bims-mecmid 2022-05-01 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2022–05–01
nine papers selected by
Mauricio Cardenas Rodriguez, University of Padova

Drp1 Regulated Mitochondrial Hypofission Promotes the Invasion and Proliferation of Growth Hormone-Secreting Pituitary Adenomas via Activating STAT3.
Mitochondrial fission in macrophages fuels phagocytosis of tumor cells.
Fibroblast growth factor 21, a stress regulator, inhibits Drp1 activation to alleviate skeletal muscle ischemia/reperfusion injury.
Positively charged amino acids at the N-terminus of select mitochondrial proteins mediates early recognition by import proteins αβ'-NAC and Sam37.
L-OPA1 deficiency aggravates necroptosis of alveolar epithelial cells through impairing mitochondrial function during ALI in mice.
Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition.
A highly photostable and bright green fluorescent protein.
Chloroplast protein import machinery and quality control.
Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.

Front Oncol. 2022 ;12 739631

Drp1 Regulated Mitochondrial Hypofission Promotes the Invasion and Proliferation of Growth Hormone-Secreting Pituitary Adenomas via Activating STAT3.

Yin Zhang, Lei Zhang, Kexia Fan, Yajun Gou, Zhenle Zang, Xiao Ding, Hui Yang, Song Li.

  The invasiveness and high proliferation rate of growth hormone-secreting pituitary adenomas (GHPAs) are closely related to poor prognosis in patients. We previously reported that abnormal glycolysis participates in this process; however, the role of mitochondria in the invasion and proliferation of GHPAs remains unknown. In the current study, stereological methods were first used to quantitatively calculate the number and morphology of mitochondria. The results revealed that the numbers, volumes and membrane areas of mitochondria were decreased in invasive GHPAs (IGHPAs) samples compared to noninvasive GHPAs (NIGHPAs) samples. Furthermore, significantly downregulated mRNA and protein levels of dynamin-related protein 1 (Drp1) were detected in IGHPAs, but no notable changes in fusion related molecules (Mfn1, Mfn2 and OPA1) were detected, suggesting that the abnormal mitochondrial dynamics in IGHPAs are characterized by hypofission. Mitochondrial hypofission caused by Mdivi-1, a specific Drp1 inhibitor, enhanced the invasion and proliferation of GH3 cell lines and primary cells from patients with GHPAs in vitro and in vivo, while overexpression of Drp1 reversed these processes. Mechanistically, mitochondrial hypofission might activate signal transducer and activator of transcription 3 (STAT3). Specifically, elevated nuclear pSTAT3Y705 may promote GH3 cell invasion by upregulating the activity of matrix metalloproteinase 2/9, and elevated mitochondrial pSTAT3S727 may promote GH3 cell proliferation by inhibiting the mitochondria-dependent apoptotic pathway. Taken together, our findings suggest that mitochondrial hypofission induced by Drp1 might strengthen the invasion and proliferation of GHPA tumor cells by activating STAT3, providing us with a new perspective on how mitochondria regulate the development of IGHPAs.

Keywords:  DRP1; growth hormone-secreting pituitary adenomas; invasion; mitochondrial fission; proliferation; stat3

DOI:  https://doi.org/10.3389/fonc.2022.739631
Nat Cancer. 2022 Apr;3(4): 384-385

Mitochondrial fission in macrophages fuels phagocytosis of tumor cells.

DOI: https://doi.org/10.1038/s43018-022-00350-9
Lab Invest. 2022 Apr 29.

Fibroblast growth factor 21, a stress regulator, inhibits Drp1 activation to alleviate skeletal muscle ischemia/reperfusion injury.

Baoxiang Li, Limin Liu.

Abnormal Drp1 activation and subsequent excessive mitochondrial fission play a critical role in ischemia-reperfusion injury (I/RI). Although fibroblast growth factor 21 (FGF21) protects organs against I/RI and regulates metabolism, which indicates that FGF21 is involved in mitochondria homeostasis, the detailed mechanism remains unclear. Herein, we investigated whether FGF21 had an effect on Drp1 activation during skeletal muscle I/RI. Drp1 phosphorylation and its translocation to mitochondria, as regulated by FGF21, was examined in mouse and C2C12 cell I/RI models. Mice overexpressing FGF21 displayed alleviation of serum index, histological lesions and apoptosis levels. Moreover, FGF21 markedly decreased cyclin-dependent kinase 1 (CDK1) and Drp1 phosphorylation at Ser616, accompanied by reduced accumulation in mitochondria. In parallel in vitro studies, cells with FGF21 knockdown displayed enhanced Drp1 activation, and the reverse effect was found when FGF21 was added. More importantly, FGF21 attenuated mitochondrial fission with linear mitochondria rather than fragmented mitochondria. Furthermore, a CDK1 inhibitor reduced Drp1 activation and mitochondrial fission due to FGF21 knockdown. This study shows that FGF21 inhibits Drp1 activation to protect mitochondria from fission, thereby rescuing cells from I/RI-induced apoptosis. Our findings may provide a new therapeutic approach to ameliorate skeletal muscle I/RI.

