and cellular proteostasis. Cellular responses to translocation failure have been defined in yeast. We developed the cell line-based translocase clogging model to discover molecular mechanisms that resolve failed import events in humans. The mechanism we uncover differs significantly from these described in fungi, where ATPase-driven extraction of blocked protein is directly coupled with proteasomal processing. We found human cells to rely primarily on mitochondrial factors to clear translocation channel blockage. The mitochondrial membrane depolarization triggered proteolytic cleavage of the stalled protein, which involved mitochondrial protease OMA1. The cleavage allowed releasing the protein fragment that blocked the translocase. The released fragment was further cleared in the cytosol by VCP/p97 and the proteasome.

DOI: https://doi.org/10.1083/jcb.202306051
Cell Death Differ. 2024 Mar 22.

Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species.

Shun-Ichi Yamashita, Yuki Sugiura, Yuta Matsuoka, Rae Maeda, Keiichi Inoue, Kentaro Furukawa, Tomoyuki Fukuda, David C Chan, Tomotake Kanki.

Mitophagy plays an important role in the maintenance of mitochondrial homeostasis and can be categorized into two types: ubiquitin-mediated and receptor-mediated pathways. During receptor-mediated mitophagy, mitophagy receptors facilitate mitophagy by tethering the isolation membrane to mitochondria. Although at least five outer mitochondrial membrane proteins have been identified as mitophagy receptors, their individual contribution and interrelationship remain unclear. Here, we show that HeLa cells lacking BNIP3 and NIX, two of the five receptors, exhibit a complete loss of mitophagy in various conditions. Conversely, cells deficient in the other three receptors show normal mitophagy. Using BNIP3/NIX double knockout (DKO) cells as a model, we reveal that mitophagy deficiency elevates mitochondrial reactive oxygen species (mtROS), which leads to activation of the Nrf2 antioxidant pathway. Notably, BNIP3/NIX DKO cells are highly sensitive to ferroptosis when Nrf2-driven antioxidant enzymes are compromised. Moreover, the sensitivity of BNIP3/NIX DKO cells is fully rescued upon the introduction of wild-type BNIP3 and NIX, but not the mutant forms incapable of facilitating mitophagy. Consequently, our results demonstrate that BNIP3 and NIX-mediated mitophagy plays a role in regulating mtROS levels and protects cells from ferroptosis.

DOI: https://doi.org/10.1038/s41418-024-01280-y
Biology (Basel). 2024 Feb 26. pii: 146. [Epub ahead of print]13(3):

ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor.

Adrien Corne, Florine Adolphe, Jérôme Estaquier, Sébastien Gaumer, Jean-Marc Corsi.

  Cellular integrated stress response (ISR), the mitochondrial unfolded protein response (UPRmt), and IFN signaling are associated with viral infections. Activating transcription factor 4 (ATF4) plays a pivotal role in these pathways and controls the expression of many genes involved in redox processes, amino acid metabolism, protein misfolding, autophagy, and apoptosis. The precise role of ATF4 during viral infection is unclear and depends on cell hosts, viral agents, and models. Furthermore, ATF4 signaling can be hijacked by pathogens to favor viral infection and replication. In this review, we summarize the ATF4-mediated signaling pathways in response to viral infections, focusing on human immunodeficiency virus 1 (HIV-1). We examine the consequences of ATF4 activation for HIV-1 replication and reactivation. The role of ATF4 in autophagy and apoptosis is explored as in the context of HIV-1 infection programmed cell deaths contribute to the depletion of CD4 T cells. Furthermore, ATF4 can also participate in the establishment of innate and adaptive immunity that is essential for the host to control viral infections. We finally discuss the putative role of the ATF4 paralogue, named ATF5, in HIV-1 infection. This review underlines the role of ATF4 at the crossroads of multiple processes reflecting host-pathogen interactions.

Keywords:  AIDS; ER stress; ISR; UPR; immunity; mitochondria

DOI:  https://doi.org/10.3390/biology13030146
Anal Methods. 2024 Mar 27.

A pH-response-based fluorescent probe for detecting the mitophagy process by tracing changes in colocalization coefficients.

Nongyi Hao, Zekun Jiang, Lina Zhou, Xiaoyu Dai, Xiuqi Kong.

Mitochondria are not only the center of energy metabolism but also involved in regulating cellular activities. Quality and quantity control of mitochondria is therefore essential. Mitophagy is a lysosome-dependent process to clear dysfunctional mitochondria, and abnormal mitophagy can cause metabolic disorders. Therefore, it is necessary to monitor the mitophagy in living cells on a real-time basis. Herein, we developed a pH-responsive fluorescent probe MP for the detection of the mitophagy process using real-time tracing colocalization coefficients. Probe MP showed good pH responses with high selectivity and sensitivity in spectral testing. Probe MP is of positive charge, which is beneficial for accumulating into mitochondrial in living cells. Cells exhibited pH-dependent fluorescence when they were treated with different pH media. Importantly, the changes in the colocalization coefficient between probe MP and Lyso Tracker® Deep Red from 0.4 to 0.8 were achieved in a real-time manner during the mitophagy stimulated by CCCP, starvation and rapamycin. Therefore, combined with the parameter of the colocalization coefficient, probe MP is a potential molecular tool for the real-time tracing of mitophagy to further explore the details of mitophagy.

DOI: https://doi.org/10.1039/d4ay00211c