DOI: https://doi.org/10.1038/s41374-022-00787-7
J Biol Chem. 2022 Apr 26. pii: S0021-9258(22)00424-0. [Epub ahead of print] 101984

Positively charged amino acids at the N-terminus of select mitochondrial proteins mediates early recognition by import proteins αβ'-NAC and Sam37.

Maria Clara Avendaño-Monsalve, Ariann E Mendoza-Martínez, J Carlos Ponce-Rojas, Augusto César Poot-Hernández, Ruth Rincón-Heredia, Soledad Funes.

A major challenge in eukaryotic cells is the proper distribution of nuclear-encoded proteins to the correct organelles. For a subset of mitochondrial proteins, a signal sequence at the N-terminus (MTS) is recognized by protein complexes to ensure their proper translocation into the organelle. However, the early steps of mitochondrial protein targeting remain undeciphered. The cytosolic chaperone NAC, that in yeast is represented as the two different heterodimers αβ- and αβ'-NAC, has been proposed to be involved during the early steps of mitochondrial protein targeting. We have previously described that the mitochondrial outer membrane protein Sam37 interacts with αβ'-NAC and together promote the import of specific mitochondrial precursor proteins. In this work, we aimed to detect the region in the MTS of mitochondrial precursors relevant for their recognition by αβ'-NAC during their sorting to the mitochondria. We used targeting signals of different mitochondrial proteins (αβ'-NAC-dependent Oxa1 and αβ'-NAC-independent Mdm38) and fused them to green-fluorescent protein (GFP) to study their intracellular localization by biochemical and microscopy methods, and additionally followed their import kinetics in vivo. Our results reveal the presence of a positively charged amino acid cluster in the MTS of select mitochondrial precursors, such as Oxa1 and Fum1, which are crucial for their recognition by αβ'-NAC. Furthermore, we explored the presence of this cluster at the N-terminus of the mitochondrial proteome and propose a set of precursors whose proper localization depends on both αβ'-NAC and Sam37.

DOI: https://doi.org/10.1016/j.jbc.2022.101984
J Cell Physiol. 2022 Apr 28.

L-OPA1 deficiency aggravates necroptosis of alveolar epithelial cells through impairing mitochondrial function during ALI in mice.

Hui-Ling Jiang, Hui-Hui Yang, Yu-Biao Liu, Chen-Yu Zhang, Wen-Jing Zhong, Xin-Xin Guan, Ling Jin, Jie-Ru Hong, Jin-Tong Yang, Xiao-Hua Tan, Qing Li, Yong Zhou, Cha-Xiang Guan.

  Necroptosis, a recently described form of programmed cell death, is the main way of alveolar epithelial cells (AECs) death in acute lung injury (ALI). While the mechanism of how to trigger necroptosis in AECs during ALI has been rarely evaluated. Long optic atrophy protein 1 (L-OPA1) is a crucial mitochondrial inner membrane fusion protein, and its deficiency impairs mitochondrial function. This study aimed to investigate the role of L-OPA1 deficiency-mediated mitochondrial dysfunction in AECs necroptosis. We comprehensively investigated the detailed contribution and molecular mechanism of L-OPA1 deficiency in AECs necroptosis by inhibiting or activating L-OPA1. Firstly, our data showed that L-OPA1 expression was down-regulated in the lungs and AECs under the lipopolysaccharide (LPS) challenge. Furthermore, inhibition of L-OPA1 aggravated the pathological injury, inflammatory response, and necroptosis in the lungs of LPS-induced ALI mice. In vitro, inhibition of L-OPA1 induced necroptosis of AECs, while activation of L-OPA1 alleviated necroptosis of AECs under the LPS challenge. Mechanistically, inhibition of L-OPA1 aggravated necroptosis of AECs by inducing mitochondrial fragmentation and reducing mitochondrial membrane potential. While activation of L-OPA1 had the opposite effects. In summary, these findings indicate for the first time that L-OPA1 deficiency mediates mitochondrial fragmentation, induces necroptosis of AECs, and exacerbates ALI in mice. This article is protected by copyright. All rights reserved.

Keywords:  L-OPA1; acute lung injury; alveolar epithelial cells; mitochondrial fragmentation; necroptosis

DOI:  https://doi.org/10.1002/jcp.30766
Nat Cancer. 2022 Apr;3(4): 453-470

Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition.

Jiang Li, Yingying Ye, Zhihan Liu, Guoyang Zhang, Huiqi Dai, Jiaqian Li, Boxuan Zhou, Yihong Li, Qiyi Zhao, Jingying Huang, Jingwei Feng, Shu Liu, Peigang Ruan, Jinjing Wang, Jiang Liu, Min Huang, Xinwei Liu, Shubin Yu, Ziyang Liang, Liping Ma, Xiaoxia Gou, Guoliang Zhang, Nian Chen, Yiwen Lu, Can Di, Qidong Xia, Jiayao Pan, Ru Feng, Qingqing Cai, Shicheng Su.

Phagocytosis is required for the optimal efficacy of many approved and promising therapeutic antibodies for various malignancies. However, the factors that determine the response to therapies that rely on phagocytosis remain largely elusive. Here, we demonstrate that mitochondrial fission in macrophages induced by multiple antibodies is essential for phagocytosis of live tumor cells. Tumor cells resistant to phagocytosis inhibit mitochondrial fission of macrophages by overexpressing glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which can be targeted to improve antibody efficacy. Mechanistically, increased cytosolic calcium by mitochondrial fission abrogates the phase transition of the Wiskott-Aldrich syndrome protein (WASP)-Wiskott-Aldrich syndrome interacting protein (WIP) complex and enables protein kinase C-θ (PKC-θ) to phosphorylate WIP during phagocytosis. GFPT2-mediated excessive use of glutamine by tumor cells impairs mitochondrial fission and prevents access of PKC-θ to compartmentalized WIP in macrophages. Our data suggest that mitochondrial dynamics dictate the phase transition of the phagocytic machinery and identify GFPT2 as a potential target to improve antibody therapy.

DOI: https://doi.org/10.1038/s43018-022-00354-5
Nat Biotechnol. 2022 Apr 25.

A highly photostable and bright green fluorescent protein.

Masahiko Hirano, Ryoko Ando, Satoshi Shimozono, Mayu Sugiyama, Noriyo Takeda, Hiroshi Kurokawa, Ryusaku Deguchi, Kazuki Endo, Kei Haga, Reiko Takai-Todaka, Shunsuke Inaura, Yuta Matsumura, Hiroshi Hama, Yasushi Okada, Takahiro Fujiwara, Takuya Morimoto, Kazuhiko Katayama, Atsushi Miyawaki.

The low photostability of fluorescent proteins is a limiting factor in many applications of fluorescence microscopy. Here we present StayGold, a green fluorescent protein (GFP) derived from the jellyfish Cytaeis uchidae. StayGold is over one order of magnitude more photostable than any currently available fluorescent protein and has a cellular brightness similar to mNeonGreen. We used StayGold to image the dynamics of the endoplasmic reticulum (ER) with high spatiotemporal resolution over several minutes using structured illumination microscopy (SIM) and observed substantially less photobleaching than with a GFP variant optimized for stability in the ER. Using StayGold fusions and SIM, we also imaged the dynamics of mitochondrial fusion and fission and mapped the viral spike proteins in fixed cells infected with severe acute respiratory syndrome coronavirus 2. As StayGold is a dimer, we created a tandem dimer version that allowed us to observe the dynamics of microtubules and the excitatory post-synaptic density in neurons. StayGold will substantially reduce the limitations imposed by photobleaching, especially in live cell or volumetric imaging.

DOI: https://doi.org/10.1038/s41587-022-01278-2
FEBS J. 2022 Apr 26.

Chloroplast protein import machinery and quality control.

Jean-David Rochaix.

  Most chloroplast proteins are nucleus-encoded, translated on cytoplasmic ribosomes as precursor proteins and imported into chloroplasts through TOC and TIC, the translocons of the outer and inner chloroplast envelope membranes. While the composition of the TOC complex is well established, there is still some controversy about the importance of a recently identified TIC complex consisting of Tic20, Tic214, Tic100 and Tic56. TOC and TIC form a supercomplex with a protein channel at the junction of the outer and inner envelope membranes through which preproteins are pulled into the stroma by the ATP-powered Ycf2 complex consisting of several FtsH-like ATPases and/or by chloroplast Hsp proteins. Several components of the TOC/TIC system are moonlighting proteins with additional roles in chloroplast gene expression and metabolism. Chaperones and co-chaperones, associated with TOC and TIC on the cytoplasmic and stromal side of the chloroplast envelope, participate in the unfolding and folding of the precursor proteins and act together with the ubiquitin proteasome system in protein quality control. Chloroplast protein import is also intimately linked with retrograde signaling, revealing altogether an unsuspected complexity in the regulation of this process.

Keywords:  autophagy; chloroplast; protein aggregation; protein import; retrograde signaling; translocon; ubiquitin proteasome system; unfolded protein response

DOI:  https://doi.org/10.1111/febs.16464
Nat Chem Biol. 2022 May;18(5): 461-469

Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.

Michael P Murphy, Edward T Chouchani.

Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands out owing to its multiple roles in disparate pathways, its dramatic concentration changes and its selective cell release. Here we propose that succinate has evolved as a signaling modality because its concentration reflects the coenzyme Q (CoQ) pool redox state, a central redox couple confined to the mitochondrial inner membrane. This connection is of general importance because CoQ redox state integrates three bioenergetic parameters: mitochondrial electron supply, oxygen tension and ATP demand. Succinate, by equilibrating with the CoQ pool, enables the status of this central bioenergetic parameter to be communicated from mitochondria to the rest of the cell, into the circulation and to other cells. The logic of this form of regulation explains many emerging roles of succinate in biology, and suggests future research questions.

DOI: https://doi.org/10.1038/s41589-022-01004-8